FertilityPhase 4NCT02969590
Regulation of Cervical Mucus Secretion
A Phase 4 study testing Leuprolide acetate, Estrogen and Progesterone Replacement and Progestin in people with Fertility and Contraception, run by Oregon Health and Science University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Fertility, Contraception
- What is being tested?
- Leuprolide acetate, Estrogen and Progesterone Replacement and Progestin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Mar 2015to 23 Aug 2017
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Show all 10Show fewer
- 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.
Who cannot join
- 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
Show all 17Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
Oregon Health & Science University
Portland, Oregon, 97239
About this study
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.
Read the 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.
- Conditions
- Fertility, Contraception
- Being tested
- Leuprolide acetate, Estrogen and Progesterone Replacement, Progestin
- Keywords
- Contraception, Mucus, Cervix, progestin, hormones
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Leuprolide acetateDrug
Also called Lupron
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.
Estrogen and Progesterone ReplacementDrug
Also called Estradiol (vivelle-dot), Progesterone (prometrium, progestin)
Replace hormones exogenously to create an artificial cycle
ProgestinDrug
Also called Norethindrone, NET
Synthetic progestin to assess effects on cervical mucus.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Leuprolide acetate; Drug: Estrogen and Progesterone Replacement; Drug: Progestin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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."
Measured: Baseline
Sperm Penetration Scores
Measuring sperm penetration scores in different hormonal conditions
Measured: 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."
Measured: 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."
Measured: 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."
Measured: 24 hours
Secondary outcomes (1)
Change in PGRMC1 During Menstrual Cycle
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
Measured: 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Nov 2016 (estimated)
- Study start29 Mar 2015
- Primary completion23 Aug 2017
- Study completion23 Aug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for FertilityStudies of the same condition, open and under way.
- More trials run by Oregon Health and Science UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Investigator
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oregon Health and Science University
- Sponsor type
- University, hospital or other
- Collaborators
- Society of Family Planning
- Responsible party
- Principal investigator, Leo Han, Oregon Health and Science University
- Investigators
- Leo Han, MD, Principal investigator, Oregon Health and Science University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02969590
- Sponsor's protocol ID
- OHSU IRB 11532
- Status last verified
- Oct 2019
- First submitted
- 27 May 2015
- Last updated
- 18 Oct 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 29457758
Study at a glance
From the registry record, last updated by the sponsor on 18 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Regulation of Cervical Mucus Secretion
- ClinicalTrials.gov ID
- NCT02969590
- Acronym / sponsor ID
- OHSU IRB 11532
- Conditions
- Fertility, Contraception
- Keywords
- Contraception, Mucus, Cervix, progestin, hormones
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Oregon Health and Science UniversityUniversity, hospital or other
- Collaborators
- Society of Family Planning
- Study start
- 29 Mar 2015 (actual)
- Primary completion
- 23 Aug 2017 (actual)
- Study completion
- 23 Aug 2017 (actual)
- First posted
- 21 Nov 2016 (estimated)
- Results
- Posted 18 Oct 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: Leuprolide acetate, Drug: Estrogen and Progesterone Replacement, Drug: ProgestinThis 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. |
| E2WD Arm - Estradiol (4 months) | Active comparator | Drug: Leuprolide acetate, Drug: Estrogen and Progesterone Replacement, Drug: ProgestinThis 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. |
Who may qualify
- Ages
- 21 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (17 listed)
- 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®)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Leuprolide acetateAlso: LupronFollowing 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. | Drug | E2WD Arm - Estradiol (4 months), NET Arm - Norethindrone (4 months) |
| Estrogen and Progesterone ReplacementAlso: Estradiol (vivelle-dot), Progesterone (prometrium, progestin)Replace hormones exogenously to create an artificial cycle | Drug | E2WD Arm - Estradiol (4 months), NET Arm - Norethindrone (4 months) |
| ProgestinAlso: Norethindrone, NETSynthetic progestin to assess effects on cervical mucus. | Drug | E2WD Arm - Estradiol (4 months), NET Arm - Norethindrone (4 months) |
Primary outcome
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."
Sperm Penetration Scores
Time frame: Approximately one year
Measuring sperm penetration scores in different hormonal conditions
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."
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."
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."
1 secondary outcome
Change in PGRMC1 During Menstrual Cycle
Time frame: 1 month
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Oct 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29457758Han 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Leo Han, MD principal investigator
Oregon Health and Science University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Leuprolide acetate, Estrogen and Progesterone Replacement and Progestin in people with Fertility and Contraception, run by Oregon Health and Science University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Median Cervical Mucus Score - Baseline (time frame: Baseline). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02969590, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2019.