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Regulation of Cervical Mucus Secretion

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ClinicalTrials.gov Identifier: NCT02969590
Recruitment Status : Completed
First Posted : November 21, 2016
Results First Posted : October 18, 2019
Last Update Posted : October 18, 2019
Sponsor:
Collaborator:
Society of Family Planning
Information provided by (Responsible Party):
Leo Han, Oregon Health and Science University

Study Description
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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.

Condition or disease Intervention/treatment Phase
Fertility Contraception Drug: Leuprolide acetate Drug: Estrogen and Progesterone Replacement Drug: Progestin Phase 4

Detailed Description:
This proposed study is to evaluate the temporal changes in human cervical mucus in response to progesterone and progestins as an initial step toward clarifying these relationships. Our hypothesis is that direct effects of progesterone on the endocervix, independent of estrogen withdrawal, cause contraceptive changes to cervical mucus. To study this, a randomized, prospective, crossover study will be conducted by examining cervical mucus changes in a small cohort of women in whom investigators will suppress circulating hormonal levels by administering a GnRH antagonist. Investigators will then artificially replace Estrogen and Progesterone in order to differentiate their effects on clinical and laboratory measurements of mucus quality. The investigators will be looking closely at the immediate changes in mucus when .35 mg of norethindrone, a marketed drug is administered in this experimental setting. Cervical cell samples will also be collected at various time points and perform RT-PCR to determine whether genes for membrane bound progesterone receptor are expressed and regulated by Estrogen and Progesterone.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Investigator)
Primary Purpose: Basic Science
Official Title: Regulation of Cervical Mucus Secretion
Actual Study Start Date : March 29, 2015
Actual Primary Completion Date : August 23, 2017
Actual Study Completion Date : August 23, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Birth Control

Arms and Interventions
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Arm Intervention/treatment
No Intervention: No Intervention: Spontaneous Cycle (1 month)
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).
Active Comparator: NET Arm - Norethindrone (4 months)

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
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.
Other Name: Lupron

Drug: Estrogen and Progesterone Replacement
Replace hormones exogenously to create an artificial cycle
Other Names:
  • Estradiol (vivelle-dot)
  • Progesterone (prometrium, progestin)

Drug: Progestin
Synthetic progestin to assess effects on cervical mucus.
Other Names:
  • Norethindrone
  • NET
Active Comparator: E2WD Arm - Estradiol (4 months)

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
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.
Other Name: Lupron

Drug: Estrogen and Progesterone Replacement
Replace hormones exogenously to create an artificial cycle
Other Names:
  • Estradiol (vivelle-dot)
  • Progesterone (prometrium, progestin)

Drug: Progestin
Synthetic progestin to assess effects on cervical mucus.
Other Names:
  • Norethindrone
  • NET


Outcome Measures
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Primary Outcome Measures :
  1. Median Cervical Mucus Score - Baseline [ Time Frame: 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."

  2. Sperm Penetration Scores [ Time Frame: Approximately one year ]
    Measuring sperm penetration scores in different hormonal conditions

  3. Median Cervical Mucus Score - 2 Hour [ Time Frame: 2 hours ]
    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."

  4. Median Cervical Mucus Score - 6 Hour [ Time Frame: 6 hours ]
    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."

  5. Median Cervical Mucus Score - 24 Hour [ Time Frame: 24 hours ]
    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."


Secondary Outcome Measures :
  1. Change in PGRMC1 During Menstrual Cycle [ Time Frame: 1 month ]

    Measuring the mean transcript change of membrane bound progestin receptors (PGRMC1) from follicular phase to ovulation to luteal phase of spontaneous menstrual cycle.

    Total RNA (ribonucleic acid) was isolated from endocervical cell samples and analyzed for expression of PGRMC1 using real-time PCR (polymerase chain reaction) relative to levels of ribosomal (S10) RNA. An endocervical brush will be inserted into the os and then immediately rinsed into a special RNA preserving reagent. After total RNA is isolated and purified, it will be reverse transcribed into cDNA using primers.

    Ratio of PGRMC1 to 18s RNA

    Gene expression of membrane bound progesterone receptors in endocervical cells



Eligibility Criteria
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Ages Eligible for Study:   21 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Normal menstrual cycles of 25-35 days in length for at least previous 3 cycles
  • 21-40 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.

Exclusion Criteria:

  • 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
  • Use of an investigational drug within the past 2 months
  • History of excisional or ablative treatment procedure on cervix (ie. LEEP, Cryotherapy, Cold Knife Cone)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02969590


Locations
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United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
Sponsors and Collaborators
Oregon Health and Science University
Society of Family Planning
Investigators
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Principal Investigator: Leo Han, MD Oregon Health and Science University
  Study Documents (Full-Text)

Documents provided by Leo Han, Oregon Health and Science University:
Study Protocol and Statistical Analysis Plan  [PDF] November 12, 2018

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Leo Han, Instructor, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT02969590    
Other Study ID Numbers: OHSU IRB 11532
First Posted: November 21, 2016    Key Record Dates
Results First Posted: October 18, 2019
Last Update Posted: October 18, 2019
Last Verified: October 2019
Keywords provided by Leo Han, Oregon Health and Science University:
Contraception
Mucus
Cervix
progestin
hormones
Additional relevant MeSH terms:
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Leuprolide
Norethindrone
Estradiol
Estrogens
Progesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents, Hormonal
 Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Fertility Agents, Female
Fertility Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Contraceptives, Oral, Hormonal
Contraceptives, Oral
Contraceptives, Oral, Synthetic