Ovulation Incidence in Oral Contraceptive Users

Since the introduction of the combined hormonal contraceptive pill, dosages of ethinyl estradiol (EE) have steadily decreased from more than 150mcg to 20mcg in an attempt to improve the risk profile associated with the COC. In 2010, the Food and Drug Administration approved a oral contraceptive pill containing EE 10mcg/NET acetate 1mg (Tradename Lo loestrin). However, no studies have compared this formulation to pills containing either higher doses of estrogen or progestin alone. It is not known whether EE 10mcg is sufficient to prevent follicular development or to support the endometrium as well as higher doses of EE. This trial addresses the question of whether an oral contraceptive pill with EE 10mcg/Norethindrone acetate 1mg will better suppress ovulation or have a better side effect profile than a progestin only pill with a nearly equal dose of norethindrone.

Study Overview

• Status: Completed
• Conditions: Contraception; Ovulation
• Intervention / Treatment: Drug: Ethinyl Estradiol, Norethindrone acetate, ferrous fumarate; Drug: Norethindrone

Detailed Description

Use of combined hormonal contraceptives (CHC) containing estrogen is associated with venous thromboembolic events. In an effort to decrease the risks of estrogen, the dose of ethinyl estradiol (EE) contained in combined oral contraceptive (COC) pills has decrease substantially from >100mcg to 20mcg. In 2012, a COC with only 10mcg of EE (Tradename LoLoestrin) was approved by the Food and Drug Administration. However, no studies have compared this formulation to pills containing progestin alone to determine if this very low dose of EE decreases ovulation or improves unscheduled uterine bleeding beyond what is seen with a progestin only pill (POP).

We aim to compare a COC with EE 10mcg/norethindrone (NET) acetate 1mg to a POP containing a nearly equal amount of progestin (norethindrone 1.05mg). The objective of the study is to compare the incidence of ovulation among users of a COC with only EE10mcg/NET acetate 1mg to users of a POP with a nearly identical progestin dose of NET 1.05mg. We plan to recruit 58 women between the ages of 18 and 45 years old, who are ovulatory at baseline based on serum progesterone levels. Subjects will be randomized to take either a COC containing EE 10mcg/NET acetate 1mg or a POP containing NET 1.05mg for one month. During the month of study treatment, we will measure ovulation incidence using a single serum progesterone levels of >=4.0ng/dl, sperm penetration of cervical mucus using the Eggert Kruse classification system, pill compliance by NET serum levels, and side effects including unscheduled uterine bleeding via subject daily diaries.

Our primary outcome, ovulation incidence, will be compared between study arms. Secondary outcomes will compare cervical mucus quality, sperm penetration of cervical mucus, side effects (including uterine bleeding), and pill compliance between users of these two pills.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90065
      • Brian T. Nguyen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Reproductive aged women 18-45 years old.
• Menstrual cycle length 25-35days
• BMI less than or equal to 40
• English or Spanish speaking

Exclusion Criteria:

• Pregnant or breastfeeding in the previous 3 months.
• Use of OC, hormonal vaginal rings or patches, levonorgestrel containing intrauterine device, or etonogestrel implant in the previous 1 month. No use of depot medroxyprogesterone acetate (DMPA) injection in the previous 6 months and at least one menses since discontinuation.
• Medical contraindications to estrogen or progestin use. Specifically: smoking among participants over 35 years old, migraines with aura, history of blood clots, ischemic heart disease, stroke, breast cancer, cervical cancer, liver disease, symptomatic gallbladder disease, uncontrolled hypertension, antiphospholipid antibody syndrome, hyperlipidemia, diabetes with end organ damage (retinopathy, nephropathy, neuropathy) or diagnosis >20 years ago, organ transplant
• Desire to become pregnant in the next 4 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Combination oral contraceptive pill; Ethinyl Estradiol 10mcg/Norethindrone acetate 1mg/ferrous fumarate 75mg Taken cyclically as 24 tablets containing EE 10mcg/NET acetate 1mg 2 tablets of EE 10mcg only 2 tablets of ferrous fumarate 75mg	Drug: Ethinyl Estradiol, Norethindrone acetate, ferrous fumarate; Combination Oral Contraceptive Pill. Ethinyl Estradiol 10mcg/Norethindrone acetate 1mg/ferrous fumarate 75mg; Other Names: Loestrin
Experimental: Progestin only pill; Norethindrone 0.35mg Marketed use for 1 tablet per day. For study dosing, patients will take 3 tablets daily for a total of 1.05mg daily.	Drug: Norethindrone; Norethindrone 1.05mg; Other Names: Micronor; Camilla

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ovulation	Ovulation based on a single serum progesterone level of 4ng/dl or greater	A single 28 day cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sperm penetration of cervical mucus	The average distance sperm will travel in vitro in a test tube of cervical mucus collected from the participant.	A single 28 day cycle
Cervical mucus quality	Scoring of the ovulatory quality (thickness, cellularity, etc.) of cervical mucus collected from the participant	A single 28 day cycle
Side effects	Side effects self reported by the participant	A single 28 day cycle
Uterine bleeding	A daily calendar counting the number of days of uterine bleeding participants experience during the study cycle.	A single 28 day cycle

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pill complaince	Number of pills missed or forgotten over the course of a single 28 day cycle	A single 28 day cycle

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: Society of Family Planning
• Investigators: Principal Investigator: Brian T Nguyen, MD, MSc, University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: April 4, 2017
• First Submitted That Met QC Criteria: April 7, 2017
• First Posted (Actual): April 10, 2017

Study Record Updates

• Last Update Posted (Actual): December 26, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Norpregnenes; Norpregnanes; Norsteroids; Norpregnatrienes; Estrogenic Steroids, Alkylated; Norethindrone Acetate; Ethinyl Estradiol; Norethindrone; ferrous fumarate; norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination
• Other Study ID Numbers: HS-09-00669

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO