Comparing Female Fertility Drugs: Use Cases, Effectiveness, Risks

February 05, 2024 - Infertility, or the inability to conceive, is characterized by one year of unprotected sex without a subsequent pregnancy. Although infertility can result from male or female partners, most available fertility drugs work on addressing infertility in women.

Approximately 19% of women between 15 and 49 deal with infertility; however, the causes of infertility vary from person to person. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, a subset of the NIH, notes that after diagnosis, 50% of infertile women can successfully conceive with treatment; however, the treatment protocol is dependent on the cause of infertility.

Many individuals undergo testing to identify the source of their infertility, which helps their provider choose the appropriate fertility treatment. However, some infertility cases cannot be boiled down to a root cause. Even so, fertility drugs are often the first line of treatment for infertility.

Fertility Drug Types

According to the American Pregnancy Association, there are multiple kinds of fertility medications to aid in conception. These medications play a critical role in infertility treatments, including in vitro fertilization procedures.

The United Kingdom’s Human Fertilization and Embryology Authority notes that fertility drugs are considered or recommended for patients with polycystic ovary syndrome (PCOS), irregular or absent menstrual cycles, and pituitary-related fertility problems.

Some medications are used for ovarian stimulation, including clomiphene citrate, synthetic human chorionic gonadotropin, follicle-stimulating hormone, human menopausal gonadotropins, gonadotropin-releasing hormone, and bromocriptine and cabergoline.

Other medications, such as gonadotropin-releasing hormone agonists and antagonists, are used to prevent premature ovulation.

Finally, methylprednisolone, doxycycline, progesterone, and fertility supplements may also be used to enhance fertility treatments.

Clomiphene

Clomiphene or clomiphene citrate is an FDA-approved oral selective estrogen receptor modulator that is indicated in treating anovulatory or oligo-ovulatory infertility. The drug works by binding to estrogen receptors to increase the production of luteinizing hormone and follicle-stimulating hormone (FSH) and subsequently help the eggs mature.

The NICHD notes that most people taking clomiphene can conceive within six menstrual cycles or roughly six months. However, after the six-month mark, if a patient does not become pregnant, providers may consider alternative or adjunct treatment options.

The drug is taken at the beginning of the patient’s menstrual cycle, causing roughly 80% of patients on the drug to ovulate. However, one potential side effect is an increased risk of multiple births, with approximately a 10% probability of conceiving twins. 

Letrozole

Letrozole is another oral pill that manages fertility. While clomiphene is FDA-approved for infertility, letrozole is approved for treating breast cancer but is used off-label as a fertility treatment.

This treatment promotes estrogen production to stimulate egg release. Unlike clomiphene, this medication is taken toward the end of the menstrual cycle for approximately five days. Research from 2015 supporting the drug’s efficacy suggested that 19% of couples with unexplained infertility conceived after being treated with letrozole for four months compared to clomiphene, which has a 23% conception rate for those with unexplained infertility.

However, the NICHD notes that some research shows that letrozole may be superior to clomiphene for patients with polycystic ovary syndrome (PCOS).

Gonadotropins

Meanwhile, gonadotropins, like FSH, can be given directly to infertile women to stimulate egg growth and ovulation. Gonadotropins are used to mimic the hormones that are supposed to be produced by the pituitary gland.

Typically, these drugs are prescribed when other fertility medications have not worked, as the provider and patient look toward assisted reproductive technology (ART) as a means of conception.

These medications are injectables, administered early in the menstrual cycle for 7–12 days. The medicines are significantly more likely to result in multiple births, with roughly 20% of individuals conceiving twins and 10% conceiving triplets or larger multiple births.

Human chorionic gonadotropin (hCG) mimics luteinizing hormone to trigger egg release.

Bromocriptine and Cabergoline

Bromocriptine and cabergoline are oral pills that help reduce high levels of prolactin, which interferes with ovulation, achieving normal levels in 90% of women with elevated prolactin. After their hormone levels normalize, 85% of women will begin to ovulate regularly.

Other Fertility Drugs

Aside from the most common fertility drugs, other medications may enhance fertility and assist in conception.

• Metformin: This is another drug that can play a critical role in fertility treatments. While the drug is not strictly a fertility treatment, it can be used to manage insulin resistance, which may cause patients to be resistant to medications that induce ovulation. The medication was previously used on its own to induce ovulation until research proved that clomiphene was more effective. However, some providers may consider treating patients with metformin first if they display symptoms of insulin resistance or glucose intolerance.
• Methylprednisolone (Medrol): This is a daily steroid taken four days during the cycle to promote pre-embryo implantation.
• Doxycycline: This oral antibiotic is provided to the male partners while the female partner is being stimulated with other drugs or treatments to kill bacteria that may be found in semen, helping improve the probability of conception. Additionally, female partners may take the drug after ART is used for egg retrieval to minimize the risk of infection.
• Progesterone: Progesterone injections are administered two days after egg retrieval and continue until the placenta has made the appropriate amount of progesterone.
• Fertility supplements: While not verified as a fertility treatment, some individuals may take non-prescription supplements, such as vitamins, minerals, antioxidants, or herbs, to assist in fertility. It is important to note that the supplement industry is not validated or regulated by recognized healthcare authorities like the United States FDA. Some of these compounds may be labeled inappropriately and interfere with health if a licensed healthcare professional does not recommend them. However, the Human Fertilization and Embryology Authority notes, “There is some evidence to suggest that certain antioxidants and vitamins including zinc, selenium, vitamin C, and vitamin E may help to improve the fertility of men with a low sperm count or sperm that isn’t moving properly (low motility). However, more research is needed.”

Fertility Drug Risks

According to the Mayo Clinic, there are multiple risks associated with fertility drugs, with the most common being multiple births. Although many people deliver healthy multiples, the risk of premature labor, low birth weight, and developmental problems increases as the number of fetuses increases.

Beyond multiple births, fertility drugs have been linked to ovarian hyperstimulation syndrome (OHSS), a rare but severe condition caused by excess ovulation. Symptoms of OHSS include swollen and painful ovaries, mild abdominal pain, bloating, nausea, vomiting, or diarrhea.

Another severe side effect of fertility drug use is an elevated risk of ovarian tumors. While the available data has not established a causational link between fertility drugs and ovarian tumors, some studies have suggested that using these medications for a year or longer without conceiving correlates with an elevated risk of ovarian tumors.

However, the Mayo Clinic notes, “Women who never have pregnancies have an increased risk of ovarian tumors, so it might be related to the underlying problem rather than the treatment. Since success rates are typically higher in the first few treatment cycles, reevaluating medication use every few months and concentrating on the treatments that have the most success appear to be appropriate.”

Infertility can be a challenging condition for many individuals and couples trying to conceive. In addition to choosing an appropriate treatment, providers should consider providing comprehensive and robust treatment, including counseling and other tools to reduce the pressures associated with infertility and its treatments.