Fertility Medications and Side Effects

Posted on September 16, 2005 by Inception Fertility

What are the side effects of the fertility medications I will be taking?" This is a most appropriate question to which I'd like to provide an in-depth answer.

When discussing any fertility medication, it is important to keep in mind some concepts when discussing "side effects." Side effects are really those symptoms, usually minor, most commonly suffered by a significant proportion of patients taking the medication. Typically, this would include nausea or headaches.

There are also "adverse effects." These are more serious events, usually rare and often unpredictable. Examples would be a stroke or a heart attack. An example of a less severe adverse effect would be ovarian hyperstimulation syndrome. If a drug has been found to have a significant incidence of severe adverse effects, it is not likely to pass FDA approval. If the adverse effect is extremely rare, it may not be discovered until very large numbers of patients have taken the drug and the medication may be pulled from the market after approval (e.g. Bextra).

Separate from side effects and adverse effects, are "long term effects." These are generally serious adverse effects not discovered until well after the drug therapy is undertaken. An example of this is the effect on the uteri of daughters of mothers who took the drug DES during pregnancy. When patients ask us about the safety of fertility medications, they are usually referring to adverse or long-term effects as much as concerns about side effects.

When reading the FDA-approved package labeling for almost all fertility medications, fertility drugs included, it's important to be aware that any possible adverse effect anyone has ever experienced on the drug will be reported. Unfortunately, this almost renders this information useless because there are virtually no drugs that someone somewhere has taken without something happening at the same time. It is often impossible to prove whether or not that medical event was related to taking the drug or not.

None of the medications that are in use for fertility treatment are known to have such serious adverse effects that the FDA has even considered withdrawing its approval.

Overall, we believe fertility medications to be very safe, usually associated with only very mild side effects, relatively rare and treatable adverse effects (mostly commonly ovarian hyperstimulation) and no known significant long term effects.

Below is a list of some of the most common side effects our patients mention, as well as some of the more common adverse effects. It is by no means an authoritative or exhaustive list.


Clomiphene (Clomid, Serophene®)

• FDA: FDA-approved for ovulation induction in anovulatory women, but widely used for unexplained infertility in women who do ovulate regularly on their own.

• Most common side effects: Hot flashes, night sweats, dizziness, mood swings

• Adverse reactions: ovarian hyperstimulation, abdominal pain or bloating, temporary visual disturbances.

• Long term effects: Possible increased incidence of noninvasive ("borderline") ovarian tumors – not proven to be causative. Most recent studies find no link with invasive ovarian cancer.

GnRH agonists (Lupron, Synarel)

• FDA: Although Lupron and Synarel are not FDA-approved for IVF use, they are widely used in the U.S. to prevent premature ovulation in IVF cycles.

• Most common side effects: Mild headache

• Adverse reactions: Patients with unrecognized pituitary tumors can experience a type of pituitary "stroke" when on Lupron. This is very rare but potentially serious.

• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

Gonadotropins (Follistim, Gonal-f, Repronex, Menopur)

• FDA: FDA-approved for super-ovulation and in IVF to recruit multiple eggs.

• Most common side effects: Tiredness, local injection site skin reactions such as pain and redness (especially Repronex), abdominal fullness, bloating. Contrary to popular belief, we rarely hear our patients complaining of mood swings on gonadotropins.

• Adverse reactions: Ovarian hyperstimulation, multiple pregnancies (twins or more).

• Long term effects: Some concern was raised in the early 1990's about whether these drugs could increase a woman's risk of ovarian cancer. Most recent studies are reassuring that there is not an increased risk. These studies are ongoing because this class of drugs has only been in wide use for about 25 years.

GnRH Antagonists (Ganirelix, Cetrotide)

• FDA: FDA-approved for use in IVF to prevent premature ovulation.

• Most common side effects: None that we have seen.

• Adverse reactions: Earlier (pre-FDA approval) versions of these medications were sometimes associated with severe allergic reactions but we have not seen any yet in our practice.

• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

hCG (Novarel, Pregnyl)

• FDA: FDA-approved for ovulation induction. Commonly used in clomiphene, gonadotropin and IVF cycles to time insemination or egg retrieval.

• Most common side effects: Some increased discomfort, rarely outright pain, at the time of ovulation.

• Adverse reactions: If a patient has multiple follicles on gonadotropins, hCG can be the final kick to the ovaries to tip someone over into hyperstimulation syndrome. This is not seen in natural cycles or in most patients on clomiphene.

• Long term effects: None known.

Progesterone (Prometrium, Progesterone suppositories, Progesterone in oil)

• FDA: Only Prometrium is FDA approved and it is approved for use in menopause in conjunction with estrogen hormone replacement. It is pure oral micronized progesterone. Progesterone suppositories and Progesterone in oil are usually compounded by individual specialty pharmacies (pharmacies that specialize in distributing fertility drugs). Most progesterone packaging advises not to use in pregnancy but these drugs are the exact same progesterone produced by the human ovary in the luteal phase and in early pregnancy so are widely used in fertility treatment.

• Most common side effects: Mostly very minor things like breast tenderness or mild bloating. For patients on progesterone in oil, local pain and redness at injection sites is common.

• Adverse effects: Local vaginal reactions such as irritation or itching from suppositories. Severe local skin reactions to progesterone in oil are fairly rare.

• Long term effects: Questions have been raised as to whether high doses of progesterone in early pregnancy may be associated with urinary tract abnormalities in the fetuses of the mothers taking progesterone. There has never been any such association proven.

-- Carolyn Givens, MD

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