About This Article

The following is a summary of the original study on frozen embryo transfer without GnRH agonist suppression, published in Fertility and Sterility and summarized by Christine M. Schroeder, Ph.D.: Researchers at Hadassah University Hospital in Jerusalem studied 140 patients undergoing 185 frozen embryo transfer cycles. They found that an artificial cycle protocol using estrogen and progesterone — without the addition of a GnRH agonist (Lupron) — was effective for patients with functioning ovaries, achieving an ongoing pregnancy rate of 17.7 percent. This was an important early finding that helped establish that the GnRH agonist step was not universally necessary. The full original summary can be found here: [link to original article].

Much has changed since that study was published. The article below explains what we know now — in plain language, from the beginning.

Part One: Why Frozen Embryo Transfer Exists

If you have been through IVF or are preparing for it, you have probably heard the term frozen embryo transfer, or FET. But it helps to understand why freezing embryos became such a central part of fertility treatment in the first place.

When IVF began, the goal was straightforward: stimulate the ovaries to produce eggs, retrieve them, fertilize them in the laboratory, and transfer the resulting embryo into the uterus — all in the same cycle. This is called a fresh transfer. It still happens today, and for some patients it is the right approach. But over time, clinicians noticed something important: the same hormones used to stimulate the ovaries during egg retrieval can sometimes make the uterine lining less receptive to an embryo. In other words, the very medications that help produce the eggs can temporarily make it harder for an embryo to implant.

Add to that the risk of a condition called ovarian hyperstimulation syndrome (OHSS) — a potentially serious overreaction to stimulation medications that causes the ovaries to swell and can lead to fluid accumulation in the abdomen — and there were strong reasons to consider separating the retrieval and the transfer into two different cycles.

The solution was the freeze-all strategy: retrieve and fertilize the eggs, freeze all of the resulting embryos, let the body return to its natural state, and then transfer the embryo in a calmer, more prepared cycle later.

Today, freeze-all has become the standard approach at many fertility clinics, particularly for patients at high risk of OHSS, patients undergoing preimplantation genetic testing (PGT-A) to check embryo chromosomes before transfer, and increasingly for many other patients as well. Research shows that for high responders — patients who produce a large number of eggs — freeze-all improves live birth rates compared to fresh transfer. For normal responders, the evidence is more mixed, and the decision is individualized.

The key takeaway: frozen embryo transfer is not a second-best option. In many cases, it is the preferred one.

Part Two: What Happens Before a Frozen Transfer — Preparing the Uterus

Once embryos are frozen and waiting, the next step is preparing the uterine lining — called the endometrium — to receive them. This is where protocol choices come in, and where patients often feel confused by the options their clinic presents.

The endometrium needs to go through a specific sequence of hormonal changes to be ready for an embryo. In a natural menstrual cycle, this happens automatically: estrogen thickens the lining during the first half of the cycle, and after ovulation, progesterone transforms it into a receptive state that can support implantation. The embryo needs to arrive at exactly the right moment in this sequence — what clinicians call the window of implantation.

In a frozen embryo transfer cycle, the clinic has to either work with your natural cycle or create those conditions artificially using medications. That choice — natural versus artificial — is one of the most important decisions in FET planning, and it depends on your individual situation.

Part Three: The Three FET Protocol Options — What They Mean for You

Natural Cycle FET

In a natural cycle FET, your body does the work. The clinic monitors your cycle with ultrasound and blood tests to track when you ovulate, and then times the embryo transfer to coincide with the natural post-ovulatory window. No medications are used to prepare the uterine lining — though progesterone supplements may be added after ovulation to support the early luteal phase.

This approach has some significant advantages. It is simpler, involves fewer medications, and recent research suggests it may be associated with better pregnancy rates and lower obstetric risks for some patients. A large study of over 2,000 FET cycles found live birth rates of 32.3 percent for natural cycle FET versus 26.6 percent for artificial cycle preparation. Growing evidence also shows that natural cycle FET may carry lower risks of pregnancy complications including high blood pressure and preeclampsia — conditions that have been more commonly associated with artificial cycle protocols.

The limitation: natural cycle FET only works if you ovulate regularly and predictably. If your cycles are irregular, absent, or unpredictable — as they often are with PCOS/PMOS, hypothalamic amenorrhea, or other conditions — a natural cycle is not a viable option.

Modified Natural Cycle FET

The modified natural cycle is a middle ground. Your body still ovulates naturally, but the clinic adds a trigger shot — usually hCG, the same hormone used in egg retrieval cycles — to control the exact timing of ovulation. This makes scheduling the transfer more predictable while still preserving the hormonal environment of a natural cycle, including the corpus luteum (the temporary gland formed after ovulation that produces progesterone).

For patients who ovulate but have timing variability, the modified natural cycle is often a good option.

Artificial Cycle FET (Also Called Programmed or Medicated FET)

In an artificial cycle FET, medications are used to fully control the hormonal environment. Estrogen is given first, typically as pills, patches, or injections, to thicken the uterine lining. Once the lining reaches an adequate thickness — usually eight millimeters or more — progesterone is added, and the embryo transfer is timed based on the progesterone start date.

The natural cycle is suppressed, meaning the body does not ovulate on its own. This gives the clinic maximum control over timing and allows transfers to be scheduled with precision. It also means more monitoring visits and more medications.

Artificial cycle FET is often the only viable approach for patients who do not ovulate, patients who have had their ovaries removed, or patients receiving donor embryos. It is also widely used for convenience and scheduling flexibility — including for patients who ovulate but whose cycles are difficult to predict.

The original Schroeder study summary on this page describes an artificial cycle protocol using estrogen and progesterone, without the addition of a GnRH agonist. That brings us to the next important piece of this puzzle.

Part Four: What Is a GnRH Agonist — and What Is a GnRH Antagonist?

These terms appear frequently in fertility treatment and confuse almost everyone who encounters them for the first time. Here is what they actually mean.

Starting with GnRH itself

GnRH stands for gonadotropin-releasing hormone. It is a hormone produced in the brain — specifically in the hypothalamus — that signals the pituitary gland (another part of the brain) to release two critical hormones: FSH (follicle-stimulating hormone) and LH (luteinizing hormone). FSH drives egg development in the ovaries. LH triggers ovulation — the release of the mature egg.

In a natural cycle, the brain releases GnRH in carefully timed pulses to orchestrate the entire process. During an IVF or FET cycle, the clinic needs to control this system — to prevent ovulation from happening at the wrong time and to ensure eggs or the uterine lining develop on the clinic’s schedule.

GnRH Agonists: The Slow Off Switch (Lupron)

A GnRH agonist is a medication that mimics GnRH. When you take it, it initially tells the pituitary to release more FSH and LH — which sounds counterproductive — but after a few days of continuous exposure, the pituitary becomes overwhelmed and shuts down. It essentially stops responding to GnRH signals altogether. This is called downregulation or pituitary suppression.

The result: LH production is suppressed, which means ovulation cannot happen on its own. The clinic now has full control over the cycle.

The most well-known GnRH agonist is leuprolide acetate, sold under the brand name Lupron. It is typically started before or early in a cycle, given as a daily injection, and continued until the clinic triggers ovulation artificially or until an embryo transfer is ready.

Advantages of agonists: very thorough suppression of the pituitary, which makes cycles highly predictable and reduces the risk of a premature LH surge. Widely used for decades with a well-established track record.

Disadvantages: it takes time to work — often several weeks — which means a longer treatment period. During the initial phase, patients often experience side effects similar to menopause, including hot flashes, headaches, and mood changes. It also increases the risk of OHSS in stimulation cycles.

GnRH Antagonists: The Fast Off Switch (Ganirelix, Cetrotide)

A GnRH antagonist works differently and more directly. Instead of mimicking GnRH to overwhelm the system, it blocks the GnRH receptor in the pituitary immediately — like putting a lock on a door. The pituitary cannot receive GnRH signals, so it stops releasing LH, and ovulation is prevented.

The most commonly used GnRH antagonists are ganirelix acetate (brand name Antagon or Fyremadel) and cetrorelix acetate (brand name Cetrotide). They are given as daily injections during the stimulation phase of an IVF cycle, typically starting when the follicles reach a certain size.

Advantages of antagonists: they work immediately — no lead-in period needed. They carry a lower risk of OHSS. Treatment duration is shorter. Side effects are generally milder than agonists. They also allow for a GnRH agonist trigger shot at the end of stimulation instead of hCG, which further reduces OHSS risk in high-risk patients.

Disadvantages: requires more careful monitoring to time the start correctly. In some patients, suppression may be less thorough than with agonists.

Why Does This Matter for FET?

In a frozen embryo transfer using an artificial cycle, the question is whether to use a GnRH agonist to suppress the pituitary before starting estrogen — to make sure your natural cycle cannot interfere with the medicated one. The original study on this page showed that for patients with functioning ovaries, this suppression step was often unnecessary. Subsequent research has confirmed this for most patients.

However, for specific situations — particularly for patients with adenomyosis, recurrent implantation failure, or certain hormonal profiles — GnRH agonist pretreatment before an artificial cycle FET has been shown to improve outcomes. This is an area where individualized decision-making matters enormously.

Part Five: The Freeze-All and PGT-A Connection

One reason frozen embryo transfer has become so prevalent is the rise of preimplantation genetic testing for aneuploidy, or PGT-A. This is the process of biopsying a few cells from a blastocyst-stage embryo (day 5 or 6) and analyzing the chromosomes before transfer. Embryos with the correct number of chromosomes — called euploid embryos — are far more likely to implant and result in a live birth than chromosomally abnormal ones.

Because PGT-A requires the embryos to be biopsied and then frozen while the results are processed — which takes several days — it is by definition a freeze-all situation. The embryo that will eventually be transferred is always a frozen-thawed embryo.

PGT-A has changed the landscape of who undergoes FET and why. Women of advanced reproductive age, women with a history of recurrent miscarriage, and women with recurrent implantation failure are among those most likely to be offered PGT-A — and therefore most likely to be planning a frozen transfer.

It is worth noting that PGT-A is not right for everyone, and ASRM’s 2024 guidelines emphasize that it should be offered selectively based on individual clinical circumstances rather than as a universal screening tool.

Part Six: Why There Is No Single Right Protocol — and Why That Matters

This is the heart of what every patient reading this should take away.

Fertility treatment is deeply individual. The right FET protocol for you depends on whether you ovulate regularly, your underlying diagnosis, your age, your hormonal profile, your embryo quality and quantity, whether you have conditions like adenomyosis or PCOS/PMOS, your response to previous cycles, and your clinic’s scheduling and monitoring capabilities. It also depends on what the research shows for patients in your specific situation — and that research is evolving.

A natural cycle FET may be ideal for a 32-year-old with regular cycles and a single vitrified blastocyst. An artificial cycle with GnRH agonist suppression may be the right choice for a 39-year-old with adenomyosis and a history of failed transfers. A modified natural cycle might be perfect for someone in between.

There is no cookbook. There is no one-size-fits-all protocol. If your clinic is recommending a specific approach without explaining why it is right for you specifically, that is a conversation worth having. Good questions to ask include:

Why are you recommending this protocol for my situation?

Am I a candidate for a natural or modified natural cycle?

Is GnRH agonist suppression necessary in my case, and why?

What does the research say about patients with my profile?

What will you monitor during the cycle, and what are the criteria for proceeding or canceling?

Your reproductive endocrinologist should be able to explain not just what they are recommending, but why it fits your individual clinical picture. If the answer is “this is just what we do,” that is worth pushing back on gently — because the best outcomes come from protocols matched to patients, not patients matched to protocols.

A Final Note

The study summarized on this page was published in 1999. Its core finding — that GnRH agonist suppression is not always necessary — has held up well. But the world of frozen embryo transfer has changed enormously since then. Vitrification has replaced slow freezing. Blastocyst transfer has replaced cleavage-stage transfer. PGT-A has become widely available. Natural cycle FET has been rehabilitated by large-scale studies showing it may be superior for many ovulatory patients. And the understanding of obstetric risks associated with artificial cycle protocols has grown.

All of this is to say: the question is no longer simply whether to use a GnRH agonist. It is which protocol — from a menu of well-studied options — is the right fit for this patient, at this moment, in this cycle.

That question deserves a thoughtful, individualized answer. And you deserve to understand the reasoning behind it. This is an INCIID Editorial Staff article, 2026 Peer-reviewed sources cited throughout. All medical decisions should be made in consultation with your reproductive endocrinologist.

Please contact us with your questions.

References

1. Simon A, et al. A flexible protocol for artificial preparation of the endometrium without prior GnRH agonist suppression in women with functioning ovaries undergoing frozen-thawed embryo transfer cycles. Fertility and Sterility. 1999;71(4):609-613.
2. Dmitrovic R, et al. Live birth rates in natural compared to artificial frozen blastocyst transfer cycles. Reproduction and Fertility. 2025;6(3):e240104.
3. Endometrial preparation methods prior to FET: a retrospective cohort study comparing true natural cycle, modified natural cycle and artificial cycle. PMC9470615. 2022.
4. GnRH agonist pretreatment prior to FET in women with adenomyosis: a systematic review and meta-analysis. Reproductive BioMedicine Online. June 2025.
5. Freezing of all embryos in IVF is beneficial in high responders, but not intermediate and low responders: an analysis of 82,935 cycles from the SART registry. PubMed. 2018.
6. ASRM Practice Committee. The use of preimplantation genetic testing for aneuploidy: a committee opinion. Fertility and Sterility. 2024.
7. ASRM Practice Committee. Guidance on the limits to the number of embryos to transfer. Fertility and Sterility. 2021.
8. Protocol-specific outcomes of GnRH agonist use in luteal phase support during FET cycles. International Journal of Women’s Health. 2025.
9. GnRH agonist vs antagonist in IVF/ET. PMC3442989.
10. Yi X, et al. GnRH agonist pretreatment in hormonal endometrial preparation: a comparison of two protocols for FET outcomes. Frontiers in Medicine. 2025.