What is ovarian stimulation and why is it done?

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Ovarian stimulation (OS), also called controlled ovarian stimulation (COS) is a 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 process “stims” for short. The treatment consists of ovarian stimulating drugs that help with the development and maturation of the 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-Mullerian hormone (AMH) level test.ⁱⁱ These evaluations help the RE forecast ovarian response, and based on the results, determine dosage of the meds for OS.

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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

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When do you start ovarian stimulation in your cycle?

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The first day of the menstrual cycle is known as Cycle Day 1 (CD1)—by convention this is the first day of full menstrual flow. This will be the day the patient calls the fertility clinic to schedule baseline bloodwork and an ultrasound. Typically, OS treatment begins on CD2-CD5. The length of ovarian stimulation for IVF will depend on how the follicles respond, as determined by ultrasounds and bloodwork.^v On average, women take stim meds for 8-12 days, but this can be shorter or longer due to differences between patients and protocols. Recent research suggests that under certain circumstances, OS can commence anytime during a menstrual cycle, because follicles develop in 2-3 waves during the same menstrual cycle. This timing is known as a "random start."^vi  

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What drugs are used for ovarian stimulation?

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There is no one option that is standard protocol for all women 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 your physician will refer to as your stimulation protocol.^vii The RE will determine the protocol based on your history as well as your baseline ultrasound and bloodwork. AFC and AMH are commonly used to predict ovarian response.^viii

Often, depending upon the AFC and AMH in addition to the patient’s age, the fertility specialist may try a lower intervention to assist a pregnancy. This might entail, for example, using clomiphene citrate (Clomid ®) or gonadotropins in IUI. However, this method may increase a woman's risk of multiple births.^ix More involved intervention includes OS and completing an IUI cycle or moving straight to IVF, which will include OS and a retrieval procedure.

Based on the patient’s situation, the physician will prescribe FSH, LH, or a combination of these drugs for OS in IVF.^x Examples of FSH-only drugs include Follistim ®, Elonva ®, Gonal-f ®, Puregon ®, and Ovaleap ®. Menopur ® and Pergoveris® consist of both FSH and LH, while Luveris ® is LH only.^xi

Dosages of OS medications vary based on ovarian reserve, age, and prior IVF outcomes. A common starting gonadotropin dose is 150 international units (IU) daily for women with an expected normal ovarian response. The gonadotropin dosage will likely not exceed 450 IU since this is the maximum dosage recommended by the National Institute for Health and Care Excellence.^xii

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What are common protocols used for ovarian stimulation?

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There are two main types of protocols: agonist cycles and antagonist cycles. They are categorized based on the way in which they suppress ovulation, i.e., by preventing the LH surge. Gonadotropin-releasing hormone (GnRH) agonists, such as Lupron®, trigger the release of LH before stimulation so that there is none available for the LH surge. GnRH antagonist drugs such as Cetrotide ® or Ganirelix ® directly block the release of LH.  

The GnRH long agonist protocol involves starting injections of an agonist, such as Lupron®, on CD21 of the previous cycle. This is followed by injections of gonadotropins, typically starting on CD2 or CD 3. This is the most traditional and has historically been the most widely used protocol worldwide for women with a normal response.^xiii Some studies show that long agonist protocols increase the number of pre-ovulatory follicles and eggs while also reducing cycle cancellation rates.^xiv This protocol receives the long moniker because the suppression begins in the previous cycle and thus the treatment protocol is longer in duration. The traditional long agonist protocol consists of approximately three weeks of daily subcutaneous injections of a GnRH agonist such as Lupron ®.^xv In contrast, suppression in short agonist cycles begins on CD1 or CD2. Often women with poor ovarian reserve will undergo this shorter duration of GnRH-agonist administration.^xvi

For the antagonist protocol, a GnRH antagonist such as Cetrotide ® is only administered once there is a risk of an LH surge (determined from estradiol levels and size of growing follicles). The GnRH antagonists block the LH release almost immediately, whereas agonists require 7-10 days for this downregulation.^xvii Because agonists are faster-acting, it usually only requires 5-6 daily injections.^xviii With fewer total injections and a shorter duration than agonist protocols, some patients may prefer antagonist protocols.

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What should I expect from ovarian stimulation?

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The fertility specialist will aim to retrieve between eight and 15 eggs to balance the risk of 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 can increase the risk of OHSS.^xix

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 oocytes will be mature enough for retrieval based on their size and rises in serum estradiol levels as estrogen is released from the growing follicles.^xx 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 trigger to help predict the risk of OHSS.^xxi

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What are the potential side effects of ovarian stimulation?

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Any treatment has the potential to cause side effects, including the 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.^xxii 

Although uncommon, some women experience ovarian torsion, a condition where the ovaries and fallopian tube twist.^xxiii The most serious side effect of OS is ovarian hyperstimulation syndrome (OHSS), which occurs when the ovaries have an adverse reaction to the hormones and swell up. Initially, this 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 initiated cycles.^xxiv The RE carefully evaluates this risk and prescribes a protocol accordingly. A preventative measure for OHSS includes the administration of a GnRH agonist trigger (instead of hCG trigger), and/or using a freeze-all approach for the retrieved eggs whereby the retrieved eggs are immediately frozen for later use.^xxv

OHSS is induced by either the external administration of human chorionic gonadotropin (hCG, trigger and/or booster), or an internal natural increase of hCG due to embryo implantation. Early onset OHSS tends to occur due to an exaggerated response to the hCG trigger, and typically occurs within nine days of egg retrieval. Conversely, late-onset OHSS occurs from natural  hCG from an initiated pregnancy, happening 10 days or more after egg retrieval.^xxvi

To reduce risk of OHSS, a physician will alter the protocol based on the likelihood of the condition. Studies indicate a short GnRH antagonist protocol with a GnRH agonist trigger reduces the chance of this condition.^xxvii

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What is poor ovarian response?

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Poor ovarian response means that the follicles in the ovaries are responding poorly to the stimulation medication, in that few follicles are growing or they are growing too slowly. By definition, a poor or low ovarian response is when fewer than four oocytes are likely to be retrieved after a standard IVF protocol (i.e., at least 150IU/day of FSH).^xxviii,xxixIn these cases, cycle cancellation is more likely as the probability of pregnancy is significantly decreased. Poor ovarian response occurs in 10 to 20 percent of IVF cycles and increases with age.^xxx

To improve outcomes, agonist protocols,^xxxi mini-IVF,^xxxii or dual stimulation,^xxxiii may be used.

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What are some other types of ovarian stimulation protocols?

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As noted previously, depending on the anticipated or actual response to ovarian stimulation, an RE may suggest an alternative approach in order to maximize egg retrieval. For example, Double/Dual stimulation (also known as DuoStim) refers to two stimulations and two oocyte retrievals performed in the same cycle. In this case, ovarian stim meds begin at the start of the follicular phase, i.e., CD2-3 for the first retrieval. Then, following oocyte 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.^xxxiv

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Another form of OS is what is referred to as mini-IVF, which uses minimal stimulation. This protocol uses lower doses of gonadotropins or other stim meds so that the patient produces a maximum of five to six eggs.^xxxv Since its discovery, it has become a promising solution because traditional IVF causes a heightened risk of ovarian hyperstimulation syndrome (OHSS) as well as a higher chance of conceiving multiple pregnancies. Furthermore, a mini-IVF treatment costs less than a traditional one.^xxxvi A mini-IVF treatment typically involves an extended regimen of clomiphene citrate (ex. Clomid ®) to stimulate follicles. Usually, the regimen consists of 50 to 100 mg per day orally, starting on CD3 and lasting until trigger. Clomid ® will stimulate the brain to release FSH and LH, inducing follicle development, maturation, and ovulation.^xxxvii

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Usually during mini-IVF a doctor will recommend Clomid ® for five days only, as when this particular medication is given for more than five days, it suppresses LH release.^xxxviii In addition to Clomid, mini-IVF protocols will often include daily gonadotropin injections of 75 to 150 IU daily beginning on CD4-CD7. The exact gonadotropin dosage depends on body mass index (BMI) and ovarian reserve. Some protocols may also use Letrozole® for stimulation or include other oral medications. In addition, sometimes the physician will 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 a subcutaneous injection of hCG trigger or an intramuscular GnRH agonist trigger. If the plan is for a fresh transfer, the physician will usually recommend hCG.^xxxix

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What happens after ovarian stimulation?

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Ovarian stimulation typically ends the day of trigger, approximately 36 hours prior to egg retrieval. In some cases, as when a patient has had a poor response, it may end with the cancellation of the retrieval. 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 stims and retrieval.

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Conclusion

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Ovarian stimulation is one of the methodologies used to maximize the number of eggs retrieved during the IVF process. There are different protocols that are used, and they can be somewhat complex, but the OS procedure is considered an integral part of IVF. A woman undergoing IVF or considering it should speak to her physician about what protocol will be used and why, in order to understand this important part of the process.