Regulation of Cervical Mucus Secretion

NCT02969590 | Completed Phase 4 Results

• 1 other identifier: OHSU IRB 11532
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to help us determine how hormones impact the production of cervical mucus which is a fluid secreted by the opening of the uterus, also called the cervix. During a normal menstrual cycle, cervical mucus changes in response to two hormones that the ovaries make: estrogen and progesterone. Many of the birth control methods women use thicken mucus and make it less likely for sperm to enter the uterus. The goal of this study is to better understand the effects estrogen and progesterone have on the cervical mucus in the body. To do this, the investigators will be using a drug that suppresses natural hormone production for 3 months. Estrogen and progesterone will be artificially replaced to better understand their effects. The investigators will also be studying the effect of a common birth control pill that may work by thickening cervical mucus. Last, the investigators will study some of the cells in the cervix that produce mucus.

Conditions

Fertility; Contraception

Keywords

Contraception; Mucus; Cervix; progestin; hormones

Outcome Measures

Primary Outcomes (5)

• Median Cervical Mucus Score - Baseline

  Measurement of median cervical mucus scores at baseline. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."

  Baseline

• Sperm Penetration Scores

  Measuring sperm penetration scores in different hormonal conditions

  Approximately one year

• Median Cervical Mucus Score - 2 Hour

  Measurement of median cervical mucus scores 2 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."

  2 hours

• Median Cervical Mucus Score - 6 Hour

  Measurement of median cervical mucus scores 6 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."

  6 hours

• Median Cervical Mucus Score - 24 Hour

  Measurement of median cervical mucus scores 24 hours following norethindrone administration. The current clinical standard for appraising cervical mucus is the cervical mucus score (ie. Insler score) that examines mucus based on 5 metrics including volume, spinnbarkeit (stretch), ferning, viscosity and cellularity on a 15-point scale. Per WHO guidelines, scores above 10 are considered "mucus favoring penetration" and scores below 10 are considered to be "unfavorable to penetration."

  24 hours

Secondary Outcomes (1)

• Change in PGRMC1 During Menstrual Cycle

  1 month

Study Arms (3)

No Intervention: Spontaneous Cycle (1 month)

NO INTERVENTION

In order to qualify for the intervention phase, subjects needed to demonstrate favorable mucus at ovulation (Insler score of greater than or equal to 10 within 24h of an LH surge) and progesterone level in the luteal phase consistent with ovulation (a single P4 of greater than or equal to 3ng/ ml between days 18-35 of menstrual cycle).

NET Arm - Norethindrone (4 months)

ACTIVE COMPARATOR

This arm will receive Norethindrone (NET) first then experience estradiol withdrawal (E2WD). On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects. On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four. Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.

Drug: Leuprolide acetate; Drug: Estrogen and Progesterone Replacement; Drug: Progestin

E2WD Arm - Estradiol (4 months)

ACTIVE COMPARATOR

This arm will experience estradiol withdrawal (E2WD) first and then receive Norethindrone (NET). On the day prior to each admission, we instructed subjects to apply three fresh estradiol (E2) patches (0.3mg/day) to achieve mid-cycle level E2 effects. On the day of the first and third admission, subjects were randomized to the experimental condition, either: (1) oral progestin administration (e.g., a single dose of 0.35mg norethindrone) with continuation of the E2 patches ; or (2) estradiol withdrawal (e.g., removal of the patches). Subject then received the converse intervention for admissions two and four. Subjects resumed treatment with the 0.1mg E2 patch until their next scheduled inpatient assessment. We required a minimum of five days at this level before repeating the dose escalation and the next evaluation.

Drug: Leuprolide acetate; Drug: Estrogen and Progesterone Replacement; Drug: Progestin

Interventions

Leuprolide acetate DRUG

Following this spontaneous cycle, participants received a single intramuscular injection of leuprolide acetate (11.25mg, LupronVR; Abbvie, Chicago, IL), a dose documented to suppress ovarian function for at least 3 months. Ovarian suppression is confirmed with serum E2 less than or equal to 35 pg/ml 21-28 day post-injection.

Also known as: Lupron

E2WD Arm - Estradiol (4 months); NET Arm - Norethindrone (4 months)

Estrogen and Progesterone Replacement DRUG

Replace hormones exogenously to create an artificial cycle

Also known as: Estradiol (vivelle-dot), Progesterone (prometrium, progestin)

E2WD Arm - Estradiol (4 months); NET Arm - Norethindrone (4 months)

Progestin DRUG

Synthetic progestin to assess effects on cervical mucus.

Also known as: Norethindrone, NET

E2WD Arm - Estradiol (4 months); NET Arm - Norethindrone (4 months)

Eligibility Criteria

• Age: 21 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Normal menstrual cycles of 25-35 days in length for at least previous 3 cycles
• years of age
• BMI \>18, \<30
• Serum P4 ≥ 3 ng/ml on single sample collected between days 18-25 of self-reported menstrual cycle
• Flexible schedule allowing morning blood draws on less than 48 hour notice
• In good general health
• Commit to remain on stable diet during study period (no changes to normal dietary habits)
• Commit to using non-hormonal contraceptive methods during study period except those prescribed in the experimental protocol
• No objections to taking study drugs
• No objections to refraining from intercourse the night before any sampling and willing to using condoms during vaginal intercourse.

You may not qualify if:

• Oral contraceptive use or other hormone supplement within the preceding 2 months
• Women with current cervical infection
• Evidence of abnormal cervical cytology
• Use of Paragard IUD for contraception
• Long-acting hormonal contraceptive use in the past 12 months (e.g., Depo-Provera®)
• Contraindications to study drugs
• Current or past pregnancy within the previous 6 months or currently trying to conceive
• Desiring to conceive in the next 8 months
• Breastfeeding in the past 2 months
• Diagnosed Diabetes or Metabolic Syndrome
• Current or previous use of cholesterol lowering drugs within the preceding 12 months
• Diagnosed Polycystic Ovary Syndrome
• History of, or self-reported, substance abuse
• Smoker
• Previous infertility treatment excluding male factor issues

Sponsors & Collaborators

• Oregon Health and Science University: lead
• Society of Family Planning: collaborator

Study Sites (1)

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Related Publications (1)

• Han L, Padua E, Edelman A, Jensen JT. Appraising cervical mucus: a new approach to evaluating contraceptives. Eur J Contracept Reprod Health Care. 2018 Feb;23(1):78-83. doi: 10.1080/13625187.2018.1437134. Epub 2018 Feb 19.

  PMID: 29457758 DERIVED

MeSH Terms

Interventions

Leuprolide; Estrogens; Estradiol; Progesterone; Progestins; Norethindrone

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners; Norpregnenes; Norpregnanes; Norsteroids

Results Point of Contact

• Title: Ob/Gyn Regulatory Specialist
• Organization: Oregon Health & Science University

mccrimmo@ohsu.edu

5034940757

Study Officials

• Leo Han, MD

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor

Study Record Dates

• First Submitted: May 27, 2015
• First Posted: November 21, 2016
• Study Start: March 29, 2015
• Primary Completion: August 23, 2017
• Study Completion: August 23, 2017
• Last Updated: October 18, 2019
• Results First Posted: October 18, 2019

Record last verified: 2019-10

Locations

US (1)