Understanding Lupron: Its Uses and Effects in Fertility Treatments

In fertility medicine, I frequently encounter questions about the various medications used in fertility treatments and one of the most commonly asked about is Lupron (Leuprolide). For those of you who might have stumbled onto this blog post, my name is Dr. Lucky Sekhon, and I am a RE based in New York. Today, I want to share with you my insights on what Lupron is, how it works, and the different ways we use it in our field. This blog is the next in a series of posts I am doing on fertility medications, previously I did a similar breakdown of Clomid and it’s role in fertility medicine.

What is Lupron?

Lupron is a GnRH (gonadotropin-releasing hormone) agonist. It acts similarly to a hormone produced in the hypothalamus, a part of the brain that controls the pituitary gland. The pituitary gland, often referred to as the master gland, regulates several major hormones in the body. Specifically, Lupron influences the release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone). These are signals that go directly to the ovaries and cause the selection of a dominant follicle, the maturation of the egg inside that follicle, and the eventual ovulation of that egg.

How Does Lupron Work?

Initially, Lupron stimulates the pituitary gland to release more FSH and LH. However, with prolonged exposure, it has a paradoxical effect and ultimately suppresses the secretion of these hormones. This suppression is beneficial in various fertility treatment protocols where controlling hormone levels is crucial. These differing effects from Lupron means that it can be used in many different ways during fertility treatment and is often a source of confusion. Let’s explore some common ways that Lupron is used in fertility medicine.

Lupron as a Trigger Shot for Egg Maturation

One of the most common uses of Lupron in my practice is as part of the trigger shot, the final step in egg maturation before retrieval. Traditional protocols often use high doses of hCG (human chorionic gonadotropin) for this purpose. However, modern approaches frequently employ a dual trigger, combining a reduced dose of hCG with Lupron. How this works is that instead of just giving 10,000 units of hCG, the highest possible dose, as the trigger shot to mature the eggs, oftentimes we’re using a fraction of that dose now, sometimes even zero hCG! Instead, we’re able to supplement the trigger shot with Lupron. By giving 40 or 80 units of Lupron with a little bit of hCG, we achieve the same effect of the trigger shot, but through a different mechanism. By taking Lupron, it’s replacing that hormone signal that would normally get sent to the pituitary, and it forces your pituitary to release FSH and LH. That LH is just like the LH signal that you release mid-cycle to mature and ovulate an egg. By giving Lupron as part of the trigger shot, it can allow you to mature the eggs that have been growing during the course of the stimulation. This combination mimics the natural LH surge, triggering the final maturation of the eggs with a lower risk of ovarian hyperstimulation syndrome (OHSS).

The nice thing about Lupron compared to hCG is that LH, when you’re releasing it endogenously, has a very short half-life, and so it has a much lower risk of hyperstimulation. So just to be very clear, the ability to mature the eggs with Lupron causing your pituitary gland to release LH has allowed us to use lower doses of hCG or no hCG at all. And hCG, which has a really long half-life, would normally continue to stimulate the ovaries, and that’s been a huge culprit in years past when it comes to hyperstimulation syndrome. So by being able to eliminate using it at all or really minimizing the amount that’s used, it has greatly reduced the risk associated with egg retrieval when it comes to hyperstimulation syndrome.

Aspect	Purely hCG Trigger Shot	Dual Trigger Shot (hCG + Lupron)
Hormonal Mechanism	hCG acts similarly to LH, binding to LH receptors and stimulating final egg maturation.	Lupron stimulates the pituitary gland to release natural LH and FSH, while hCG provides additional LH support.
Risk of OHSS	Higher risk due to prolonged stimulation of ovaries.	Lower risk due to shorter half-life of endogenous LH.
Side Effects	Greater risk of hyperstimulation, bloating, and discomfort.	Reduced side effects due to minimized hCG dosage.
Effectiveness	Effective for final maturation of eggs.	Equally effective, with additional benefits of Lupron.
Cost	May be more cost-effective due to single medication.	Potentially higher cost due to use of two medications.
Suitability	Suitable for patients without a history of OHSS.	Better for patients at risk of OHSS or with a history of OHSS.
Clinical Outcomes	Effective for egg maturation and retrieval.	Equally effective, with improved safety profile.

Microflare or Microdose Lupron IVF Protocol

In certain IVF (in vitro fertilization) protocols, I use Lupron in microdoses throughout the stimulation cycle. The most common one where we see it being used today with modern-day IVF is in a protocol called microflare or microdose Lupron, where you’re giving very small doses of Lupron, usually morning and night. By day three or day four of the cycle, these microdoses of Lupron actually has a stimulation effect on the pituitary gland where it releases more FSH and LH. This protocol is particularly beneficial for low responders, providing a double stimulation effect via the externally administered shots of FSH and LH. However, one drawback to this approach is that it is an aggressive protocol which means you can’t use Lupron for the trigger, it has to be hCG.

Now, what’s interesting about the microdose Lupron protocol is that while it is causing this burst of activity from the pituitary and causing it to release of FSH and LH at the beginning of your cycle, it’s actually going to start to blunt your pituitary’s response and actually start to prevent the release of FSH and LH as your cycle progresses. Thus, in the microdose protocol, Lupron plays a dual, almost contradictory, role of stimulating your ovaries at the start of your cycle while preventing ovulation before egg retrieval.

Downregulation IVF Protocol

The downregulation or long protocol was one of the earliest IVF protocols. This protocol involves the use of medications, Lupron in this case, to temporarily shut down the body’s natural reproductive hormone cycle before stimulating the ovaries to produce multiple eggs. The process of daily Lupron injections begins in the cycle preceding the ovarian stimulation, typically around a week after ovulation. The goal is to suppress the pituitary gland’s release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This suppression prevents premature ovulation and allows for controlled ovarian stimulation in the subsequent cycle. Once suppression is confirmed, ovarian stimulation begins with daily injections of gonadotropins (FSH and/or LH), in addition to the continued doses of Lupron, to stimulate the growth of multiple ovarian follicles while preventing ovulation up until the hCG trigger shot is administered. Despite newer protocols being available, downregulation is still used, especially in cases where precise control over ovulation is needed. Generally, the downregulation protocol is a good choice for patients with a high risk of premature ovulation, patients with endometriosis or those respond poorly to stimulation protocols.

Benefits of Downregulation Protocol

Controlled Ovulation: By suppressing the natural hormonal cycle, the risk of premature ovulation is minimized, allowing for precise timing of egg retrieval. Improved Follicular Response: Suppression of the pituitary gland ensures a more synchronized and robust response to gonadotropin stimulation, often resulting in the development of multiple mature follicles. Reduced Cycle Cancellation: The protocol decreases the likelihood of cycle cancellation due to premature LH surge and ovulation.

Drawbacks of the Downregulation Protocol

Extended Duration: The protocol is longer compared to other IVF protocols, requiring more time and commitment from patients. Increased Medication Use: The use of Lupron and extended gonadotropin injections can increase the overall medication cost. Potential Side Effects: Patients may experience side effects from Lupron, such as hot flashes, headaches, and mood swings due to low estrogen levels. Suppression Variability: In some cases, achieving adequate suppression may be challenging, requiring close monitoring and potential adjustments to the medication regimen.

Embryo Transfer Preparation

Lupron is also a valuable tool in preparing for embryo transfer. There are two major ways I use it for this purpose. One is as part of a downregulation protocol similar to what I described above. However, in this case instead of using a downregulation protocol to prepare for a retrieval, in this case we are using it to prepare for a transfer. In this case, Lupron is administered starting a week after ovulation in the preceding cycle and continued through your period, where you will shed your lining. However, you continue taking daily injections of Lupron and then start estrogen therapy to prepare and thicken the uterine lining. Once the lining looks thick enough to schedule the transfer, we would stop the Lupron and add in progesterone. This is something that I will often use in patients who were on a medicated prep cycle for frozen transfer and they somehow broke through and ovulated despite being on estrogen pills three times a day. This is a really effective way to control the ovaries and to prevent ovulation, and it’s often sometimes a go-to from day one for patients who have diminished ovarian reserve, especially patients who are much older, because they’re at highest risk of breaking through and ovulating early causing us to cancel the cycle and start prepping again.

For patients with endometriosis, Lupron can be used for one to three months prior to embryo transfer to suppress the disease and improve the uterine environment. While not universally standardized, this approach can be beneficial for enhancing pregnancy outcomes in women with severe endometriosis. Even though there aren’t any randomized controlled trials that have looked at this properly, we do know that Lupron is a very potent way to suppress the process that feeds endometriosis. I like to be as aggressive as possible with my patients who suffer endometriosis in the lead up to the transfer to try and optimize the environment and raise our chances of success.

Side Effects and Considerations

Lupron’s potent suppression of the pituitary gland can lead to significantly reduced estrogen levels. This is why it is sometimes referred to as inducing a temporary menopause. Common side effects include hot flashes and vaginal dryness. Long-term use can thin bones and increase the risk of osteoporosis, making it unsuitable for extended treatment duration.

Despite these side effects, Lupron’s ability to control hormone levels makes it invaluable in fertility treatments. Its careful application can minimize risks while maximizing the chances of successful egg retrieval and embryo transfer.

Conclusion

Understanding the role of Lupron in fertility treatments highlights its versatility and importance in modern reproductive medicine. Whether used for egg maturation, stimulation protocols, downregulation, or managing endometriosis, Lupron’s targeted hormone control can significantly enhance the effectiveness of fertility treatments.

By sharing my knowledge and experience, I hope to provide clarity on how Lupron works and why we use it in different protocols. As always, please do not use this article as a substitute for medical advice from your OB/GYN or RE. Please consult with your doctor to understand whether any of the protocols I mentioned above might be the right choice for you. If you are interested in learning more about fertility medications, please checkout some of my other posts on the topic here. If you just stumbled on this article and found it somewhat useful, please follow me on Instagram where I regularly post content on women’s reproductive health and fertility treatments.

Below you can find a video I’ve made which goes into more detail on how I use Lupron to help my patients in their fertility journey.

References

Albeitawi S, Marar EA, Reshoud FA, Hamadneh J, Hamza R, Alhasan G, Omeish H, Vigano P. Dual trigger with gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves oocyte yield in normal responders on GnRH-antagonist cycles. JBRA Assist Reprod. 2022 Jan 17;26(1):28-32. doi: 10.5935/1518-0557.20210039. PMID: 34463444; PMCID: PMC8769195.

Eftekhar M, Mohammadian F, Yousefnejad F, Khani P. Microdose GnRH Agonist Flare-Up versus Ultrashort GnRH Agonist Combined with Fixed GnRH Antagonist in Poor Responders of Assisted Reproductive Techniques Cycles. Int J Fertil Steril. 2013 Jan;6(4):266-71. Epub 2013 Mar 3. PMID: 24520450; PMCID: PMC3850311.

Hughes, E. G., et al. (2019). “GnRH agonist versus GnRH antagonist protocols for pituitary suppression in assisted reproduction.” Cochrane Database of Systematic Reviews, 3, CD001750.

Surrey ES. GnRH agonists in the treatment of symptomatic endometriosis: a review. F S Rep. 2022 Nov 21;4(2 Suppl):40-45. doi: 10.1016/j.xfre.2022.11.009. PMID: 37223763; PMCID: PMC10201290.

Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998 Jan;91(1):16-24. doi: 10.1016/s0029-7844(97)00620-0. PMID: 9464714.

Gonçalves, M. L., et al. (2020). “Long-term use of GnRH agonists in endometriosis: risks and benefits.” Reproductive Sciences, 27(7), 1323-1330.