Ovulation Induction: Cost, Success Rates, Risks & Common Medications

Ovulation induction is utilized in around 50% of fertility treatment cycles, either as a first line approach, or as part of a more complex treatment plan involving IUI or IVF. Learn about the benefits of this more affordable treatment option and what to expect from the process.

• What is ovulation induction?
• PCOS & Ovulation Induction
• Fertility Treatment with Ovulation Induction
• How much does ovulation induction cost?
• Ovarian Stimulation vs. Ovulation Induction
• Success Rates for Ovulation Induction
• Medications for Ovulation Induction
• How long does ovulation induction take?
• Step-by-Step Guide to Ovulation Induction
• How Ovulation Induction Works
• What does Clomid® do?
• What does letrozole do?
• What are gonadotropins?
• Odds of Having Twins with Ovulation Induction
• Potential Risks of Ovulation Induction
• Ovulation Induction Side Effects
• What if ovulation induction doesn't work?

Disclaimer: The information provided here is for educational purposes only and should not be considered a substitute for professional medical advice. Always consult with a qualified healthcare provider regarding any questions or concerns about your health or fertility treatment options.

What is ovulation induction? 

Approximately 25% of women with infertility have issues with ovulation, meaning they either ovulate infrequently, irregularly, or simply don't ovulate at all. For those hoping to become parents, fertility treatment methods like ovulation induction can help.

Ovulation induction is the process of using medications to cause a follicle (the fluid-filled sac in the ovary that contains the egg) to grow, mature, and ultimately rupture, thereby releasing the egg (ovulation). This popular fertility treatment method uses medication to increase the chance of conception by stimulating the ovaries to produce mature follicles.

The Role of Ovulation

If you struggle with ovulation issues, you will also typically have irregular (or absent) menstrual cycles, which makes it exceptionally difficult to accurately track your cycle and pinpoint an optimal window for conception.

The root cause of irregular or absent ovulation is usually uncovered during the fertility testing process, and each patient's treatment plan will differ depending on the underlying problem causing the ovulatory dysfunction.

Ovarian stimulation is often used to treat couples with unexplained infertility or as part of an in vitro fertilization (IVF) cycle, but the primary goal in each scenario differs: 

• With unexplained infertility (meaning all fertility tests are normal, including semen analysis and fallopian tubes are open), the goal is to stimulate one or more eggs to be released with the hope that at least one will fertilize and result in a pregnancy.
• With IVF, the goal is to stimulate the growth of multiple follicles so that several eggs can be retrieved, fertilized, and make multiple embryos. This allows for the "best" embryo to be transferred into the uterus. 

Who is a good candidate for ovulation induction?

Generally, if you have ovulatory dysfunction, you may be a good candidate for ovulation induction. However, at least one open fallopian tube and a relatively normal semen analysis (for the male partner) are also important for a successful ovulation induction cycle. 

When would ovulation induction not be recommended?

Those with letrozole/clomiphene-resistant PCOS or hypothalamic dysfunction may "over-respond" to gonadotropins (developing multiple follicles instead of one). This increases the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy.

In these cases, in vitro fertilization (IVF) is preferable to ovulation induction, as a single embryo can be transferred, thereby lowering the risk of multiple pregnancy.

Other cases where ovulation induction may not be recommended:

• Ovarian insufficiency: Those experiencing premature menopause or those who have not previously responded to ovulation induction medications would not be candidates for their use.
• Medical concerns: Those with a contraindication to getting pregnant (due to medical problems) should not use ovulation induction medications.  
• Severe fertility issues: If there is significant male factor infertility or blocked fallopian tubes, a couple would be directed towards IVF instead.
• Allergies: While relatively uncommon, some patients are allergic to the medications used in ovulation induction cycles. Your doctor may suggest an alternative medication.

PCOS & Ovulation Induction

According to a Harvard study, around 49% of participants with polycystic ovary syndrome (PCOS) also noted having irregular menstrual cycles.

Patients with PCOS are most often prescribed letrozole (sometimes with metformin added if insulin resistance is present), while those with hypothalamic dysfunction would be more likely to require gonadotropins.

Although most women with PCOS will ovulate with letrozole or clomiphene, some may require an alternative method of treatment. If insulin resistance is identified, taking metformin may help the body respond to clomiphene or letrozole.

When taken on their own for 4–6 months, insulin-sensitizing agents (such as metformin) can lead to regular menstrual periods and ovulation in some women with PCOS.  

Fertility Treatment with Ovulation Induction

While it would be nice to jump straight into treatment, your first step will be meeting with a fertility specialist (preferably, a board-certified reproductive endocrinologist) who will review your medical history, conduct a physical exam, and order various tests to assess your overall health and identify any underlying causes of infertility.

These tests may include blood work to check hormone levels, ultrasounds to examine your ovaries and uterus, and other specialized tests as needed. After reviewing test results, your fertility specialist will recommend the most appropriate treatment plan for you.

There are a few fertility treatment pathways that frequently utilize ovulation stimulation: timed intercourse, intrauterine insemination (IUI), and in vitro fertilization (IVF). 

1. Timed Intercourse with Ovulation Induction

The least invasive treatment method utilizing ovulation induction involves timed intercourse using ovulation predictor kits (which identify a surge in leutinizing hormone, or LH) or following a trigger shot.

Timed intercourse without the use of medication is also an option for some.

2. IUI with Ovarian Induction

Intrauterine insemination (IUI) may be considered if there is a mildly reduced sperm count or motility or if donor sperm is being used. Some patients opt for IUI along with ovulation induction just to try to maximize their chances of success.

IUI is routinely performed as part of ovarian stimulation for unexplained infertility, as the combination of the ovarian stimulation and IUI is necessary to get the full therapeutic effect of the treatment. 

3. IVF with Ovarian Stimulation

For in vitro fertilization (IVF), ovarian stimulation is performed and usually involves the use of gonadotropins. Gonadotropins are essential to reproductive health, supporting maturity and functionality of the sex glands (gonads refer to ovaries in those assigned female at birth, or testicles, in those assigned male at birth).

Ovarian Stimulation vs. Ovulation Induction

While both ovarian stimulation and ovulation induction involve the use of medications to influence the ovaries, they have distinct goals and applications:

Ovarian Stimulation

• Goal: Stimulate the growth of multiple ovarian follicles (including for those without ovulation issues).
• Common Use Cases: In vitro fertilization (IVF), where multiple eggs are needed for retrieval and subsequent fertilization in a laboratory setting.
• Outcome: Aims to produce a larger number of mature eggs for retrieval and potential fertilization.

Ovulation Induction 

• Goal: To induce ovulation (the release of a single mature egg) in those who are not ovulating regularly or at all.
• Common Use Cases: Women with conditions like polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, or other ovulatory disorders.
• Outcome: Aims to produce a single mature eggs, suitable for natural conception or intrauterine insemination (IUI).

What causes irregular periods?

An expert fertility nurse explains what typically leads to cycle irregularity and how you can still conceive successfully.

How much does ovulation induction cost?

The cost of ovulation induction treatment varies widely, making it difficult to provide a precise range. However, the average cost of treatment is around $1,000 to $2,000+ per cycle. What you will pay for treatment depends on several factors, including the following:

Insurance

Some insurance plans will cover the cost of ovulation induction treatment, but each insurer has their own set of coverage guidelines for fertility treatments. Some plans may offer partial or full coverage for ovulation induction, while others may not cover it at all. It's essential to review your specific plan documents or contact your insurance provider to understand your benefits.

In many cases, insurance will only cover ovulation induction if it is deemed "medically necessary." This means that your doctor will need to provide documentation demonstrating that the treatment is needed to address a specific medical condition affecting your fertility.

Some insurance plans may require prior authorization before covering ovulation induction treatment. They may also require you to try less invasive options (like oral medications) before covering more expensive ones (like injectable medications).

Keep in mind: Even if you have insurance coverage for treatment, you may still be responsible for certain copays, deductibles, or other out-of-pocket costs.

Medications

Oral medications are typically less expensive, ranging from $30 to $130+ per cycle, while injectable medications can cost significantly more, ranging from $3,000 to $5,500+ per cycle. Medications may be covered by your insurance plan. 

Monitoring

The cost of monitoring appointments at your fertility clinic, including ultrasounds and blood tests, can also contribute to the overall cost of treatment (if not covered by your plan).

Additional Procedures

Any add-on services will also influence the cost of treatment. For example, if an intrauterine insemination (IUI) procedure is performed in conjunction with ovulation induction, this will increase your total cost (if not covered by insurance). 

Success Rates for Ovulation Induction

Remember, the chances of success with ovulation induction is very dependent on the age of the woman, as pregnancy rates decline with increasing age. 

Clomiphene citrate (often referred to by its brand name, Clomid®) will induce ovulation in approximately 80% of cycles of anovulatory women. Around 10-15% of those who ovulate will conceive. Approximately 70-75% of anovulatory women who respond to clomiphene will conceive within 6-9 cycles of treatment.

Pregnancy rates with letrozole are similar to those of clomiphene citrate. However, pregnancy rates for those with polycystic ovary syndrome (PCOS) are better on letrozole, which is why it is often the first line of treatment for this population. 

In most cases, gonadotropin treatment of anovulatory women results in ovulation, with pregnancy rates of approximately 15% per cycle in women younger than 40.

Medications for Ovulation Induction 

Before choosing which medications to include in your ovulation induction protocol, the doctor will carefully consider the results of your fertility work-up in order to avoid unnecessary risks and maximize chances of success.

Clomiphene citrate (Clomid®) is the most commonly prescribed medication for inducing ovulation. Other frequently used ovulation induction medications include aromatase inhibitors (such as letrozole) and gonadotropins like follicle stimulating hormone (FSH), human menopausal gonadotropin (hMG), and human chorionic gonadotropin (hCG).

Additional medications may be prescribed if specific endocrine disorders are identified:

• Hyperprolactinemia, a disorder that results in high levels of the hormone prolactin; often treated with medications such as bromocriptine and cabergoline.
• Insulin resistance, which is often associated with PCOS and occurs when cells in the body don't respond well to insulin, may be treated with insulin-sensitizing agents like metformin.
• Hypothyroidism, a condition in which the thyroid gland doesn't produce enough thyroid hormone, may be treated with thyroid medications like levothyroxine.

How quickly do stimulation medications take effect?

It usually takes several days to notice initial side effects after beginning medications.

With clomiphene citrate or letrozole, it typically takes 4-12 days for a mature follicle to develop (after taking the last dose of medication) but varies by patient and even by cycle. Similarly, with gonadotropins, it can take anywhere from 8-16 days of injections to develop a mature follicle.

How long does ovulation induction take?

Without accounting for the time it takes to undergo initial fertility testing, a basic ovulation induction cycle typically takes 1-2 weeks and may involve a combination of oral and injectable medications, ultrasounds, and blood work.

Step-by-Step Guide to Ovulation Induction

Before diving deeper into how all these medications work, let's walk through the ovulation induction process one step at a time. Here's what you can expect from a typical protocol:

Day 1: Start of Menstrual Cycle

The first day of your period marks the beginning of the ovulation induction cycle. Note that Day 1 will always refer to your first day of "full flow," not just spotting. You will notify your fertility clinic Care Team when this occurs, and they will explain your next steps.

Note: If you don't have regular periods, your doctor may prescribe a medication called progestin, which will be taken for 5-10 days to bring on a period before moving forward.

Before starting any medications, you will typically visit your fertility clinic again for baseline testing, which often includes an ultrasound (to assess your ovaries and uterus) and blood work (to check your hormone levels).

Days 2-5: Begin Medication Protocol

This is a general guide, and your specific treatment plan and dosages may vary based on your individual circumstances and provider's recommendations. Always follow your doctor's instructions.

Early on in your menstrual cycle (around 2-5 days after menstruation begins), you will typically start with a standard dosage of one of two different oral fertility medications, Clomid® or  Femara® (or their generic equivalents).

Standard starting dosages are:

• Clomiphene citrate (Clomid®): 50-100 mg once daily for 5 consecutive days.
• Letrozole (Femara®): 2.5 mg or 5 mg once daily for 5 consecutive days; may be increased to 7.5 mg per day if lower doses fail to induce follicle growth.

Days 10-14: Monitoring

Throughout your treatment cycle, you will be closely monitored via regular ultrasounds and blood work (performed at your fertility clinic). Ultrasounds will track the growth and development of follicles in your ovaries and blood work will measure hormone levels to assess your response to the medication and determine optimal timing for ovulation.

Around Day 12-16: Trigger Shot

Once your follicles reach a mature size, your Care Team will instruct you to administer a trigger shot, usually containing 5,000 - 10,000 IU of human chorionic gonadotropin (hCG). This injection mimics the natural surge of luteinizing hormone (LH) that triggers the release of a mature egg from the ovary.

After Trigger Shot: Timed Intercourse or IUI

Depending on your treatment plan, your fertility specialist may recommend timed intercourse or IUI (either the same day as your trigger shot or 24-36 hours afterwards).

Timed intercourse involves having sexual intercourse at an optimal time around ovulation to increase the chances of fertilization. IUI involves placing specially prepared sperm directly into the uterus around the time of ovulation to improve the odds of fertilization.

When will I know if my cycle was successful?

A pregnancy test performed via blood work may already show a positive 7-10 days after ovulation occurs, however it is standard to schedule this blood work for around 12-14 days after ovulation to allow enough time for hormone levels to rise.

Beta hCG test: Also known as a quantitative hCG test, this blood test measures the amount of hCG in the blood in milli-international units per milliliter (mIU/mL). 

At-home urine pregnancy tests typically take a few more days to show a positive and confirm a pregnancy. This is why your fertility specialist will usually recommend you wait at least 14 days after ovulation before taking a pregnancy test at home.

What should I avoid during ovulation induction?

While undergoing treatment, it is important to:

1. Lead a healthy lifestyle (adequate sleep and balanced diet)
2. Avoid toxic habits (i.e. cigarettes, marijuana, heavy alcohol use)
3. Limit caffeine intake (stick to 1-2 cups of coffee per day)
4. Reduce stress levels if possible
5. Take prenatal vitamins

How Ovulation Induction Works

Now that we've broken down the ovulation induction process day by day, let's discuss how each commonly used medication functions within your body.

What does Clomid® do? 

Clomiphene citrate (often referred to by its brand name version, Clomid®) works by causing the pituitary gland at base of the brain to make more follicle stimulating hormone (FSH). This stimulates one or more follicles in the ovary to grow. 

As each follicle (the tiny, fluid-filled sac that contains a single egg) grows, it secretes estrogen (estradiol) into the bloodstream. About a week after the last dose of Clomid® is taken, high estradiol levels will lead to a surge in leutinizing hormone (LH) from the pituitary gland. This LH surge causes the egg in the mature (or dominant) follicle(s) to be released.

What does letrozole do?

Letrozole blocks estrogen production which, like clomiphene citrate, leads to elevations in FSH (follicle-stimulating hormone). This leads to ovarian follicular development and ovulation. Pregnancy rates appear to be higher among women with PCOS treated with letrozole when compared with clomiphene. 

Monitoring for ovulation when using clomiphene or letrozole usually is done by use of urinary LH kits or follicular monitoring using transvaginal ultrasound examinations. Once the "lead follicle" is deemed mature (usually 17 to 20 mm average diameter), ovulation may be triggered using an injection of human chorionic gonadotropins (hCG).  

What are gonadotropins?

Gonadotropins are fertility medications that contain FSH (follicle stimulating hormone) alone or together with LH (luteinizing hormone). Unlike clomiphene citrate, aromatase inhibitors, and insulin-sensitizing agents which are taken orally, gonadotropins are injectable.

There are several gonadotropin preparations including Gonal-F and Follistim (which are FSH alone) and Menopur (which has both FSH and LH activity). 

When are gonadotropins used?

Gonadotropins are often used in the ovarian stimulation phase of IVF, and sometimes for the treatment of unexplained infertility (with IUI). They are less commonly used for ovulation induction. They can also be used to help women whose pituitary gland does not produce enough FSH and LH (called hypothalamic dysfunction). 

Gonadotropins are also used in cases of PCOS where letrozole or clomiphene citrate are unsuccessful in inducing ovulation despite using maximum dosages. In these cases, a "step up" protocol is usually recommended.  

What is hCG?

Human chorionic gonadotropin (hCG) does not stimulate follicle growth but is instead used as a "trigger shot" once a mature follicle has developed. hCG is similar in chemical structure and function to LH, so it mimics an LH surge and causes the dominant follicle to release its egg and ovulate.  

Trigger Shot 101

A "trigger shot" is an injection of hCG, typically used in ovulation induction cycles. It works by mimicking the LH surge and causes rupture of the mature follicle and release of the egg approximately 36-40 hours after it is injected.

Another medication (leuprolide acetate or Lupron) may be used as a trigger, but this medication is not typically used in an ovulation induction cycle and is usually limited to use in certain IVF cycles to reduce the risk of OHSS.

What happens if you ovulate before a trigger shot?

Most women will respond to ovulation induction with clomiphene or letrozole and have a natural LH surge, so a trigger shot isn't required in these cases. Occasionally, a mature follicle will develop, but no LH surge will occur. To avoid this, and to ensure that ovulation will occur, trigger shots are then used for timing intercourse or inseminations.

With gonadotropin ovulation induction treatment, trigger shots are always used because there isn't always a spontaneous (natural) LH surge. If follicles grow but an LH surge doesn’t occur, and no trigger is given, the follicle will not ovulate, the egg will not be released and will be lost. 

Sometimes trigger shots are unnecessary if an LH surge is seen during monitoring (before the trigger is given). In cases like these, ovulation will occur because of a natural LH surge, making the trigger unnecessary. 

What size should follicles be for trigger shot?

Depending on the type of medication used, a lead follicle of at least 17 to 20 mm in diameter with correspondingly appropriate estradiol levels is required to give the trigger shot. The size of the follicles is monitored via transvaginal ultrasound, and the levels of estradiol (and sometimes other hormones, like LH and progesterone) are measured via blood work. 

This monitoring is done during the treatment prior to ovulation and may be repeated several times as necessary. The purpose of regular monitoring is to safely induce ovulation (making sure there are not too many follicles developing) and to sometimes adjust the medications when using gonadotropins.

Monitoring is also necessary to time the trigger shot when the follicle is deemed mature. With the help of ovarian ultrasound monitoring and blood work to measure estradiol and LH levels, your doctor will determine when the optimal time for the trigger shot is.

How long after ovulation induction do you ovulate? 

If a trigger is used, ovulation typically occurs 36 to 40 hours after the trigger. If an ovulation predictor kit (OPK) is used, ovulation usually occurs 36 to 40 hours after onset of the LH surge. A positive result on an OPK indicates the surge started around 24 hours before the test was taken. Ovulation can occur between 12 and 40 hours after a positive OPK.

Why would a treatment cycle be cancelled?

Hearing that your cycle is cancelled is disappointing and frustrating, but can be necessary in some cases. If the response to medications is too strong (with more than two maturing follicles), or if the estradiol level is too high, a cycle may be canceled to avoid the increased risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. 

On the flip side, a lack of response to the medications (either due to Clomid® or letrozole resistance or premature ovarian insufficiency) would also be a reason for cycle cancellation.

In some cases, "converting" to an IVF cycle is recommended in order to prevent multiple pregnancy through the use of elective single embryo transfer (eSET). 

Potential Risks of Ovulation Induction

The potential risks of clomiphene citrate and letrozole are very small and include a low (but significant) risk of multiple pregnancy and a very rare risk of OHSS. 

The major risks of gonadotropin treatment are multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). Great care is needed in managing these cycles, and frequent monitoring should be overseen by a reproductive endocrinologist.

Metformin therapy is uncommonly associated with liver dysfunction, and, in very rare cases, a severe condition called lactic acidosis. Blood tests to check liver and kidney function should be done periodically.

Treatment with fertility medications does not appear to increase the risk of breast, ovarian, endometrial, or other hormonally-sensitive cancers.   

The Odds of Having Twins with Ovulation Induction

While desirable to some, multiple pregnancies do significantly increase the risk of pregnancy complications, especially preterm delivery, which can be associated with serious health consequences for newborns (severe breathing problems, cerebral palsy, bleeding in the brain, infections, and even death).

Does Clomid® increase the chance of twins?

Development of one or two follicles is typical with clomiphene, though more follicles will occasionally develop. The risk of multiple pregnancy, although increased (compared to spontaneous ovulatory cycles), is still only around 8%.

The majority are twin pregnancies, with higher order multiples being a rare occurrence.

Does letrozole increase the chance of twins?

Letrozole has similar (or slightly lower) twin rates than clomiphene citrate, around 3-5%.

Multiple pregnancies can usually be avoided by using the lowest effective dose (utilizing the "step-up" protocol for PCOS patients) and by cancelling cycles (not giving hCG trigger shots) when there are more follicles developing than desired.

Do gonadotropins increase the chance of twins?

Multiple pregnancy occurs in up to 30% of pregnancies resulting from gonadotropin cycles. Around two thirds are twins and one third are triplets or higher order multiples.

Ovulation Induction Side Effects

Everyone responds to medication differently, but you may encounter these side effects:

• Clomiphene citrate (Clomid®) - Hot flashes, mood swings, breast tenderness, and nausea (common). Severe headaches and visual disturbances, including blurred vision or double vision (uncommon). When visual disturbances occur, you should stop treatment and consider alternative methods of ovulation induction.  
• Letrozole - Hot flashes, headaches, and mood swings (less common than with Clomid®).
• Metformin - Gastrointestinal issues (ex: nausea, vomiting, and diarrhea).
• Gonadotropins - Breast tenderness, swelling, rash at injection site, mood swings, depression, abdominal bloating, and sometimes mild pelvic discomfort.

If abdominal bloating or pelvic discomfort develop, try to limit or avoid any activities that worsen these symptoms, and always follow your doctor's guidance closely.

Can these medications cause OHSS?

Ovarian hyperstimulation syndrome (OHSS) is rarely observed with clomiphene citrate or letrozole treatment - even in PCOS patients. It is also rare in well-managed gonadotropin ovulation induction cycles where the goal is the development of a single mature follicle.

The risk of OHSS increases when using gonadotropins for ovarian stimulation with IUI or IVF, simply because multiple follicles are desired in those cases. 

PCOS patients using gonadotropins are also at higher risk of OHSS because they often respond to these medications by producing more than one follicle (egg). In these cases, a "step up" protocol is recommended, and patients are monitored very carefully throughout treatment. 

What is the "step-up" protocol for ovulation induction?

A "step-up" protocol for ovulation induction with gonadotropins is often used to treat polycystic ovary syndrome (PCOS) patients who are resistant to clomiphene or letrozole, and has been shown to be more effective in achieving ovulation of a single follicle (the desired outcome in ovulation induction cycles).

Gonadotropins are started at a very low dose, then gradually increased in small increments until a single follicle begins to develop.

The first attempt is usually a "dose-finding" cycle to identify the specific dosage a patient requires in order to respond. The first cycle can take several weeks. In subsequent cycles, treatment usually begins just below the threshold of response determined by the first cycle, shortening the length of the treatment cycle.

Note: By limiting the body's response to one or two follicles, "step-up" protocols help reduce the risk of complications such as OHSS and multiple pregnancy.

What if ovulation induction doesn't work?

When ovulation induction with oral medications isn't effective, injectable gonadotropins may be used. If there is no response to gonadotropins, higher doses may be required. Dosage increases can sometimes be given right away, rather than waiting for a subsequent treatment cycle.

If there is no response to high doses of gonadotropins, ovarian insufficiency may be suspected. In these cases, an egg donor can offer the best chance at a healthy pregnancy.

If ovulation induction is successful in leading to ovulation, but pregnancy does not occur after multiple attempts (usually 3-6 cycles), then IVF treatment should be considered. 

Taking the Next Step

Navigating all these different treatment options and medication protocols isn't easy!

That's why having a trusted, experienced Care Team by your side throughout the process is so important. While infertility can feel incredibly personal and isolating, there is an entire field of medicine dedicated to helping you achieve your goals - and many supportive, compassionate people you will meet along the way.

As you navigate the next phase of your own personal journey, remember that you don't have to go it alone. Reach out to fertility experts for guidance, explore fertility testing, connect with others who are also struggling to conceive, and take care of your mind and body.