Progestin Contraceptives for Birth Control Effects

Overseen By Women's Health Research Unit Research Unit Department of OB/Gyn

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: Oregon Health and Science University

Must not be taking: NSAIDs, Anticoagulants, P450 inducers

Disqualifiers: Uterine pathology, Abnormal bleeding, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 12 months

52 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the study is to learn more about menstrual changes in progestin contraception users. The investigators are hoping to find out what changes in the endometrium lead to different bleeding patterns during the first year of progestin contraception use. Participants will choose to receive the contraceptive implant (Etonogestrel implant also called Nexplanon) or the contraceptive injectable (Depo-medroxyprogesterone acetate (DMPA) also called Depo-Provera) for up to 12 months. They will be asked to have 4 endometrial biopsies over the course of the study, as well as blood draws, physical exams, and pregnancy tests. Participants will also use a daily text message or email diary to report bleeding patterns. This study's plan is to comprehensively phenotype bleeding patterns and profile the entire endometrium using single-cell RNA seq data (sCRNAseq).

Will I have to stop taking my current medications?

The trial requires that you stop using hormonal contraceptives and certain other medications before enrolling. Specifically, you must not have used oral hormonal contraceptives for at least one month, implantable contraceptives for at least two months, or injectable hormonal contraceptives for the past nine months. Additionally, you should not be using NSAIDs regularly or any anticoagulants.

Is the etonogestrel implant generally safe for use as a contraceptive?

The etonogestrel implant, known as Nexplanon or Implanon, is generally considered safe, but it can rarely cause moderate or severe allergic reactions. A study in France assessed its safety and found some adverse effects, but these are not common. ^{1 2 3 4 5}

How is the drug DMPA and Etonogestrel implant unique compared to other birth control options?

The DMPA injection and Etonogestrel implant are unique because they provide long-term contraception with simple options for reversal or removal. The implant is one of the most effective forms of contraception, and both methods are safe for use postpartum, during breastfeeding, and immediately after abortion. However, they may cause changes in menstrual bleeding patterns and, in the case of DMPA, potential reversible bone mineral density loss. ^{5 6 7 8 9}

Research Team

Alison B Edelman, MD, MPH

Principal Investigator

Oregon Health and Science University

Eligibility Criteria

This trial is for women aged 18-40 with regular menstrual cycles, a BMI of 19-35, and no contraindications to DMPA or hormonal implants. They shouldn't be pregnant, breastfeeding, or planning pregnancy during the study; have used certain contraceptives recently; have uterine pathology; fall under CDC's category 3/4 for contraceptive use; smoke heavily; or take specific medications regularly.

Inclusion Criteria

Regular menstrual cycles (25-35 day cycle length with bleeding 8 days or less)

Body Mass Index of 19-35

I can safely use birth control shots or implants.

Exclusion Criteria

Centers for Disease Control Medical Eligibility for Contraceptive use category 3 or 4 for contraceptive usage

I have experienced unusual bleeding from my uterus.

Chronic use of cigarettes (More than 1 cigarette per week)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the contraceptive implant (Nexplanon) or the contraceptive injectable (Depo-Provera) for up to 12 months, with 4 endometrial biopsies, blood draws, physical exams, and pregnancy tests

12 months

4 visits for biopsies, regular visits for blood draws and exams

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the analysis of bleeding patterns and endometrial profiling

6 months

Treatment Details

Interventions

• DMPA
• Etonogestrel implant

Trial Overview The study examines how progestin contraception (Nexplanon implant or Depo-Provera injection) affects menstrual changes by analyzing endometrial biopsies and blood samples over a year. Participants will also track their bleeding patterns daily via text or email.

Participant Groups

Group I: DMPA Active Control 1 Intervention

Group II: Etonogestrel implant Active Control 1 Intervention

DMPA is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Depo-Provera for:

• Contraception
• Endometriosis
• Renal carcinoma
• Cushing's syndrome

Approved in European Union as Depo-Provera for:

• Contraception
• Endometriosis
• Renal carcinoma
• Cushing's syndrome

Approved in Canada as Depo-Provera for:

• Contraception
• Endometriosis
• Renal carcinoma
• Cushing's syndrome

Who Is Running the Clinical Trial?

Oregon Health and Science University

Lead Sponsor

Trials

1,024

Recruited

7,420,000+

Findings from Research

Nexplanon® is a long-acting contraceptive implant that is generally considered safe, but it can occasionally cause moderate to severe adverse reactions.

A specific case of delayed-type hypersensitivity reaction to Nexplanon® was reported, which resolved after the implant was removed, highlighting the importance of monitoring for potential allergic reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed-type hypersensitivity reaction against Nexplanon®. Serati, M., Bogani, G., Kumar, S., et al.[2014]

In a national pharmacovigilance study in France, 39 unintended pregnancies were reported among users of the Implanon contraceptive implant, primarily due to insertion technique errors (77% of cases).

The study highlights the importance of proper training for healthcare providers in the insertion of Implanon to prevent complications, as issues with insertion can lead to migration of the implant and difficulties in removal, potentially requiring invasive procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Insertion problems, removal problems, and contraception failures with Implanon]. Bensouda-Grimaldi, L., Jonville-Béra, AP., Beau-Salinas, F., et al.[2014]

In a study of 385 high-risk women, those using the intrauterine device (IUD) had lower rates of discontinuation compared to those using depo-medroxyprogesterone acetate (DMPA), with 18.8% of IUD users discontinuing versus 67.0% of DMPA users.

While women using DMPA were initially found to have a higher likelihood of subsequent sexually transmitted diseases (STDs), this association diminished when accounting for other factors, suggesting that the choice of contraceptive may be influenced by sexual risk factors rather than inherent safety differences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term, reversible contraception use among high-risk women treated in a university-based gynecology clinic: comparison between IUD and depo-provera. Cropsey, KL., Matthews, C., Campbel, S., et al.[2022]

Over a 10-year period, 5433 adverse effects (AEs) were reported for the etonogestrel contraceptive implant, with only 7% classified as serious, indicating that while AEs are common, they are mostly not severe.

The introduction of Nexplanon® has significantly reduced complications related to insertion and migration of the implant, highlighting improvements in safety and efficacy compared to its predecessor, Implanon®.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety profile of etonogestrel contraceptive implant (Nexplanon&#174; and Implanon&#174;) reported in France]. Simon, C., Agier, MS., Béné, J., et al.[2017]

The study involving 18 HIV-negative women found that the use of the etonogestrel Implant (Eng-Implant) was associated with a moderate increase in the availability of HIV target cells (CCR5+CD4+ T cells) in the genital tract, but the activation of these cells did not increase, suggesting no clear elevation in HIV risk.

Overall immune responses showed minimal changes after implant placement, indicating that while there are some shifts in HIV target cell populations, it remains uncertain whether these changes significantly affect the risk of acquiring HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood. Haddad, LB., Swaims-Kohlmeier, A., Mehta, CC., et al.[2020]

Progestin-only contraceptives (POCs) like pills, injections, IUDs, and implants are effective first-line options for preventing unwanted pregnancies, offering various advantages and disadvantages that need to be communicated to users.

Clinicians play a crucial role in ensuring women are well-informed about potential side effects and benefits of POCs, which can enhance adherence and reduce the likelihood of discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Considerations for the use of progestin-only contraceptives. Freeman, S., Shulman, LP.[2022]

In a study of 89 women undergoing medical abortion, the addition of a progestin-based contraceptive (either an etonogestrel implant or DMPA injection) on the same day as mifepristone did not affect the high success rate of the procedure, which was 98%.

This success rate is comparable to previous findings where medical abortion was performed without the concurrent administration of progestin contraceptives, indicating that the use of these contraceptives is safe and does not compromise the effectiveness of medical abortion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progestin-based contraceptive on the same day as medical abortion. Park, J., Robinson, N., Wessels, U., et al.[2018]

Progestin-only contraception methods, such as implants and injections, are highly effective and have few contraindications, making them safe options for long-term birth control.

While both methods can cause changes in menstrual bleeding patterns and potential bone mineral density loss, these effects are generally reversible, and there is no significant increased risk of cancer associated with their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contraception Update: Progestin-Only Implants and Injections. Deshmukh, P., Antell, K., Brown, EJ.[2018]

The subdermal contraceptive implant etonogestrel (Implanon) primarily prevents pregnancy by inhibiting ovulation, while also causing complex changes in the endometrium, such as alterations in histology and menstrual bleeding patterns.

Current research is exploring how etonogestrel affects endometrial functions, including vascular and angiogenic processes, which may contribute to breakthrough bleeding experienced by some users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial effects of etonogestrel (Implanon) contraceptive implant. Varma, R., Mascarenhas, L.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Delayed-type hypersensitivity reaction against Nexplanon®. [2014]

2. France pubmed.ncbi.nlm.nih.gov

[Insertion problems, removal problems, and contraception failures with Implanon]. [2014]

3. United States pubmed.ncbi.nlm.nih.gov

Long-term, reversible contraception use among high-risk women treated in a university-based gynecology clinic: comparison between IUD and depo-provera. [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Safety profile of etonogestrel contraceptive implant (Nexplanon&#174; and Implanon&#174;) reported in France]. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Considerations for the use of progestin-only contraceptives. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Progestin-based contraceptive on the same day as medical abortion. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Contraception Update: Progestin-Only Implants and Injections. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Endometrial effects of etonogestrel (Implanon) contraceptive implant. [2021]