Ultrasound Imaging for Ovulatory Dysfunction

Overseen By Angela R Baerwald, PhD,MD,CCFP

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of Saskatchewan

Must not be taking: Hormonal contraception

Disqualifiers: Pregnancy, Smoking, Hypertension, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 1-7 days

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The research aims to compare diagnosis of ovulation and anovulation in 2D and 3D ultrasonography.

Will I have to stop taking my current medications?

The trial requires that participants are not on any hormonal medications that affect reproduction, including hormonal contraception. If you are taking such medications, you would need to stop them to participate.

What data supports the idea that Ultrasound Imaging for Ovulatory Dysfunction is an effective treatment?

The available research does not provide any data on the effectiveness of Ultrasound Imaging for Ovulatory Dysfunction. Instead, the research focuses on the use of drugs like methimazole and propylthiouracil for thyroid-related conditions, such as Graves' disease and hyperthyroidism, and their safety and efficacy. Therefore, there is no information here to support the effectiveness of Ultrasound Imaging for Ovulatory Dysfunction. ^{1 2 3 4 5}

Is indomethacin generally safe for humans?

Indomethacin is generally effective for treating joint pain, but it can cause stomach and small intestine ulcers in both animals and humans. In a study comparing it to aceclofenac, indomethacin had more adverse events, with 29.1% of patients experiencing side effects like heartburn and vertigo. ^{6 7 8 9 10}

How does the drug Indomethacin differ from other treatments for ovulatory dysfunction?

Indomethacin is unique because it is a nonsteroidal anti-inflammatory drug (NSAID) that works by reducing inflammation and pain, which may help in conditions like ovulatory dysfunction by potentially affecting the release of eggs from the ovaries. Unlike hormonal treatments, it does not directly alter hormone levels but may influence the ovulation process through its anti-inflammatory properties. ^{11 12 13 14 15}

Research Team

Angela R Baerwald, PhD,MD,CCFP

Principal Investigator

University of Saskatchewan

Eligibility Criteria

This trial is for individuals experiencing ovulatory dysfunction. To participate, they must meet certain health criteria that will be determined by the study team.

Inclusion Criteria

I am a healthy woman.

Regular menstrual cycles (21-35 days)

Exclusion Criteria

Pregnancy

I have had a hysterectomy or oophorectomy.

Breastfeeding mothers

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive indomethacin 30 mg three times daily for 1-7 days, with daily 2D and 3D ultrasound scans and hormonal assays

1-7 days

Daily visits (in-person)

Follow-up

Participants are monitored with ultrasound scans and hormonal assays on days 1, 3, and 7 after anovulation

1 week

3 visits (in-person)

Treatment Details

Interventions

• Indomethacin

Trial Overview The study is testing the effectiveness of using both 2D and 3D ultrasonography to diagnose ovulation versus anovulation, alongside finger prick blood tests and urine tests.

Participant Groups

Group I: Indomethacin Experimental Treatment 4 Interventions

Oral indomethacin 50 mg three times daily for 1-7 days. The administration is terminated when signs of anovulation are observed.

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

Approved in United States as Indocin for:

• Ankylosing Spondylitis
• Back Pain
• Bartter Syndrome
• Bursitis
• Cluster Headaches
• Frozen Shoulder
• Gitelman Syndrome
• Gout, Acute
• Langerhans' Cell Histiocytosis
• Osteoarthritis
• Pain
• Patent Ductus Arteriosus
• Rheumatoid Arthritis
• Sciatica
• Tendonitis

Approved in European Union as Indomethacin for:

• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Gout
• Painful shoulder caused by bursitis or tendinitis

Who Is Running the Clinical Trial?

University of Saskatchewan

Lead Sponsor

Trials

261

Recruited

156,000+

Findings from Research

In a study comparing 133 children and adolescents with Graves' disease treated with either propylthiouracil (PTU) or methimazole (MMI), both medications showed similar effectiveness in normalizing thyroid hormone levels and achieving remission rates after 10 years.

However, PTU was associated with a longer time to normalize T4 levels and a higher incidence of minor adverse effects, particularly at higher doses, suggesting that MMI may be the preferred initial treatment option for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome. Sato, H., Minagawa, M., Sasaki, N., et al.[2022]

In a study of over 2.2 million individuals in Denmark, the use of antithyroid drugs (ATDs) like methimazole (MMI) and propylthiouracil (PTU) was linked to a low incidence of serious side effects, with agranulocytosis occurring in 0.16% and liver failure in 0.03% of those exposed.

Among pregnant women using ATDs, birth defects were observed in 3.4% of exposed children, indicating a significantly higher risk compared to the rare occurrences of agranulocytosis and liver failure, suggesting that careful management of ATD use in early pregnancy could help reduce these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithyroid Drug Side Effects in the Population and in Pregnancy. Andersen, SL., Olsen, J., Laurberg, P.[2022]

Pregnant women treated with methimazole (MMI) have a higher risk of congenital anomalies compared to those treated with propylthiouracil (PTU), suggesting that PTU is a safer option during pregnancy.

Switching between MMI and PTU does not significantly reduce the risk of birth defects compared to using PTU alone, indicating that PTU should be the preferred treatment for hyperthyroidism in pregnant women, especially during the first trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the safety between propylthiouracil and methimazole with hyperthyroidism in pregnancy: A systematic review and meta-analysis. Liu, Y., Li, Q., Xu, Y., et al.[2023]

A network meta-analysis of 21 trials found that methimazole (MMI) combined with cholestyramine or iodine effectively regulates thyroid hormones (FT3 and FT4) in the early stages of Graves hyperthyroidism, showing significant advantages in reducing these hormone levels.

Long-term treatment with MMI combined with immunosuppressants not only helps in regulating FT3 and FT4 but also reduces relapse rates in patients with Graves hyperthyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

THERAPEUTIC EFFECTS OF COMBINATION REGIMENS INCLUDING METHIMAZOLE ON GRAVES HYPERTHYROIDISM: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. Wang, M., Yu, Y.[2021]

Propylthiouracil (PTU) significantly increases the expression of the sodium/iodide symporter (NIS) in rat thyroid cells, enhancing iodide uptake, while methimazole (MMI) does not have this effect.

The study suggests that although both PTU and MMI are effective in blocking thyroid hormone production, their differing impacts on thyroid-specific gene expression and function could influence their overall therapeutic effectiveness in treating Graves' disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH. Sue, M., Akama, T., Kawashima, A., et al.[2021]

In a study involving 60 outpatients with rheumatoid arthritis and osteoarthritis, the new drug acemetacin was found to be effective in treating pain and inflammation associated with these conditions.

Acemetacin was better tolerated than indomethacin, with a notable reduction in the occurrence of headaches, which are common side effects of indole compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Open clinical study on the efficacy and tolerance of acemetacin in rheumatoid arthritis and osteoarthrosis]. Gospodinoff, A., Fiore, L., Dardano, B., et al.[2014]

The prodrug 1-(2,6-dichlorophenyl)indolin-2-one shows significant anti-inflammatory effects similar to diclofenac but without causing gastric ulceration, making it a safer long-term NSAID option.

This prodrug effectively reduces levels of PGE(2), COX-2 expression, and cellular influx in inflammation models, indicating its potential for treating inflammatory conditions without the common side effects associated with traditional NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. Santos, JL., Moreira, V., Campos, ML., et al.[2021]

In a 12-week clinical trial involving 219 patients with rheumatoid arthritis, aceclofenac (100 mg bid) demonstrated comparable efficacy to indomethacin (50 mg bid), with significant improvements in joint pain, swelling, and grip strength.

Aceclofenac was better tolerated than indomethacin, with fewer reported adverse effects (18.4% vs. 29.1%), suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of aceclofenac compared to indomethacin in patients with rheumatoid arthritis. Kornasoff, D., Maisenbacher, J., Bowdler, J., et al.[2019]

Indomethacin, when administered at a maximum therapeutic dose of 4 mg/kg, caused significant ulceration and damage in the stomach pylorus and proximal duodenum during the first two weeks of treatment, indicating its potential for gastrointestinal toxicity.

After three weeks of treatment, the severity of damage decreased, suggesting that prolonged use may lead to a reduced impact on the gastrointestinal tract, although initial lesions were still observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological changes in parts of foregut of rat after indomethacin administration. Ilahi, M., Khan, J., Inayat, Q., et al.[2013]

Tenoxicam is effective for treating acute and painful rheumatic conditions, showing a rapid onset of action and reliable pain relief after both intramuscular (i.m.) and intravenous (i.v.) administration.

The drug is well tolerated, with only about 10% of patients experiencing typical non-steroidal anti-inflammatory drug (NSAID) related adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenoxicam used as a parenteral formulation for acute pain in rheumatic conditions. Jeunet, F., Enz, W., Guentert, T.[2019]

In a study involving 107 normally fertile women and 794 ultrasound scans, the disappearance or sudden decrease in follicle size was found to be the most reliable indicator of ovulation, with a sensitivity of 84% and specificity of 89.2%.

Ultrasonic echoes in the follicle showed significantly lower sensitivity (38.4%) and specificity (79.7%) compared to other ultrasound indices, indicating it is less effective for confirming ovulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitivity and specificity of ultrasound indices of ovulation in spontaneous cycles. Ecochard, R., Marret, H., Rabilloud, M., et al.[2022]

The study found that both intraobserver and interobserver variability in measuring ovarian volume using three-dimensional power Doppler ultrasonography was very good, with correlation coefficients of 1.00 and 0.99, respectively, indicating high reliability in these measurements.

While measurements of vascularization index (VI), vascularization flow index (VFI), and mean grayness (MG) showed good reproducibility, the flow index (FI) had poor interobserver reproducibility (inter-CC = 0.29), suggesting that caution should be taken when interpreting FI measurements in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraobserver and interobserver variability of ovarian volume, gray-scale and color flow indices obtained using transvaginal three-dimensional power Doppler ultrasonography. Järvelä, IY., Sladkevicius, P., Tekay, AH., et al.[2016]

The study successfully used an ovine model to visualize ovarian microcirculation using the contrast agent Sonovue, showing a significant enhancement of 248% in visualization for an average duration of 74.2 seconds after injection.

No adverse side effects were observed from Sonovue, indicating its safety for use in this model, and the results demonstrated that the ovary undergoing ovulation had a much stronger enhancement compared to the non-ovulating ovary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovine model to evaluate ovarian vascularization by using contrast-enhanced sonography. Marret, H., Brewer, M., Giraudeau, B., et al.[2019]

The study involving 48 women showed that using an oil-based contrast medium (Lipiodol UF) during ultrasound-imaged hysterosalpingography is safe and feasible, with no serious adverse events reported.

However, the ongoing pregnancy rate was lower in the oil-contrast group (17%) compared to the saline group (37%), and there were minor changes in thyroid function observed in the oil group, indicating a need for further investigation into its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oil-based or saline contrast for sono-hysterosalpingography in infertile women: a pilot randomized controlled double blind trial. Legro, RS., Stetter, CM., Kunselman, AR., et al.[2023]

Monitoring ovulation induction solely with ultrasound (US) is safe and effective, showing strong correlations between follicular growth, uterine measurements, and endometrial thickness with estradiol (E2) concentrations.

An endometrial thickness of 11 mm or greater in the midluteal phase is a good predictor of early pregnancy, while thickness of 7 mm or less is associated with no pregnancies after hCG administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements. Shoham, Z., Di Carlo, C., Patel, A., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome. [2022]

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

Antithyroid Drug Side Effects in the Population and in Pregnancy. [2022]

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

Comparison of the safety between propylthiouracil and methimazole with hyperthyroidism in pregnancy: A systematic review and meta-analysis. [2023]

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

THERAPEUTIC EFFECTS OF COMBINATION REGIMENS INCLUDING METHIMAZOLE ON GRAVES HYPERTHYROIDISM: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. [2021]

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

Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH. [2021]

6. Italy pubmed.ncbi.nlm.nih.gov

[Open clinical study on the efficacy and tolerance of acemetacin in rheumatoid arthritis and osteoarthrosis]. [2014]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of aceclofenac compared to indomethacin in patients with rheumatoid arthritis. [2019]

9. Pakistan pubmed.ncbi.nlm.nih.gov

Histological changes in parts of foregut of rat after indomethacin administration. [2013]

10. Norway pubmed.ncbi.nlm.nih.gov

Tenoxicam used as a parenteral formulation for acute pain in rheumatic conditions. [2019]

11. Ireland pubmed.ncbi.nlm.nih.gov

Sensitivity and specificity of ultrasound indices of ovulation in spontaneous cycles. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Intraobserver and interobserver variability of ovarian volume, gray-scale and color flow indices obtained using transvaginal three-dimensional power Doppler ultrasonography. [2016]

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

Ovine model to evaluate ovarian vascularization by using contrast-enhanced sonography. [2019]

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

Oil-based or saline contrast for sono-hysterosalpingography in infertile women: a pilot randomized controlled double blind trial. [2023]

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

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements. [2019]