What is Clomiphene?

Clomiphene is an oral drug prescribed for the treatment of infertility and hypogonadism (low levels of sex hormones). It is formulated in 50 mg tablets.

It is used to promote the development and release of eggs in women who have ovulation problems and also to increase the number and quality of sperm cells in men.

There are several brand names under which clomiphene is marketed, including Clomid and Serophene, along with generic formulations. You might also find references to Milophene, though this brand is no longer on the market.

Who Can Take Clomiphene?

In women, clomiphene is prescribed in cases where ovulation is rare or not occurring at all. It is also usually the drug of choice for women diagnosed with polycystic ovary syndrome (PCOS).

It is also used in:

  • Controlled ovulation - When fertilization is performed in the uterus, the use of clomiphene will "force" ovulation to occur within 5 to 10 days after the last day of the treatment cycle, creating a narrow window of time in which insemination efforts can be focused.
  • Lactation suppression - Clomiphene may be used to suppress lactation, but there is little evidence of its effectiveness.
  • Unexplained infertility - Even in cases where ovulation appears normal but there is difficulty in conception, clomiphene may still be prescribed, as the hormonal boost it provides generally improves the conception rate.

Clomiphene cannot be prescribed for conditions that include blocked fallopian tubes.

In men, this drug is used as an alternative to testosterone replacement therapy, both for reproductive purposes (improving sperm cell count, motion and shape) and for hormonal regulation (in men presenting with low sex drive, stamina and other symptoms of low testosterone levels), although these uses are “off-label,” as the drug was originally intended for women.

How Does Clomiphene Improve Fertility?

In both men and women, clomiphene binds to the same receptors as the sex hormone estrogen, in a region of the brain called the hypothalamus. When it attaches to these receptors, this drug produces no response, while simultaneously preventing its natural counterpart from binding to them, in the same way a broken off piece of a key doesn't actually unlock a door while also preventing another key from being used.

This effectively fools the sex hormone regulatory system into reacting as if estrogen levels are too low, leading to an increase in the levels of two key sex hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

In women, the increase in LH and FSH leads to an accelerated maturing of ovarian follicles (the structures that mature into eggs), and their subsequent release.

In men, an increase in LH and FSH leads to an increase in testosterone, and gonadotrophin-releasing hormone, improving sperm cell count, motion and shape.

What is the Success Rate With Clomiphene Usage?

Clomiphene has a high success rate for women who experience irregular ovulation, with around 80% of women achieving at least one released egg on the first treatment cycle. One month after treatment, the probability of success is 30%, (which exceeds that of couples without fertility issues at 25%), and then rises to 50% after 6 months of treatment.

The success rate of clomiphene treatments does vary with a number of factors like body weight. Women with extremely high or low body weight also experience very low success rates with clomiphene. Most importantly, a woman's ovarian reserve impacts the outcome of clomiphene treatment, with success rates dropping drastically for women with diminished ovarian reserve (DOR).

How Long Can You Take Clomiphene?

For Women

Guidelines recommend up to 6 full cycles of clomiphene treatment, as the resulting sustained high levels of sex hormones may increase the risk of ovarian, breast, and uterine cancer.

The first cycle consists of 5 consecutive days taking one 50 mg tablet per day, starting on the fifth day after menstruation. If necessary, a second cycle using a 100 mg per day dosage, may be started as early as 30 days after the end of the first. An additional 4 more cycles may be attempted, maintaining the 100 mg daily dosage, with 30-day intervals.

For Men

Unlike women, men require continuous daily therapy with 25 mg (half a pill), since sperm cells are produced continuously. Due to this, testosterone levels must be carefully controlled, as it is possible for them to increase to a point where sperm count actually decreases.

What Are the Side Effects of Clomiphene?

The most common side effects of clomiphene are skin flushing (warm and reddened skin), breast tenderness, headaches and abnormal vaginal bleeding. All of these are related to the sudden increase in sex hormones and are similar to those experienced by women who suffer from premenstrual syndrome (PMS), and they normally subside in a couple of days.

In the event that side effects persist or include any of the following:

  • Blurred or double vision
  • Visual spots or flashes
  • Stomach pain and/or swelling
  • Weight gain
  • Shortness of breath

You are advised to seek medical attention as soon as possible, as the serious side effect ovarian hyperstimulation syndrome (OHSS) may be developing.

Due to its stimulating effect on ovulation, multiple ovulation and subsequent pregnancies can also occur.

In men, serious clomiphene side effects are rare and mostly related with visual alterations and instances of blurred or double vision that should be immediately reported. Other side effects are related to raised estrogen levels, such as nipple tenderness.

What is the Difference Between Clomiphene and Clomiphene Citrate?

Clomiphene can’t be used directly in the manufacturing of pills since, given its low water solubility, it would not be absorbed. As such, it is made to react with citric acid (the acid present in lemons), yielding the stable form of clomiphene citrate, which easily dissolves in water. Once in the body, there is no difference between one and the other.

How Much Does Clomiphene Cost?

Clomiphene is a relatively low-cost drug, with treatments ranging between $10 and $100, depending on the number of cycles. Costs average around $40 for brand name and $10 for generic presentations, making it a first-line therapy for infertility.

The cost of the drug is not the only financial consideration. Unfortunately, due to its effect on the delicate balance of sex hormone regulation, clomiphene treatments must be carefully monitored, with blood work and sonograms adding up to an average of $1100.

What is the Difference Between Brand Name and Generic Clomiphene?

When a drug patent exceeds 10 years, companies other than the patent holder are free to produce and market that drug, as long as they are capable of demonstrating that this new generic formulation is biologically indistinguishable in their effect from the original one.

Given that these tablets are produced by different companies, using potentially different methods, some variation is expected. Although both generic and brand tablets contain the same amount of clomiphene, the filler material that is added to make a tablet may change from supplier to supplier. It is possible that some patients may tolerate certain fillers better than others.

Doctors sometimes prefer brand names since they have more experience with them (as they are older than the generics) and have the same exact composition, regardless of the pharmacy where they are bought (while different pharmacies may have different generic suppliers).

What Does Your Doctor Need to Know Before Prescribing Clomiphene?

As with other drugs, a previous history of allergic reaction to clomiphene should be communicated to your doctor. As this drug is normally broken down in the liver, liver conditions may lead to it accumulating in your body, leading to overdosage. Many types of cancer are driven by sex hormones so any signs of such diseases (abnormal bleeding, ovarian cysts that are unrelated to PCOS, etc.) should also be reported. As clomiphene may adversely affect an ongoing pregnancy, patients suspecting this should also report it to their physicians.

What Additional Treatments Can Be Used if Clomiphene Doesn't Work?

When treatment with clomiphene by itself is unsuccessful, Metformin (or another drug that increases the effect of insulin) may be added to the therapy to further increase the stimulating effect on ovulation. By increasing the effect of insulin, these drugs lead to lower levels of this hormone (since it is more effective), which in turn leads (via a mechanism not fully understood) to an increase in FSH and LH and a reduction in the levels of testosterone, improving egg development and release.

In case the combined therapy fails, other treatment alternatives may be pursued, namely the direct administration of human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), human menopausal gonadotropin (hMG), instead of relying on clomiphene’s effect on sex hormone regulation.

Final Considerations

As with any medication, you should take care to follow all of your doctor’s directions, regarding not only when and how to take your medication, but also how to monitor its effect, including scheduled doctor’s appointments. In the event of side effects or unexplained changes in your health status, you should direct any questions to your doctor or pharmacist.

In order to make your treatment with clomiphene as safe and effective as possible, you should always inform your doctor about any medication you might already be taking as well as any additional medication you might be starting, as they might interfere with each other’s effect and metabolism.

You may be tempted to give or ask for advice regarding clomiphene therapy outside of your doctor’s appointments. Patients are encouraged to share their experiences, as this is empowering, but you must be aware that your therapy is carefully tailored to your individual needs and circumstances and its results are not directly translatable to or from other patients.