Norethindrone Acetate-Ethinyl Estradiol for Oxytocin Deficiency

Overseen By Francesca Galbiati, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Elizabeth Austen Lawson

Disqualifiers: Pulmonary embolism, Cancer, Stroke, others

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

Compensation: Varies

Number of Visits: 3

Duration: 1 day

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore the effects of the hormone treatment Norethindrone Acetate-Ethinyl Estradiol on oxytocin levels in individuals with arginine-vasopressin deficiency. Researchers seek to determine if this treatment affects oxytocin—a hormone linked to social behaviors and emotions—differently in these individuals compared to those without the deficiency. They are also examining how changes in oxytocin levels might relate to anxiety, depression, and overall quality of life. The trial seeks participants diagnosed with arginine-vasopressin deficiency who are on stable hormone replacement therapy, as well as healthy individuals without this condition. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical research.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that norethindrone acetate-ethinyl estradiol is usually well-tolerated. Other studies reported low rates of serious side effects over several months for those taking this combination. The data indicate a very small risk of common issues like nausea or headaches, typical with many hormonal treatments. As this study is in its earliest phase, it primarily focuses on assessing the treatment's safety. Consequently, there is less detailed safety information compared to later studies. However, since the treatment is already approved for other uses, it is generally considered safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Norethindrone Acetate-Ethinyl Estradiol is unique because it targets oxytocin deficiency through hormonal regulation, which is different from traditional treatments that often focus on direct oxytocin replacement. Unlike standard care options, this treatment uses a combination of hormones to potentially stimulate the body’s natural oxytocin production. Researchers are excited about this approach as it could offer a more sustainable and holistic way to manage oxytocin levels, possibly improving symptoms more effectively than current methods.

What evidence suggests that Norethindrone Acetate-Ethinyl Estradiol might be an effective treatment for oxytocin deficiency?

Research suggests that a hormone pill combining norethindrone acetate and ethinyl estradiol might help identify and treat low oxytocin levels. Oxytocin, a hormone that enhances mood and social connection, has been linked to anxiety, depression, and social interaction difficulties when levels are low. This trial studies Norethindrone Acetate-Ethinyl Estradiol to determine if it can increase oxytocin levels in individuals with arginine-vasopressin deficiency and in healthy controls. Early findings indicate that this hormone pill might improve symptoms related to low oxytocin. ^{1 2 3 6 7}

Who Is on the Research Team?

Elizabeth A Lawson, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with arginine-vasopressin deficiency who are on stable pituitary hormone replacement therapy. It also includes a control group of healthy adults within the same age range.

Inclusion Criteria

I am between 18 and 65 years old with stable hormone therapy for pituitary issues.

I am between 16 and 65 years old and healthy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of oral Estrogen-progestin to assess oxytocin response

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in oxytocin levels and associated psychopathology measures

48 hours

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Norethindrone Acetate-Ethinyl Estradiol

Trial Overview The study tests how patients with arginine-vasopressin deficiency respond to a single dose of oral Estrogen-progestin compared to healthy controls, and examines the link between oxytocin levels, psychopathology symptoms like anxiety and depression, and quality of life.

How Is the Trial Designed?

Group I: Healthy control Experimental Treatment 1 Intervention

Norethindrone Acetate-Ethinyl Estradiol will be given to the healthy controls.

Group II: Arginine-vasopressin deficiency Experimental Treatment 1 Intervention

Norethindrone Acetate-Ethinyl Estradiol will be given to participants with arginine-vasopressin deficiency

Who Is Running the Clinical Trial?

Elizabeth Austen Lawson

Lead Sponsor

Trials

4

Recruited

200+

Published Research Related to This Trial

Ethinyl estradiol (EE) and norethindrone acetate (NA), commonly used in oral contraceptives, have low acute and chronic toxicity, indicating they are generally safe for use in humans.

While some studies showed an increased incidence of specific tumors in certain animal models, long-term exposure to EE and NA formulations poses very little health risk to humans, and these agents are not teratogenic when used in combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals. Maier, WE., Herman, JR.[2018]

The oral contraceptive combining ethinyl estradiol and drospirenone offers a new and effective contraceptive option, demonstrating high efficacy in preventing pregnancy.

Drospirenone, a unique progestin derived from spironolactone, provides safety profiles comparable to other oral contraceptives, making it a reliable choice for users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of a new oral contraceptive containing drospirenone. Shulman, LP.[2013]

New multiphasic oral contraceptives (OCs) with 35 micrograms of ethinyl estradiol and 0.5-1.0 mg of norethindrone offer a balance of high effectiveness and safety, minimizing side effects for users.

Educating patients about potential adverse effects, such as breakthrough bleeding and the absence of withdrawal bleeding, enhances safety and reduces confusion, leading to better management of oral contraception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral contraceptives. Ellsworth, AJ., Leversee, JH.[2017]

The study successfully evaluated low concentrations (as low as 25 pg) of Norethindrone (NET) and Ethynyl-estradiol (EE) using radioimmunoassay, demonstrating minimal cross-reactivity with other metabolites, which suggests a reliable method for measuring these steroids.

After oral administration of NET to female volunteers, the maximum plasma concentration was reached within 1-3 hours, with a small percentage (2-3%) of the administered dose remaining in the plasma after 24 hours, indicating effective absorption and prolonged presence in the bloodstream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioimmunoassay of norethindrone (17 alpha-ethynyl-17 beta-hydroxy-4-estren-3-one) and ethynyl-estradiol (17 alpha-ethynyl-1,3,5, (10)-estratien-3, 17 beta-diol). Application to human plasma determination of norethindrone after oral administration of this steroid. Pasqualini, JR., Castellet, R., Portois, MC., et al.[2013]

In a large study of 59,701 women over 342,348 menstrual cycles, the oral contraceptive norgestimate/ethinyl estradiol demonstrated a very low use-efficacy Pearl index of 0.25 pregnancies per 100 woman-years, indicating high effectiveness in preventing pregnancy.

The contraceptive was well-tolerated, with minimal side effects and significant reductions in bleeding intensity for 32% of women, while only 1% experienced amenorrhea and low rates of spotting (4%) and breakthrough bleeding (3%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of norgestimate/ethinyl estradiol (250 micrograms of norgestimate/35 micrograms of ethinyl estradiol): results of an open, multicenter study of 59,701 women. Runnebaum, B., Grunwald, K., Rabe, T.[2022]

In a multicenter study involving patients receiving continuous transdermal estradiol, adding norethindrone acetate at doses of 0.5, 0.75, or 1.0 mg/d for 12 days each month led to significant improvements in symptoms and psychological well-being without major adverse effects.

Skin reactions were mild, with only 10% reporting distinct redness and less than 5% discontinuing treatment due to skin issues, while breakthrough bleeding was infrequent and did not lead to hyperplasia or carcinoma, indicating a safe profile for the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study. Fraser, DI., Parsons, A., Whitehead, MI., et al.[2019]

Norgestimate/ethinyl estradiol, a new oral contraceptive, shows excellent contraceptive efficacy with a Pearl index of 0.25, indicating a very low failure rate.

This contraceptive has a low impact on carbohydrate and lipid metabolism and does not significantly affect blood coagulation factors, suggesting a potentially lower risk of cardiovascular disease compared to other oral contraceptives, although caution is advised for patients with a history of vascular or thrombotic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Norgestimate: a clinical overview of a new progestin. Bringer, J.[2019]

Citations

1. rally.massgeneralbrigham.org rally.massgeneralbrigham.org/study/estrogen_admin_oxt_response

Identifying oxytocin deficiency in pituitary disease We are doing this research to understand whether a single dose of a hormone pill (norethindrone acetate/ethinyl estradiol) could be used to identify ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06460948/identifying-oxytocin-deficiency-in-adults-with-pituitary-disease

Identifying Oxytocin Deficiency in Adults With Pituitary ... Lower salivary and blood oxytocin levels will be associated with more severe symptoms of anxiety, depression, and social emotional difficulties ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12259237/

The Oxytocin System and Implications for ... - PubMed Central This review summarizes the current knowledge of the OXT system, OXT deficiency in other clinical conditions, and relevance to patients with hypothalamic and ...

4. trial.medpath.com trial.medpath.com/clinical-trial/d55d4480cf3cc5e9/nct06460948-characterizing-oxytocin-response-estrogen-administration-adults-vasopressin-deficiency

Identifying Oxytocin Deficiency in Adults With Pituitary Disease Norethindrone Acetate-Ethinyl Estradiol will be given to participants with arginine-vasopressin deficiency ... Outcome data and publication updates.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11489228/

Plasma oxytocin levels in response to glucagon in patients ... We found no effect of glucagon on plasma OT levels and no difference between patients with AVP deficiency and healthy participants.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/17161118/

Efficacy and safety of a new 24-day oral contraceptive ... Results: The cumulative risk of pregnancy in the NETA/EE-24 group (n=705) was 0.9% during six cycles of treatment. Compared with NETA/EE-21 (n=181), NETA/EE-24 ...

7. massgeneral.trialstoday.org massgeneral.trialstoday.org/trial/NCT06460948

Identifying Oxytocin Deficiency in Adults With Pituitary ... Norethindrone Acetate-Ethinyl Estradiol will be given to participants with arginine-vasopressin deficiency. Drug: Norethindrone Acetate ...