E.N.D.E.A.V.O.R.: An Exemestane Needed Dose Efficacy and Verification as an Ovulation Induction Regimen Study (ENDEAVOR)

The goal of this clinical trial is to learn if study drug exemestane will increase chances of ovulation for patients with polyendocrine metabolic ovarian syndrome (PMOS, formerly called polycystic ovary syndrome (PCOS)). It will also learn about side effects of study drug exemestane in this study population. The main questions it aims to answer are:

Does exemestane lead to ovulation for patients with polyendocrine metabolic ovarian syndrome (PMOS- formerly called PCOS)?

Researchers will compare exemestane to a placebo (a look-alike substance that contains no drug) to see if exemestane helps PMOS patients ovulate.

Participants will:

Take exemestane or a placebo every day for 5-10 days Visit the clinic three times for ultrasounds, labs, and to answer questions about side effects.

If they become pregnant during this study, they will tell us how their pregnancy went after the study via a registry online.

Study Overview

• Status: Not yet recruiting
• Conditions: Poly Cystic Ovary Syndrome
• Intervention / Treatment: Drug: Exemestane 25 MG; Drug: Exemestane 50 MG; Drug: Placebo

Detailed Description

Polycystic ovarian syndrome (PCOS/PMOS) is the leading cause of anovulation and infertility in reproductive age females in the United States with an overall incidence of 7-12% (1-2). The prevalence of subfertility ranges from 20-40% in women diagnosed with PCOS/PMOS (3). While the exact pathogenesis of PCOS/PMOS remains unknown, the symptoms of PCOS/PMOS are thought to be caused by abnormal elevated levels of androgens, which in turn interfere with the normal function of the ovaries (4). PCOS/PMOS is diagnosis of exclusion using the Rotterdam Criteria, which requires the presence of two out of the three from the following: oligomenorrhea/amenorrhea, polycystic ovaries on ultrasound, and clinical or biological hyperandrogenism (hirsutism or lab findings) (5).

First-line treatment of infertility in women with PCOS/PMOS focuses on ovulation induction using different medications that target the hypothalamic-pituitary axis. Current available treatment options include clomiphene citrate, a selective estrogen receptor modulator, and letrozole, a third-generation aromatase inhibitor. A 2014 landmark study by Legro et al demonstrated that letrozole was associated with higher live-birth and ovulation rate compared to clomiphene citrate (6). The study found that ovulation rates with letrozole were around 60% compared to clomiphene citrate at 48%. Women who fail treatment with clomiphene citrate or letrozole are left with minimal options for ovulation induction, often requiring more expensive and invasive infertility treatments, such as ovarian drilling or IVF (6). A 2019 study by Mejia et al in 2019 compared letrozole and clomiphene for treating infertility in women with PCOS/PMOS, using progesterone levels as the primary outcome, consistent with the approach planned for this study (9).

From the literature review, no studies have examined exemestane- a relatively newer third generation aromatase inhibitor used to treat hormone responsive breast cancer in postmenopausal women - and its potential for ovulation induction (7). Aromatase inhibitors, including letrozole and exemestane, work by preventing aromatase from converting androgens into estrogen, resulting in overall decreased synthesis of endogenous estrogen (7). This results in inhibition of the negative feedback loop of estrogen on the hypothalamus resulting in increased gonadotropin releasing hormone (GnRH) pulses, which stimulates the pituitary to produce more follicle stimulating hormone (FSH) resulting in development of dominant follicles in the ovaries (4).

Letrozole, a triazole derivative, is a reversible non-steroidal aromatase inhibitor that binds to the cytochrome P-450 component of the aromatase enzyme and occupies its substrate-binding site. This is considered reversible because letrozole can be competitively displaced from this site by endogenous substrate (8). Exemestane, a androstenedione derivative, is an irreversible steroidal aromatase inhibitor (7). Exemestane is recognized by aromatase as an alternative substrate and converted into a reactive intermediate which binds irreversibly to the substrate-binding site, resulting in permanent inactivation of aromatase (8). This difference in interaction with aromatase has the potential to lead to divergent effects, with the potential for exemestane to provide an alternative ovulation induction therapy for women with PCOS/PMOS who have failed letrozole.

Letrozole is a reversible non-steroidal aromatase inhibitor, while exemestane is an irreversible steroidal aromatase inhibitor. Exemestane binds permanently to the aromatase enzyme, potentially leading to more sustained suppression of estrogen and a different hormonal profile than letrozole. Because of this mechanistic difference, direct dose equivalency is not established, and dose exploration is necessary.

To support the investigation of exemestane for ovulation induction in women with polycystic ovary syndrome/ polyendocrine metabolic ovarian syndrome (PCOS/PMOS), an Investigational New Drug (IND) application (#180400) has been submitted to and received by the U.S. Food and Drug Administration (FDA). Receipt of this IND permits the conduct of this clinical investigation under FDA oversight and confirms that the proposed study design, dosing strategy, and safety monitoring plan are acceptable for evaluation of exemestane in this investigational indication. All study procedures will be conducted in compliance with applicable FDA regulations, Good Clinical Practice (GCP) guidelines, and institutional review board (IRB) requirements.

This study looks to examine three exemestane dosing regimens:

• 25 mg for 5 days
• 25 mg for 10 days
• 50 mg for 5 days These doses are chosen to explore both dose intensity (25 vs. 50 mg) and duration of exposure (5 vs 10 days), similar to how letrozole is used in ovulation induction, typically 2.5-7.5 mg daily for 5 days.

Dose selection was constrained by the commercially available breast cancer formulations (25 mg and 50 mg), which necessitated evaluation at these dose levels. Within this framework, the study examines both dose intensity and duration of exposure, similar to established short course dosing strategies used with letrozole in ovulation induction. This study will use a randomized control trial to evaluate if exemestane will lead ovulation in women with infertility secondary to PCOS/PMOS. Using the Rotterdam Criteria, the study would include a small cohort of females aged 18-40 with a diagnosis of PCOS/PMOS with no other causes of infertility. Study participants would either undergo ovulation induction with exemestane at differing dose ranges or with placebo. The primary outcome would be ovulation, defined as midluteal serum progesterone concentration greater than or equal to 3 ng/mL. This pilot study will evaluate if exemestane leads to ovulation as measured by midluteal phase progesterone levels. Progesterone is a hormone produced by the corpus luteum following the release of an egg during ovulation. Its presence in the bloodstream, particularly at elevated levels, serves as a reliable indicator that ovulation has occurred. Measuring serum progesterone around day 21 of a typical menstrual cycle corresponds with the mid-luteal phase, when progesterone levels naturally peak. A threshold of ≥ 3 ng/mL is widely recognized in both clinical and research settings as a biochemical marker of ovulation. This method is minimally invasive, cost-effective, and broadly accessible, making it a practical and validated endpoint for evaluating the efficacy of ovulation induction agents.

Exemestane belongs to the class of medications known as aromatase inhibitors, the same class of medications as letrozole, and they prevent converting androgens into estrogen. This removes negative feedback on the hypothalamus resulting in increased GnRH pulses, which stimulates the pituitary to produce more FSH resulting in development of dominant follicles in the ovaries (4).

While letrozole is a reversible non-steroidal aromatase inhibitor that binds to the cytochrome P-450 component of the aromatase enzyme, exemestane is an irreversible steroidal aromatase inhibitor (7). Exemestane is recognized by aromatase as an alternative substrate and converted into a reactive intermediate which binds irreversibly to the substrate-binding site, resulting in permanent inactivation of aromatase (8). This difference in interaction with aromatase has the potential to lead to divergent effects, with the potential for exemestane to provide an alternative ovulation induction therapy for women with PCOS/PMOS who have failed letrozole.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Raleigh, North Carolina, United States, 27617
      • UNC Fertility
      • Contact: Bruce D Pier, MD; Phone Number: 919-908-0000; Email: bruce_pier@med.unc.edu
      • Sub-Investigator: Chelsea Grinnan, BS
      • Sub-Investigator: Vanessa Miller, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Premenopausal female (ages 18-40);
• Undergone an evaluation for infertility at UNC Fertility;
• Previously diagnosed with polycystic ovary syndrome/ polyendocrine metabolic ovarian syndrome (PCOS/PMOS) via established clinical diagnostic criteria with no other identifiable cause of infertility (example- endometriosis, uterine fibroids), and recommended to begin ovulation induction therapy;
• Have patent fallopian tubes on hysterosalpingogram;
• Male partners must have a normal semen analysis if presenting with a male partner;
• Individuals must be ovulation induction naïve (no history of use of ovulation induction medications);
• Individuals must be able to read, speak, and understand English or Spanish sufficiently to provide informed consent and participate in study procedures.

Exclusion Criteria:

Any individual who meets one or more of the following criteria will be excluded from participation:

• Under 18 or over 40 years of age; Individuals without the diagnosis of PCOS;
• Body mass index >40 kg/m^2; Abnormal hysterosalpingogram;
• Abnormal semen analysis if presenting with a male partner;
• History of ovulation induction medication use;
• Allergy to exemestane;
• Individuals with abnormalities of Pap smear or breast examination;
• Pregnant females;
• Individuals with moderate to severe renal impairment;
• Individuals with moderate to severe hepatic impairment;
• Currently taking any of the following medications due to known or potential interactions with exemestane: Cytochrome P-450 3A4 (CYP3A4), Everolimus (Afinitor), Apixaban (Eliquis), Rivaroxaban (Xarelto), Aspirin, Diphenhydramine (Benadryl), Rosuvastatin (Crestor), Duloxetine (Cymbalta), Escitalopram (Lexapro), Atorvastatin (Lipitor), Pregabalin (Lyrica), Metoprolol, Semaglutide (Ozempic), Levothyroxine (Synthroid), Ondansetron (Zofran), Goserelin (Zoladex);
• Individuals who require a Legally Authorized Representative (LAR) to provide consent on their behalf;
• Difficulty or inability to swallow solid dosage forms (tablets/capsules of study drug)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PMOS (PCOS) patients taking 25mg for 5 days; Participants in this arm will take one tablet of study drug for 5 days	Drug: Exemestane 25 MG; Experimental Drug; Other Names: Aromasin
Experimental: 50mg Exemestane for 5 days; Participants in this arm will take two tablets of study drug for 5 days	Drug: Exemestane 50 MG; One study arm with take two tablets for 5 days (50mg per day)
Experimental: 25mg Exemestane for 10 days; Participants in this arm will take one tablet of study drug for 10 days	Drug: Exemestane 25 MG; Experimental Drug; Other Names: Aromasin
Placebo Comparator: Placebo; Participants in this arm will take placebo for 5 days	Drug: Placebo; Placebo drug that patients in placebo arm will take

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with study-defined positive progesterone levels on Day 21	The primary outcome of this study will be positive day 21 progesterone levels (positive level >/= 3 ng/mL).	day 21 of menstrual cycle that patient receives study intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of follicles greater than 10 millimeters	Mid-follicular ultrasound where ovarian follicles are measured for diameter. Any follicle with diameter >10mm will be reported.	within 2 weeks of starting study intervention
Mean Diameter of All Follicles >10mm	During mid-follicular ultrasound- all ovarian follicles are measured for diameter. All follicle diameters greater than 10mm in average will be reported with size reported.	within 2 weeks of starting study intervention
Endometrial thickness in millimeters measured by mid-follicular ultrasound	During mid-follicular ultrasound, a single image of endometrial thickness will be acquired during mid-follicular measurement, and reported in size of millimeters.	within 2 weeks of starting study intervention
Percentage of participants with a positive human chorionic gonadotropin (hCG) result	Percentage of participants who initiated treatment that report a positive human chorionic gonadotropin (hCG) level, as verified with hCG laboratory measurement.	within 3 weeks of finishing study intervention
Clinical pregnancy	Percentage of participants who initiated treatment that have ultrasound evidence of a gestational sac with fetal cardiac activity.	up to 3 months for whose participation results in a pregnancy
Live birth	Percentage of participants who initiated treatment that have live birth of an infant.	up to 12 months for whose participation results in a pregnancy

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: Bruce Pier, MD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010 Jun 30;8:41. doi: 10.1186/1741-7015-8-41.
• Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018 Aug;110(3):364-379. doi: 10.1016/j.fertnstert.2018.05.004. Epub 2018 Jul 19.
• Mejia RB, Summers KM, Kresowik JD, Van Voorhis BJ. A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2019 Mar;111(3):571-578.e1. doi: 10.1016/j.fertnstert.2018.11.030. Epub 2019 Jan 22.
• Miller WR, Bartlett J, Brodie AM, Brueggemeier RW, di Salle E, Lonning PE, Llombart A, Maass N, Maudelonde T, Sasano H, Goss PE. Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist. 2008 Aug;13(8):829-37. doi: 10.1634/theoncologist.2008-0055. Epub 2008 Aug 11.
• Geisler J. Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole--of clinical importance? Br J Cancer. 2011 Mar 29;104(7):1059-66. doi: 10.1038/bjc.2011.58. Epub 2011 Mar 1.
• Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517.
• Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014 Feb 24;(2):CD010287. doi: 10.1002/14651858.CD010287.pub2.
• Balen A, Michelmore K. What is polycystic ovary syndrome? Are national views important? Hum Reprod. 2002 Sep;17(9):2219-27. doi: 10.1093/humrep/17.9.2219.
• Collee J, Mawet M, Tebache L, Nisolle M, Brichant G. Polycystic ovarian syndrome and infertility: overview and insights of the putative treatments. Gynecol Endocrinol. 2021 Oct;37(10):869-874. doi: 10.1080/09513590.2021.1958310. Epub 2021 Aug 2.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: July 10, 2026
• First Submitted That Met QC Criteria: July 10, 2026
• First Posted (Actual): July 15, 2026

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: July 10, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: aromatase; ovulation; androgen
• Additional Relevant MeSH Terms: exemestane
• Other Study ID Numbers: 25 1427

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: beginning 9 and continuing for 36 months following publication
• IPD Sharing Access Criteria: Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No