Progestin-suppressed in vitro fertilization cycles yield similar outcomes to traditional protocols in patients with diminished ovarian reserve.

Sara C. Pierpoint: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization. Allison M. Gonzalez: Data curation. Mary C. Peavey: Writing – review & editing, Writing – original draft. Christopher D. Williams: Writing – review & editing, Data curation. Laura P. Smith: Writing – review & editing, Data curation. Scott H. Purcell: Writing – review & editing, Data curation. Linnea R. Goodman: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

A total of 669 patients were included, with a mean age of 37.3 ± 4.1 years and an AMH level of 0.65 ± 0.3 ng/mL. The mean stimulation duration was 10.9 ± 2.3 days, with a total FSH dose of 449 ± 23.4 IU/day. Patients underwent an average of 4.6 ± 1.1 monitoring visits per cycle, with a peak serum estradiol level of 1479 ± 767 pg/mL. On average, 6.0 ± 3.9 oocytes were retrieved per cycle, of which 4.7 ± 3.1 were mature metaphase II oocytes. Among 100 cycles performed for planned oocyte cryopreservation, the mean yield was 7.5 ± 4.3 oocytes, with 5.7 ± 3.7 mature oocytes cryopreserved per cycle. Among the 569 cycles intended for embryo creation, 80.9% used ICSI, whereas the remainder underwent conventional insemination. This resulted in 3.4 ± 2.5 two-pronuclear embryos and 1.6 ± 1.7 blastocyst embryos per cycle. Preimplantation genetic testing for aneuploidy was performed in 78.0% (444/569) of cycles, yielding a mean of 0.7 ± 1.0 euploid embryos per cycle. There were 241 embryo transfers performed in 194 patients, comprising 29 fresh and 212 frozen transfers. A total of 266 embryos were transferred, with a mean of 1.1 ± 0.2 embryos per transfer. Among transfers, 71.0% (171/241) involved PGT-A tested embryos. The overall positive hCG rate was 65.6%, and the ongoing pregnancy rate was 54.8% per embryo transfer. Among transfers of PGT-A tested embryos, positive hCG and ongoing pregnancy rates were 70.5% and 63.0%, respectively. The MPA cohort included 315 cycles and the non-MPA cohort included 353 cycles (228 antagonist, 125 LF). There was no difference in age, but AMH values were significantly lower in the MPA group ( Table 1 ). There were no differences in the spread of infertility diagnoses or the length of infertility between groups. Cycle cancellation rates due to low ovarian response were similar (3.8% vs. 4.8%; P =.65). Premature ovulation occurred in 0% of MPA cycles compared with 1.4% (5 cases) in the non-MPA cohort ( P =.06). Table 1 Cycle statistics. Cycle specifics MPA (n = 315) Non-MPA (n = 353) P value Age (y) 37.2 (4.2) 37.5 (3.9) 0.34 AMH (ng/ml) 0.61 (0.34) 0.68 (0.32) 0.01 Visits (n) 4.1 (0.9) 5.1 (1.1) <.01 Days of stimulation 10.7 (2.0) 11.0 (2.4) .06 Total FSH dose (IU) 4787 (998) 4932 (1124) .09 Max estradiol level (pg/ml) 1514 (782) 1448 (752) .28 Oocytes retrieved (n) 6.4 (4.1) 5.7 (3.7) .01 Mature metaphase II oocytes 5.0 (3.2) 4.3 (3.0) .02 Patients growing to blastocyst n = 257 n = 312  2PNs 3.5 (2.5) 3.3 (2.5) .30  Blastocysts 1.8 (1.6) 1.5 (1.7) .10 Patients undergoing PGT-A n = 202 n = 242  Euploid blastocysts 0.8 (1.0) 0.7 (1.0) .58 Pregnancy data (all) n = 91 transfers n = 150 transfers  + hCG 64/91 (70.3%) 94/150 (62.7%) .28  Implantation 63/93 (67.7%) 89/171 (52.0%) .02  Ongoing clinical pregnancy 54/91 (59.3%) 78/150 (52.0%) .33  Biochemical pregnancy 4/91 (4.5%) 6/150 (4.0%) .85  Spontaneous abortion 6/91 (6.8%) 10/150 (6.7%) .81 Pregnancy data (PGT-A, FET) n = 74 transfers n = 99 transfers  + hCG 53/74 (71.6%) 69/99 (69.7%) .92  Implantation 52/74 (70.3%) 69/103 (66.9%) .74  Ongoing clinical pregnancy 45/74 (60.8%) 64/99 (64.6%) .72  Biochemical pregnancy 3/74 (4.1%) 1/99 (1.0%) .42  Spontaneous abortion 4/74 (5.5%) 4/99 (4.0%) .95 Note: Data depicted as n (%) or mean (±SD). AMH = antimüllerian hormone, FET = frozen embryo transfer; FSH = follicular stimulating hormone, hCG = human chorionic gonadotropin; MPA = medroxyprogesterone acetate; PN = pronuclei, PGT-A = preimplantation genetic testing for aneuploidy. Cycle statistics. Note: Data depicted as n (%) or mean (±SD). AMH = antimüllerian hormone, FET = frozen embryo transfer; FSH = follicular stimulating hormone, hCG = human chorionic gonadotropin; MPA = medroxyprogesterone acetate; PN = pronuclei, PGT-A = preimplantation genetic testing for aneuploidy. There was no difference in cycle length or amount of medication, but there was one less monitoring visit per cycle in the MPA group. Maximum estradiol levels were similar between cohorts, but there were more oocytes and mature oocytes retrieved per MPA cycle. There were similar rates of ICSI between groups, and the numbers of two-pronuclear, blastocyst and euploid blastocyst embryos created were similar between groups ( Table 1 ). A total of 91 embryo transfers were performed in the MPA group (93 embryos transferred) and 150 transfers in the non-MPA group (173 embryos transferred). Use of PGT-A was similar across groups (MPA 78.6% vs. non-MPA 77.6%; P =.85). However, all MPA transfers were frozen, whereas 19.3% of non-MPA transfers were fresh, resulting in a higher proportion of PGT-A tested embryo transfers in the MPA group (81.3% vs. 66.0%; P =.02). Concordantly, the number of embryos transferred per cycle was lower in the MPA group (1.0 ± 0.2 vs. 1.2 ± 0.4; P <.01). The positive serum hCG and ongoing pregnancy rates were similar between groups; however, the implantation rate (gestational sac per embryo transferred) was higher in the MPA group. When only evaluating PGT-A tested embryo transfers, all rates were similar ( Table 1 , Fig. 2 A). Biochemical pregnancy rates and spontaneous abortion rates were also similar between groups. There were three cases of a viable twin intrauterine pregnancy resulting from the transfer of a single euploid embryo in the MPA group and one in the non-MPA group. There were two double embryo transfers in the MPA group (both of untested embryos), resulting in one set of twins. In the non-MPA group, there were 15 double embryo transfers and three triple embryo transfers, resulting in one set of twins. Most of the multiple embryo transfers in the non-MPA group were untested in fresh embryo transfer cycles (15/18, 83.3%). Figure 2 Comparison of cycle characteristics and pregnancy outcomes between MPA and non-MPA protocols. ( A ) Pregnancy outcomes after PGT-A tested, frozen embryo transfers in MPA (n = 74) vs. non-MPA (n = 99) cycles. All comparisons were not statistically significant (NS). ( B ) Cycle-level differences in ovulatory suppression cost, number of injections, and number of monitoring visits per IVF cycle between MPA (n = 315) and non-MPA (n = 353) groups. Asterisks (∗) denote statistically significant differences ( P <.05). Cost values are compressed to preserve figure scaling; the actual mean cost for non-MPA was $459. Abbreviations: IVF = in vitro fertilization; MPA = medroxyprogesterone acetate; PGT-A = preimplantation genetic testing for aneuploidy. Comparison of cycle characteristics and pregnancy outcomes between MPA and non-MPA protocols. ( A ) Pregnancy outcomes after PGT-A tested, frozen embryo transfers in MPA (n = 74) vs. non-MPA (n = 99) cycles. All comparisons were not statistically significant (NS). ( B ) Cycle-level differences in ovulatory suppression cost, number of injections, and number of monitoring visits per IVF cycle between MPA (n = 315) and non-MPA (n = 353) groups. Asterisks (∗) denote statistically significant differences ( P <.05). Cost values are compressed to preserve figure scaling; the actual mean cost for non-MPA was $459. Abbreviations: IVF = in vitro fertilization; MPA = medroxyprogesterone acetate; PGT-A = preimplantation genetic testing for aneuploidy. Local and mail order pharmacy data showed an average self-pay cost of $6.44 ± $2.47 for a 10-day supply of generic oral MPA. Patients in the non-MPA group who used a GnRH antagonist to suppress ovulation averaged 5.3 ± 1.4 doses of daily injectable GnRH antagonist at an average self-pay price of $99.50 ± $12.14 per dose, equaling $572.35 ± $64.34 per cycle. Patients in the non-MPA group who used GnRH agonist as the method of ovulation suppression had an average of 11.9 ± 2.7 days of stimulation with twice daily administration of the injectable GnRH agonist, which cost $255.00 ± $53.20 for a vial that lasted through the cycle. Patients in the MPA group underwent an average of 11.9 ± 3.4 fewer injections and saved $453.53 ± 60.69 per cycle compared with non-MPA patients ( Fig. 2 B). In multivariate logistic regression controlling for age and AMH, treatment group (MPA vs. non-MPA) was not associated with obtaining a usable blastocyst (Odds ratio 1.26, 95% confidence interval [CI] 0.74–1.53). Similarly, in patients undergoing embryo transfer, controlling for age, AMH, and PGT-A treatment, group was not associated with clinical pregnancy rates (OR 0.98, 95% CI 0.50–1.94) ( Table 2 ). Table 2 Logistic regression analysis. Model effect Values OR (95% CI) Odds of having a usable blastocyst  Patient age Per year 0.89 (0.77–0.85)  AMH Per 1 ng/ml 1.56 (0.90–2.80)  Group MPA vs. non-MPA 1.26 (0.74–1.53) Odds of clinical pregnancy in those that underwent FET  Patient age Per year 1.14 (1.04–1.26)  AMH Per 1 ng/ml 0.65 (0.21–2.00)  PGT-A Yes vs. no 4.55 (2.23–9.53)  Group MPA vs. non-MPA 0.98 (0.50–1.94) Note: AMH = antimüllerian hormone, CI = confidence interval; FET = frozen embryo transfer; MPA = medroxyprogesterone acetate; OR = odds ratio; PGT-A = preimplantation genetic testing for aneuploidy. Logistic regression analysis. Note: AMH = antimüllerian hormone, CI = confidence interval; FET = frozen embryo transfer; MPA = medroxyprogesterone acetate; OR = odds ratio; PGT-A = preimplantation genetic testing for aneuploidy.

This was a cohort study conducted at a single academic-affiliated private fertility center (Virginia Fertility and IVF) between January 2021 and December 2024. Patient and cycle data were prospectively collected into a quality assurance database and retrospectively reviewed. This study was approved by the University of Virginia Institutional Review Board. Patients aged 18–45 years undergoing autologous oocyte cryopreservation and IVF cycles with a serum antimüllerian hormone (AMH) value <1.2 ng/mL (value chosen on the basis of the European Society of Human Reproduction and Embryology Bologna criteria ( 23 )) were eligible. All infertility diagnoses were included, such as severe male and uterine factor infertility. Cycles were excluded if they were planned natural or minimal stimulation cycles (defined as oral ovulation induction medications ± low-dose gonadotropins without intended high-response stimulation). Each cycle was categorized as either a MPA cycle, a GnRH antagonist cycle, or a microdose leuprolide flare (LF) cycle. The GnRH antagonist and LF cycles were grouped together as the non-MPA cohort. In this clinic during this period, there were no patients treated with the long-lupron ovulation suppression protocol, so that protocol was not included in the data collected. Protocol selection was by provider preference. Baseline demographic and infertility characteristics were recorded at the start of the cycle. Reproductive outcomes, including ovulatory suppression rates, cycle yields, embryo development (of those that created embryos), and pregnancy outcomes (of those that underwent frozen embryo transfer), were prospectively captured. Controlled ovarian hyperstimulation was performed with recombinant FSH and low-dose human chorionic gonadotropin (hCG) in all cycles. Low-dose hCG was chosen instead of recombinant LH analogues because of its lower cost and similar efficacy. Medication dosing was individualized on the basis of patient-specific factors, including AMH level, antral follicle count, and prior cycle responses. All patients underwent baseline transvaginal ultrasound and serum estradiol measurement at the start of the IVF cycle. Generally, ovarian stimulation began on cycle day 3, designated as stimulation day 1. • In MPA cycles, patients initiated oral MPA (10 mg daily) on stimulation day 1. The first monitoring ultrasound and laboratories occurred on stimulation day 6, with subsequent monitoring as clinically indicated. • In non-MPA cycles, the first monitoring visit was scheduled on stimulation day 4 (to assess for antagonist initiation) or day 5 (LF protocol), with additional visits as needed. Ovulatory suppression was achieved with subcutaneous GnRH antagonist (ganirelix or cetrotide) when the lead follicle reached 12–14 mm or estradiol exceeded 400–500 pg/mL (antagonist cycles) or for LF cycles, microdose leuprolide injections were initiated twice daily beginning on cycle day 2, before starting gonadotropins ( Fig. 1 ). Figure 1 Schematic of MPA and non-MPA IVF cycles. Abbreviations: IVF = in vitro fertilization; MPA = medroxyprogesterone acetate. In MPA cycles, patients initiated oral MPA (10 mg daily) on stimulation day 1. The first monitoring ultrasound and laboratories occurred on stimulation day 6, with subsequent monitoring as clinically indicated. In non-MPA cycles, the first monitoring visit was scheduled on stimulation day 4 (to assess for antagonist initiation) or day 5 (LF protocol), with additional visits as needed. Ovulatory suppression was achieved with subcutaneous GnRH antagonist (ganirelix or cetrotide) when the lead follicle reached 12–14 mm or estradiol exceeded 400–500 pg/mL (antagonist cycles) or for LF cycles, microdose leuprolide injections were initiated twice daily beginning on cycle day 2, before starting gonadotropins ( Fig. 1 ). Figure 1 Schematic of MPA and non-MPA IVF cycles. Abbreviations: IVF = in vitro fertilization; MPA = medroxyprogesterone acetate. Schematic of MPA and non-MPA IVF cycles. Abbreviations: IVF = in vitro fertilization; MPA = medroxyprogesterone acetate. Final oocyte maturation was triggered when at least two follicles reached ≥18 mm mean diameter, using either subcutaneous hCG (5,000 or 10,000 IU) and GnRH agonist trigger (leuprolide 4 mg) (for MPA and antagonist cycles), or only hCG in LF cycles. Oocyte retrieval was performed under transvaginal ultrasound guidance 35 hours after trigger injection/s. • Mature oocytes were frozen on the day of retrieval in oocyte cryopreservation cycles. • For embryo creation, oocytes underwent either intracytoplasmic sperm injection (ICSI) or conventional insemination, as clinically indicated, with culture to the blastocyst stage. • Blastocysts were either cryopreserved on day 5 or 6, biopsied for preimplantation genetic testing for aneuploidy (PGT-A) and cryopreserved, or transferred fresh when clinically appropriate. Blastocysts were considered usable if they were suitable for cryopreservation and/or transfer (graded as ‘good’ or ‘fair’ by morphologic evaluation if not genetically tested and euploidy status if underwent PGT-A). Mature oocytes were frozen on the day of retrieval in oocyte cryopreservation cycles. For embryo creation, oocytes underwent either intracytoplasmic sperm injection (ICSI) or conventional insemination, as clinically indicated, with culture to the blastocyst stage. Blastocysts were either cryopreserved on day 5 or 6, biopsied for preimplantation genetic testing for aneuploidy (PGT-A) and cryopreserved, or transferred fresh when clinically appropriate. Blastocysts were considered usable if they were suitable for cryopreservation and/or transfer (graded as ‘good’ or ‘fair’ by morphologic evaluation if not genetically tested and euploidy status if underwent PGT-A). Primary outcomes included premature ovulation rate (defined as follicular collapse on ultrasound with free fluid within the cul-de-sac, progesterone >3.0 ng/mL [for antagonist or LF cycles], or no oocytes retrieved despite laboratory confirmation of a trigger [positive hCG, LH >20 IU/mL, progesterone >3.0 ng/mL and absence of previously identified follicles]), number of mature oocytes retrieved, and ongoing pregnancy rate (defined as fetal cardiac activity at >8 weeks of gestations) per embryo transfer. Secondary outcomes included blastocyst and euploid embryo yield (for those creating embryos), implantation rate (defined as visualization of gestational sac on ultrasound per embryo transferred), biochemical pregnancy rate (positive hCG followed by resolution without ultrasound evidence of pregnancy), miscarriage rate (pregnancy loss after confirmed ultrasound visualization of pregnancy), number of monitoring visits per cycle, and medication costs. Medication cost was calculated by multiplying the number of ovulation suppression doses by pharmacy per-dose pricing (for antagonists and agonists). The MPA costs were estimated on the basis of an average of quotes from seven national chain pharmacies. On the basis of power calculations from previous studies comparing the then novel GnRH antagonist method of ovulation suppression vs. standard GnRH agonist methods in the early 2000s ( 4 ) and on rates of 4%–7% of occurrence of premature ovulation in low responding IVF patients reported in existing studies ( 24 ), we used a two-sided Fisher’s exact test with α = 0.05 and 80% power to detect a statistically significant difference. Under these assumptions, approximately 300 participants per group would be required. Four years of planned data collection was estimated to reach that number on the basis of clinic volume. Descriptive statistics summarized demographic and cycle characteristics. Continuous variables were compared using Student’s t -test and categorical variables were analyzed using χ 2 or Fisher’s exact test, as appropriate. Multivariable logistic regression was used to assess the independent effects of patient age, AMH, use of PGT-A, and treatment group on embryo availability and clinical pregnancy outcomes. Statistical analyses were performed using Microsoft Excel and GraphPad Prism version 10.0.2. A two-tailed P <.05 was considered statistically significant.

In patients with DOR, the progestin-suppressed IVF protocol achieved comparable clinical outcomes to traditional suppression methods, with added benefits of reduced injections, lower medication costs, and fewer monitoring visits. These findings support the integration of progestin-based suppression as a cost effective, patient-friendly alternative in this vulnerable population.

This study demonstrates that the progestin-suppressed IVF protocol yields comparable reproductive outcomes to traditional GnRH antagonist and microdose flare protocols in patients with DOR. Importantly, the progestin protocol offered additional advantages of reduced clinic visits, lower medication costs, and decreased injection burden without compromising pregnancy rates. Prior studies have evaluated progestin-suppressed ovarian stimulation primarily in general IVF populations ( 3 , 25 ) or specific subgroups such as predicted high responders ( 13 , 26 ), oocyte donors ( 14 , 15 ), patients undergoing fertility preservation ( 16 ), and those with endometriosis ( 17 ). Overall, these studies reported equivalent oocyte yields, embryo development, and pregnancy outcomes compared with antagonist protocols, with the added benefits of improved patient experience and cost savings. Wang et al. ( 13 ) performed one of the first randomized controlled studies in 2016 comparing outcomes in 120 women with polycystic ovary syndrome and found that the number of oocytes retrieved between MPA and antagonist groups was similar, with the MPA group experiencing higher ongoing pregnancy rates. Similar to the conversion from agonist to antagonist cycles, early small studies of progestin protocols encountered some mixed results, slowing momentum. In another of the early randomized controlled trials, Begueria et al. ( 14 ) in 2019 investigated the progestin-suppressed protocol in 173 oocyte donation cycles and found that MPA and GnRH antagonist cycles yielded similar metaphase II oocytes retrieved (15.1 ± 8.3 vs. 14.6 ± 7.0, P >.05), but when transferred to recipients, had lower ongoing pregnancy rates (27% vs. 40%, P =.02), but similar live birth rates ( 14 ). In 2021, Zhu et al. ( 25 ) again investigated MPA within a polycystic ovary syndrome population and with a randomized controlled trial of a MPA vs. GnRH antagonist protocol found no difference in outcomes, including number of oocytes retrieved (4.6 ± 7.6 vs. 12.8 ± 8.6, P >.05) and viable embryos created (5.4 ± 3.5 vs. 5.0 ± 3.9; P >.05). In a more inclusive IVF patient population, Welp et. al ( 3 ) in 2024’s prospective cohort trial compared the outcomes of MPA with a GnRH antagonist protocol and found no difference in oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P =.83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P =0.89) created, or clinical pregnancy rate (70.4% vs. 64.2%, RR = 0.92; 95% CI: 0.72−1.18). Despite a growing body of supporting literature, data on progestin protocols in patients with DOR have been limited. In one randomized controlled trial of poor responders, Chen et al. ( 27 ) demonstrated that progestin-suppressed stimulation resulted in lower rates of premature LH surge (0 vs. 5.88%, P .05) and comparable live birth rates relative to antagonist protocols. A 2023 meta-analysis including 14 retrospective cohort studies encompassing over 4,000 Chinese patients with DOR found that progestin-suppressed protocols improved clinical pregnancy rates and reduced cycle cancellation rates compared with letrozole-based minimal stimulation protocols ( 22 ). This study builds on these findings by demonstrating that in a contemporary DOR cohort with most of frozen, genetically tested, blastocyst transfers, the progestin-suppressed protocol is not only effective but also associated with significant reductions in the logistical and financial burden of IVF. The MPA group required fewer visits, had lower ovulation suppression costs, and experienced fewer injections per cycle, all while achieving similar rates of oocyte retrieval, blastocyst development, and clinical pregnancy compared with standard protocols. Interestingly, in multivariate modeling, when accounting for AMH, PGT-A and group, odds of clinical pregnancy were counterintuitively higher with increasing age. This could be attributed to the much higher percentage of women adopting PGT-A as they age or possibly there may be an underlying pathophysiologic mechanism, separate from euploidy, distinguishable on current genetic testing platforms, that deleteriously affects the chance of pregnancy in younger women with DOR. Further studies are needed to parse out this relationship. Concurrently, the mean age of this study population was relatively young at 37 years, and future studies could focus on older women to see if these results translate to that population. Dual-stimulation protocols have been described in DOR patients to increase outcomes by performing an immediate second stimulation in the high-progesterone environment after a stimulation and retrieval cycle. Studies have been mixed regarding clinical outcomes and it does require labor-intensive back-to-back cycles ( 21 , 28 , 29 ). Using the progestin-suppressed protocol gives the benefit of flexible scheduling with the ability to initiate stimulation at any point during the menstrual cycle and at any proximity to a previous stimulation. This is supported by Braham et al. ( 16 ), who reported successful use of progestins to inhibit premature ovulation for random start cycles in fertility preservation, and is gaining popularity as freeze-all strategies predominate. Strengths of this study include its prospective collection of data, broad inclusion criteria, and focus on a clinically relevant low-responder population. Consistency in clinical and laboratory practices within a single center also strengthens the internal validity of the findings. Limitations include the nonrandomized design, which may introduce selection bias despite similar baseline characteristics between groups. In addition, no specific selection criteria were used to determine protocol, so practice patterns evolved during the study period, with increased use of MPA protocols over time, potentially introducing temporal confounders. This is evidenced by the lower number of total transfers in the MPA group, because the MPA cohort was skewed to the later part of the study with less time to accrue transfer data. As such, future randomized controlled trials are necessary to confirm these findings. Another limitation is that only AMH was used as the primary ovarian reserve marker, and integration with other markers, such as antral follicle count, could have provided a more comprehensive assessment. However, overall cycle yield data did support the accuracy of initial DOR assessment on the basis of this one marker. Finally, the requirement for frozen embryo transfer in MPA cycles may limit applicability for patients prioritizing fresh transfer strategies and that influenced study results here, in that there were only fresh transfers in the non-MPA group. However, when excluding these patients from analysis, pregnancy rates are comparable between protocols when similar situations are compared. Despite similar yields between protocols and cost savings realized from visits and medications, a freeze-all strategy does increase costs over traditional fresh transfer cycles. In a population with lower ovarian reserve who may not have many embryos to select from, an untested fresh embryo transfer may remain the most cost-effective option. These findings suggest that progestin-suppressed protocols offer a compelling option for patients with DOR, particularly given their lower treatment burden. As freeze-all strategies and elective cryopreservation become increasingly common in modern IVF, the flexibility and efficiency offered by oral progestin suppression may further enhance individualized patient care. Future randomized trials specifically targeting DOR populations are warranted to confirm these findings and to explore whether broader reductions in monitoring frequency and stimulation customization could be safely implemented in this subgroup.

During the preparation of this work, the authors used ChatGPT to review for grammar and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

In vitro fertilization (IVF) is based on two essential components which are as follows: ( 1 ) the administration of exogenous gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), to stimulate and mature multiple ovarian follicles, and ( 2 ) the concurrent suppression of a premature LH surge to prevent spontaneous ovulation. Historically, this ovulatory suppression has been achieved using injectable gonadotropin-releasing hormone (GnRH) analogues, either agonists or antagonists. More recently, oral progestins have emerged as an alternative method for ovulation suppression during stimulation ( 1 ). These agents offer several practical advantages: they are less costly, administered orally rather than via injection, can be taken at the same time as other medications, and are generally more patient friendly ( 2 , 3 ). The evolution of IVF protocols offers historical precedent for the gradual adoption of novel methods. In the early 2000s, the field witnessed a transition from GnRH agonist-based suppression to the use of GnRH antagonists. Initially, GnRH agonist protocols were considered the gold standard; however, accumulating data began to show that antagonist protocols offered comparable efficacy with reduced risk of ovarian hyperstimulation syndrome and improved cycle flexibility ( 4 ). With many shifts in clinical practice, uptake was initially slow, in part because of mixed results in smaller studies ( 5 ). Ultimately, the publication of large randomized controlled trials, first in egg donors and then in a more generalized patient population, solidified the antagonist protocol’s role, and by the mid-2000s, it had become the preferred first-line strategy in many centers ( 4 , 6 ). This pattern of gradual adoption closely mirrors the current trajectory of the progestin-suppression (or also known as progestin-primed ovarian stimulation) protocol. The concept of using progestins to block the LH surge is not new. Foundational primate studies from the 1980s demonstrated that progesterone could inhibit the estradiol-induced gonadotropin surge by acting at the hypothalamic level ( 7 , 8 ). Despite this early insight, the clinical application of progestins for ovulation suppression in IVF was limited for decades because of concerns about endometrial receptivity, particularly in the context of fresh embryo transfers ( 9 , 10 ). However, with the increasing use of elective freeze-all strategies and improvements in cryopreservation, these barriers have largely been overcome ( 11 , 12 ). In 2015, Kuang et al. ( 1 ) were among the first to describe the successful use of oral medroxyprogesterone acetate (MPA) for ovulation suppression in oocyte donors undergoing IVF, showing outcomes comparable with GnRH antagonist protocols. Subsequent studies validated its efficacy across broader IVF populations, and progestins such as MPA, dydrogesterone, and micronized progesterone have all been shown to be effective and well-tolerated, with similar clinical outcomes to standard suppression methods ( 13 , 14 , 15 , 16 , 17 , 18 , 19 ). The progestin-suppressed protocol has consistently been shown to be cost effective, well-tolerated, and comparable in outcome with antagonist protocols ( 3 , 6 , 20 ). However, as in previous eras, patients with diminished ovarian reserve (DOR), who represent a more vulnerable and challenging subgroup due to their limited follicular pool, have typically been excluded from early trials and are often the last to be studied in emerging protocols ( 21 , 22 ). Notably, patients with DOR who often have a higher care burden because of the need for multiple IVF cycles may especially benefit from a protocol that offers fewer clinical visits, injections, and/or lower medication costs. This study aims to evaluate the safety and efficacy of the progestin-suppressed protocol in this anticipated low-responder population.

S.C.P. has nothing to disclose. A.M.G. has nothing to disclose. M.C.P. has nothing to disclose. C.D.W. has nothing to disclose. L.P.S. has nothing to disclose. S.H.P. has nothing to disclose. L.R.G. has nothing to disclose.