Exogenous Progesterone as Ovulation Trigger (PRO-TRIGGER)

Exogenous Progesterone as Ovulation Trigger - a Pilot Study

The goal of this clinical trial is to learn whether the sudden administration of vaginal micronized progesterone during the late follicular phase can trigger an LH surge and reactivation of oocyte meiosis in healthy oocyte donors aged 18 to 33 undergoing a mild ovarian stimulation cycle. The main question it aims to answer is:

• Does progesterone administered in the late follicular phase induce an LH surge and subsequent oocyte meiosis reactivation?

Participants will:

• Undergo a mild ovarian stimulation with 75 IU of follitropn alfa
• Start vaginal micronized progesterone (400 mg every 12 hours) once at least one follicle reaches 15 mm
• Have blood samples collected to measure hormone levels before and after progesterone administration
• Undergo oocyte retrieval 35-36 hours after the progesterone trigger

This is a low-intervention, single-center pilot study including approximately 10 oocyte donors.

Study Overview

• Status: Not yet recruiting
• Conditions: Ovulation; Ovarian Function; Oocyte Maturation; Assisted Reproductive Treatments; Hormonal Response
• Intervention / Treatment: Drug: Vaginal micronized progesterone

Detailed Description

Ovulation is triggered by the sudden surge of gonadotropins, FSH and mainly LH, which occurs during the late follicular phase. This LH surge creates the environment for follicular eruption by increasing the activity of the proteolytic enzymes that weaken the ovarian wall leading to follicle rupture. However, the stimuli leading to the LH surge arises are not clear yet. The current scientific paradigm postulates that high levels of estradiol at the end of the follicular phase may, by positive feedback, stimulate the sudden release of gonadotropins. However, several factors seem to contradict this theory. Ovarian stimulation cycles with high doses of gonadotropins in high responders leads to high levels of estradiol in an early phase without incurring in ovulation until the late follicular phase. Thus, there may be a narrow window in the late follicular phase in which ovulation may occur. As such, the sustained high levels of estrogen in the late follicular phase could be responsible for the LH surge. Nevertheless, studies using high dose exogenous estradiol in late follicular phase showed that there was no impact on gonadotrophin surge or ovulation. On the other hand, studies based on ovarian stimulation cycles with letrozole, with much lowers serum estrogen levels, showed that the ovulatory peak occurs in the same way, even in the presence of very low or decreasing levels of estradiol. Interestingly, patients treated with letrozole may present higher levels of LH at peak. Hence, the role of estrogens in inducing the gonadotrophin peak is yet unclear.

Progesterone may eventually have a role in the physiological induction of ovulation. Long-standing studies have shown that an increase in serum progesterone levels precedes the LH peak and supports the action of the LH on the follicle rupture. Evidence has long shown that elevated serum progesterone levels during controlled ovarian stimulation are associated with a considerable risk of earlier ovulation. Likewise, previous studies have shown that the administration of intramuscular progesterone during the late follicular phase leads to the onset of an endogenous LH peak, both following controlled ovarian stimulation and in a natural cycle. Also supporting these theories is a new protocol of endometrial preparation for frozen embryo transfer presented by our research group. This strategy, in which, in an advanced follicular phase, after establishing adequate endometrial thickness on ultrasound, exogenous administration of vaginal micronized progesterone is started, simulating a second phase of the cycle, with endogenous production of estrogens and exogenous administration of progesterone. Curiously, in the first obstetric assessment the presence of an adnexal mass is frequently been noted, probably corresponding to a corpus luteum. If so, exogenous progestins may have acted as a possible trigger of ovulation.

Contrary to these theories is the fact that the exogenous administration of progestins for pituitary inhibition has been used for decades as a method of contraception. Thus, there may be a narrow window of time in the late follicular phase during which the pituitary gland is sensitive to the positive feedback effect of progesterone, leading to sudden release of gonadotropins. This may eventually be explained by the effect of the rising levels of estradiol during the follicular phase, which may prime the hypothalamus for a progesterone-induced gonadotropin surge. Another possibility is that sustained use of exogenous progestins may lead to desensitization of pituitary receptors, while in the presence of low serum progesterone levels, the receptors maintain sensitivity and the sudden increase of this hormone has a positive feedback effect on the pituitary gland.

Progestins may be administered by various routes. Vaginal micronized progesterone is a convenient form of administration and results in rapid and efficient absorption, with peak serum concentrations achieved within four to six hours.

With this study, the investigators intend to evaluate whether the sudden administration of exogenous progesterone may lead to LH peak, with resulting reactivation of oocyte meiosis.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ana Raquel Neves; Phone Number: +351 218 503 210; Email: Ana.Neves@ivirma.com
• Study Contact Backup: Name: Belisa Silva; Phone Number: +351 218 503 210; Email: Belisa.Silva@ivirma.com

Study Locations

• Portugal
  • Lisbon, Portugal, 1800-282
    • Instituto Valenciano de Infertilidade (IVI Lisboa)
    • Contact: Samuel Ribeiro; Phone Number: +351 218 503 210; Email: Samuel.Ribeiro@ivirma.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Informed Consent Form dated and signed correctly prior to the performance of any study procedure;
• Oocyte donors aged >17 and <34 years old in the moment of the recruitment;
• Patients with regular menstrual cycles (between 25 to 35 days long);
• Patients willing to participate in the study.

Exclusion Criteria:

• Presence of ovarian cyst(s) detected on the baseline (initial) ultrasound examination;
• Untreated endocrine conditions;
• Hypogonadotropic or hypergonadotropic hypogonadism;
• Any condition contraindicating the administration of vaginal progesterone;
• Any condition contraindicating vaginal ultrasound and/or vaginal oocyte retrieval;
• Participation in another ongoing clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Oocyte donors; This arm includes 10 healthy oocyte donors undergoing an ovarian stimulation cycle with 75 IU of recombinant FSH, followed by progesterone-induced ovulation triggering. All participants receive recombinant FSH starting on cycle days 1-3, following spontaneous mentsrual bleeding. Once at least one follicle reaches 15 mm, final oocyte maturation is induced with vaginal micronized progesterone 400 mg every 12 hours. Hormonal monitoring and ultrasound assessments are performed as part of standard care. Oocyte retrieval is performed 35-36 hours after "progesterone-induced ovulation triggering" by transvaginal aspiration. Progesterone will be kept until the morning of the day of oocyte retrieval.

Drug: Vaginal micronized progesterone; This intervention consists of administering vaginal micronized progesterone at a dose of 400 mg every 12 hours to induce final oocyte maturation. The intervention is initiated once at least one follicle reaches a diameter of 15 mm during controlled ovarian stimulation with recombinant FSH. Progesterone administration continues until the morning of oocyte retrieval.; Other Names: Cyclogest® 400 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of mature oocytes	The number of mature oocytes obtained during the oocyte retrieval procedure. Retrieved follicular aspirates will be examined to identify and isolate cumulus-oocyte complexes, which will be assessed for maturity according to standard embryology laboratory procedures. The count of mature oocytes reflects oocyte meiosis reactivation following progesterone-induced ovulation triggering.	35-36 hours after progesterone initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endocrinological profile (E2, P4, FSH, LH)	Serum hormone levels (estradiol, progesterone, FSH and LH) collected via blood sample (as part of standard clinical practice)	12 hours after progesterone initiation
Endocrinological profile (E2, P4, FSH, LH)	Serum hormone levels (estradiol, progesterone, FSH and LH) collected via blood sample (as part of standard clinical practice)	35-36 hours after progesterone initiation
Total number of oocytes retrieved	The total number of oocytes retrieved during the transvaginal oocyte aspiration procedure are counted. Oocyte retrieval is conducted according to routine clinical practice.	35-36 hours after progesterone initiation

Collaborators and Investigators

• Sponsor: Instituto Valenciano de Infertilidade de Lisboa
• Collaborators: Theramex
• Investigators: Principal Investigator: Ana Raquel Neves, Instituto Valenciano de Infertilidade (IVI Lisboa)

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 6, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Trigger; Progesterone; Oocyte Retrieval; Luteinizing Hormone; Oocyte Donation; Oocyte Maturation; LH Surge; Oocyte Meiosis; Late Follicular Phase; Endocrinological profile
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Corpus Luteum Hormones; Progesterone Congeners; Progesterone
• Other Study ID Numbers: 2504-LIS-054-AN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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