What is ovarian stimulation and why is it done?

Ovarian stimulation (OS), also called controlled ovarian stimulation (COS) or controlled ovarian hyperstimulation (COH), is a fertility treatment that increases the number of eggs developing in a cycle with the aim of improving pregnancy rates during assisted reproductive technology (ART). Often patients will call this part of the process “stims” for short.

The treatment consists of taking ovary-stimulating medications that help with the development and maturation of ovarian follicles and oocytes (eggs).ⁱ Prior to fertility treatment, the RE or fertility specialist will conduct various tests, such as an antral follicle count (AFC) and an anti-Müllerian hormone (AMH) level test.ⁱⁱ These evaluations help the RE forecast ovarian response and, based on the results, determine the dosage of meds for the ovarian-stimulation process.

OS medications are similar to the gonadotropins that the body normally produces: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones stimulate ovarian follicle development for timed intercourse, egg freezing, or IVF.ⁱⁱⁱ When used to stimulate the ovaries, FSH and LH promote follicular development and maturation and aim to increase the number of mature eggs retrieved during IVF.^iv

When do you start ovarian stimulation in your cycle?

The first day of the menstrual cycle is known as Cycle Day 1 (CD1). By convention, it is the first day of full menstrual flow. (Note: Spotting is typically not considered as the first day.) CD1 is the day a patient calls the fertility clinic to schedule baseline bloodwork and an ultrasound.

Typically, ovarian-stimulation medications begin between CD2 and CD5. The length of ovarian stimulation for IVF depends on how the follicles respond, as determined by ultrasounds and bloodwork.^v On average, females take stim meds for eight to 12 days, but this time period can be shorter or longer due to differences between patients and protocols.

Recent research suggests that, under certain circumstances, OS can start anytime during a menstrual cycle, because follicles develop in two to three waves during the same menstrual cycle. This timing is known as a “random start,” but it is less common.^vi

What medications are used for ovarian stimulation?

There is no one option that is standard protocol for all individuals undergoing OS, since there is no one treatment that is known to work in every case. However, typically OS will include several different medications such as injectable stimulation drugs, which the physician will refer to as the patient’s stimulation protocol.^vii

The physician will determine a patient’s protocol based on their history as well as their baseline ultrasound and bloodwork. The RE will often use age, antral follicle count (AFC), and anti-Müllerian hormone (AMH) levels to predict ovarian response to the medications.^viii A patient’s prior history of response to OS, if applicable, may also guide the choice of any future stimulation protocols.

OS before IUI

Depending on AFC, AMH, and the patient’s age, the fertility specialist may suggest IUI as a first approach prior to IVF. This recommendation is usually the case for the patients with the best prognosis. For example, this protocol could entail using clomiphene citrate (Clomid^®), letrozole (Femara ^®), or gonadotropins prior to an IUI procedure.^ix

OS before IVF

Based on the patient’s situation, the physician will prescribe FSH, LH, or a combination of these drugs for OS in IVF.^x

• ‍FSH-only drugs: Follistim^®, Elonva^®, Gonal-f^®, Puregon^®, Ovaleap^®
• ^‍FSH and LH drugs: Menopur^®, Pergoveris^®
• ^‍LH-only drugs: Luveris^®

These OS medications are similar to the gonadotropins, FSH and LH, that the body normally produces, which help to stimulate follicular growth, development, and maturation. By taking these hormones in dosages higher than the body normally produces, the idea is that the ovaries will develop multiple egg-containing follicles. This process aims to maximize the number of eggs retrieved during IVF.^xi

How is dosage determined?

Dosages of OS medications vary based on ovarian reserve, age, and prior IVF outcomes.  Common starting gonadotropin doses can range from 150 IU (international units) to 225 IU daily for females with an expected normal ovarian response. The gonadotropin dosage will typically not exceed 450 IU, since this is the maximum dosage recommended by the National Institute for Health and Care Excellence.^xii An important consideration for REs when determining dosage of OS medication is minimizing the risk of ovarian hyperstimulation (OHSS).

What are common protocols used for ovarian stimulation for IVF?

There are two main types of ovarian stimulation protocols used for IVF: agonist cycles and antagonist cycles. They are categorized based on the way the medications prevent the LH surge that normally triggers ovulation. In an agonist cycle, gonadotropin-releasing hormone (GnRH) agonists such as Lupron^® trigger the release of LH before ovarian stimulation so that there is none available for the LH surge. In an antagonist cycle, GnRH antagonist drugs such as Cetrotide^® and Ganirelix^® directly block the release of LH.

The antagonist protocol has become the most used and recommended approach to ovarian stimulation for individuals with normal ovarian reserve and individuals at higher risk of ovarian hyperstimulation syndrome (OHSS), such as patients with polycystic ovary syndrome (PCOS). Antagonist and agonist protocols remain equally appropriate for individuals with low ovarian reserve.^xiii

Agonist protocol

The GnRH long agonist protocol involves starting hormone injections of an agonist, such as Lupron^®, Synarel^®, Buserelin^®, or Zoladex^®, in the mid-luteal phase of a menstrual cycle. This step is followed by injections of gonadotropins, typically starting on CD2 or CD3 of the next menstrual cycle. This protocol is considered the most traditional and, historically, was the most widely used worldwide for females with a normal ovarian reserve.^xiv

Some studies show that long agonist protocols increase the number of pre-ovulatory follicles and eggs while also reducing cycle cancellation rates.^xv This protocol receives the “long” moniker because the ovulation suppression begins in the previous cycle, and thus the treatment protocol is long in duration. The traditional long agonist protocol consists of approximately three weeks of daily subcutaneous injections of a GnRH agonist such as Lupron^®.^xvi In contrast, suppression in short agonist cycles begins on CD1 or CD2 of the menstrual cycle in which egg retrieval will take place. Often females with poor ovarian reserve will undergo this shorter duration of GnRH-agonist medication.^xvii

Antagonist protocol

For the antagonist protocol, a GnRH antagonist such as Cetrotide^®, Antagon^®, or Ganirelix^®, is administered once there is a risk of an LH surge (determined by estradiol levels on blood tests and the size of growing follicles seen on ultrasound). The GnRH antagonists block the LH release almost immediately, whereas agonists require seven to 10 days to do it.^xviii Patients may prefer antagonist protocols due to their faster-acting nature and shorter duration.^xix

What should I expect from ovarian stimulation?

The fertility specialist will aim to retrieve between eight and 15 eggs to balance the risk of ovarian hyperstimulation syndrome (OHSS) with the best chance of achieving a live birth. Retrieving fewer than eight eggs reduces the chances of having high-quality embryos for transfer, while more than 15 eggs can increase the risk of OHSS, which is a swelling of the ovaries due to an adverse reaction to the hormones.^xx

Throughout the stimulation cycle, the fertility clinic will conduct ultrasounds to evaluate the ovaries and endometrium, measuring the size and number of growing follicles. The clinic will also monitor hormone levels and use the collected information to gauge when the eggs will be mature enough for retrieval based on their size and rises in estradiol levels in the blood, as estrogen is released from the growing follicles.^xxi The combination of both ultrasound follicle monitoring and blood hormone levels will determine how long stimulation medications will be needed. In addition, the physician will monitor estradiol levels on the day of the trigger shot (an injection given approximately 36 hours before egg retrieval) to help predict the risk of OHSS.^xxii

What are the potential side effects of ovarian stimulation?

Any fertility treatment has the potential to cause side effects, including the hormonal medications used for ovarian stimulation. Fortunately, most of the side effects from ovarian stimulation are mild. Abdominal pain and bloating are common symptoms because of hormone fluctuations, while GnRH agonists can temporarily cause menopause-like effects such as hot flashes and mood swings.^xxiii Although uncommon, some females experience ovarian torsion, a condition where the ovaries and fallopian tubes twist.^xxiv

Ovarian hyperstimulation syndrome (OHSS)

The most serious side effect of OS is ovarian hyperstimulation syndrome (OHSS), which occurs when the ovaries have a greater than expected response to OS. Historically, this syndrome was a common occurrence with IVF treatments; however, new protocols have reduced the occurrence of OHSS tremendously. Published research indicates that OHSS occurs in 0.7 to 1.7 percent of modern initiated cycles.^xxv

OHSS results from high circulating levels of human chorionic gonadotropin (hCG) in the body as a result of OS. Symptoms typically occur within a week of the egg retrieval but can be present even prior to retrieval. IVF cycles with a fresh embryo transfer complicated by OHSS are at particularly high risk of severe OHSS due to the hCG produced by the implanted embryo.^xxvi

Reproductive endocrinologists carefully evaluate each patient’s risk and prescribe a protocol accordingly. Studies indicate a short GnRH antagonist protocol with a GnRH agonist trigger (instead of an hCG trigger) reduces the chance of OHSS.^xxvii Another preventative measure for OHSS is using a freeze-all approach whereby the retrieved eggs are immediately frozen for later use in lieu of a fresh embryo transfer.^xxviii

What is poor ovarian response?

Poor ovarian response (POR) means that the follicles in the ovaries have a less-than-expected response to the stimulation medication, which could be defined by a lower-than-expected number of developing follicles and/or a slower-than-expected rate of follicular growth. By definition, a poor or low ovarian response is when fewer than four eggs are likely to be retrieved after a standard IVF protocol (i.e., at least 150 IU per day of FSH).^xxix,xxx

In these cases, cycle cancellation will be considered, since the probability of achieving pregnancy is significantly decreased. Poor ovarian response occurs in 10 to 20 percent of IVF cycles and increases with age.^xxxi To improve outcomes, agonist protocols, mini-IVF, or dual stimulation may be used. Read more on these protocols below.^{xxxii,xxxiii,xxxiv}

What are some other types of ovarian stimulation protocols?

As noted previously, depending on the anticipated or actual response to ovarian stimulation, a reproductive endocrinologist may suggest an alternative approach to maximize egg retrieval, such as dual stimulation or mini-IVF.

Dual stimulation

Dual stimulation (also known as DuoStim), refers to two stimulations and two egg retrievals performed in the same cycle. In this case, ovarian stimulation medications begin at the start of the follicular phase (i.e., CD2 to CD3) for the first retrieval. Following egg retrieval, a second round of stimulation will begin in the luteal phase. A freeze-all strategy is necessary in the case of dual-stimulation cycles.^xxxv

Mini-IVF

Another form of OS is called mini-IVF, which uses minimal stimulation. This protocol uses lower doses of gonadotropins or other stimulation medications.^xxxvi Since its discovery, it has been a promising solution for OHSS, as traditional IVF and ovarian stimulation heightens OHSS risk. Furthermore, a mini-IVF treatment costs less than a traditional IVF cycle.^xxxvii Mini-IVF can be a cost-effective alternative for poor responders since these individuals often retrieve the same number eggs whether they have maximum stimulation of low stimulation. While it is not intended to improve outcomes, it can produce the same outcome at a lower cost.^xxxviii

A mini-IVF treatment typically involves an extended regimen of clomiphene citrate (brand name Clomid^®) of 100 mg per day orally, starting on CD3 and lasting until the trigger. Clomid^® stimulates the brain to release FSH and LH, inducing follicle development, maturation, and ovulation.^xxxix Typically, the Clomid will not be given for longer than five days.^xl

In addition to Clomid^®, mini-IVF protocols often include daily gonadotropin injections of 75 to 150 IU daily beginning on CD4 to CD7. The exact gonadotropin dosage depends on body mass index (BMI) and ovarian reserve. Some protocols may also use letrozole (brand name Femara^®) for stimulation or include other oral medications. Sometimes the physician will also prescribe a GnRH antagonist such as Cetrotide^® or Ganirelix^® to prevent premature ovulation before egg retrieval.

Once the follicles have grown, egg maturation will be induced with either subcutaneous injection of hCG trigger or an intramuscular GnRH agonist trigger. If the plan is for a fresh embryo transfer, the physician will usually recommend hCG.^xli

What happens after ovarian stimulation?

Ovarian stimulation typically ends on the day of the trigger shot, approximately 36 hours prior to egg retrieval. In some cases, when a patient has had a poor response, it may end with the premature cancellation of the cycle. After egg retrieval, some patients will choose to do a fresh embryo transfer, while others will opt for a frozen transfer and/or do another IVF cycle of stimulation and retrieval.

Conclusion

Ovarian stimulation is one of the methods used to maximize the number of eggs retrieved during an IVF cycle. Various different protocols are used, and they can be somewhat complex, but the OS process is considered an integral part of IVF. Patients considering or planning IVF should speak to their physician about what protocol will be used and why to better understand this important aspect of fertility treatment.