Estradiol for Polycystic Ovary Syndrome

(CRM009 Trial)

Overseen By Christine Burt Solorzano, M.D.

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Virginia

Disqualifiers: Males, Pregnancy, Diabetes, Cancer, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether estradiol, a form of estrogen, can help manage hormone levels in women with polycystic ovary syndrome (PCOS), a condition causing irregular periods and excess male hormones. Participants will use estradiol patches to determine if their hormone levels improve. Women with irregular periods and signs of high male hormones, such as excess hair growth, might be suitable for this study. As an Early Phase 1 trial, this research aims to understand how estradiol works in people, offering participants the opportunity to be among the first to explore its effects on PCOS.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that participants should be in general good health, except for certain conditions like PCOS and adequately-treated hypothyroidism, which suggests that some medications might be allowed.

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

Research has shown that estradiol, when used as a skin patch, is generally safe. Although specific safety information for using estradiol to treat polycystic ovary syndrome (PCOS) is not available, studies with similar hormone treatments have shown positive results.

Comparisons between estradiol patches and estrogen pills have demonstrated effectiveness, and various studies have used the patches without major safety issues. This suggests potential safety, but it is important to note that this trial is in an early stage. While early tests are promising, further research is necessary to fully understand the safety of this treatment for PCOS. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for polycystic ovary syndrome?

Most treatments for Polycystic Ovary Syndrome (PCOS) involve hormonal therapy like oral contraceptives or anti-androgens. However, this new approach using estradiol is different because it's delivered through a transdermal patch. This method provides a steady and controlled release of estradiol, potentially offering more consistent hormone levels compared to oral medications. Researchers are excited because this could lead to fewer side effects and improved management of PCOS symptoms over a shorter period.

What evidence suggests that estradiol might be an effective treatment for polycystic ovary syndrome?

Research has shown that applying estradiol directly to the skin can sometimes be more effective than taking it as a pill. This type of estrogen, used in hormone replacement therapy, can help the uterine lining grow more effectively. Although specific research on skin-applied estradiol for polycystic ovary syndrome (PCOS) is limited, it might help balance hormones. In this trial, participants will receive transdermal estradiol to study its effects on balancing hormones like luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are often imbalanced in PCOS. This approach is promising because it targets specific areas and may help regulate hormones. ^{2 6 7 8 9}

Who Is on the Research Team?

Christine Burt Solorzano, M.D.

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

This trial is for adult women aged 18-30 with Polycystic Ovary Syndrome (PCOS), characterized by excess male hormones and irregular periods, but no other health issues. Participants must avoid pregnancy and have regular menstrual cycles if they're in the control group without PCOS signs.

Inclusion Criteria

I am able and willing to agree to the study's procedures and risks.

I am a woman aged 18-30 with PCOS, showing signs of high male hormones and irregular periods.

I am a woman aged 18-30, have regular periods, and show no signs of excessive male hormones.

Exclusion Criteria

I am a female.

I am over 30 years old.

My hormone levels suggest I might have a specific adrenal gland condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Estradiol Administration

Participants receive transdermal estradiol patches applied daily to maintain serum estradiol levels of 250-400 pg/ml

7-9 days

Daily visits for patch application and monitoring

Monitoring and Data Collection

Daily blood draws and urine collection for hormone measurements; transvaginal ultrasound on study day 6

7-9 days

Daily visits for blood draws and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol

Trial Overview The study tests whether estradiol, a form of estrogen, affects the secretion of hormones involved in ovulation differently in women with PCOS compared to healthy controls. It measures luteinizing hormone as its main focus and follicle-stimulating hormone secondarily.

How Is the Trial Designed?

Group I: Transdermal Estradiol Experimental Treatment 1 Intervention

Subjects will undergo estradiol administration for up to 9 days. Transdermal estradiol patches will be applied each day by study staff during study days two through nine (patches deliver 0.1 mg/day for a total dose of up to 0.6 mg/day).

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

Approved in European Union as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis
• Palliative treatment of breast cancer
• Palliative treatment of prostate cancer

Approved in Canada as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Published Research Related to This Trial

In a study of 32 women with polycystic ovary syndrome (PCOS), those treated with ethinyloestradiol and cyproterone acetate (EO-CA) for 6 months experienced significant reductions in hirsutism and serum androgen levels, but also showed decreased insulin sensitivity.

Conversely, women treated with the GnRH analogue goserelin had decreased androgen levels and improved insulin sensitivity, although they did not see a significant reduction in hirsutism, indicating different mechanisms of action between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Dahlgren, E., Landin, K., Krotkiewski, M., et al.[2019]

In a study of 92 women with Polycystic Ovarian Syndrome (PCOS), the Letrozole stair-step protocol achieved an ovulation rate of 96%, which is comparable to the 88% ovulation rate seen with Clomiphene Citrate (CC), indicating both treatments are effective for ovulation induction.

Letrozole resulted in a shorter time to ovulation (19.5 days) compared to CC (23.1 days), suggesting it may be a more efficient option for women seeking to conceive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovulation rates in a stair-step protocol with Letrozole vs clomiphene citrate in patients with polycystic ovarian syndrome. Thomas, S., Woo, I., Ho, J., et al.[2022]

In a study of 100 women with PCOS, letrozole showed a higher ovulation rate (86.0%) compared to clomiphene citrate (72.0%), although this difference was not statistically significant.

Letrozole also resulted in a significantly shorter time to ovulation (17.20 days) compared to clomiphene citrate (24.08 days), while both treatments had similar safety profiles regarding side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing efficacy and safety of stair step protocols for clomiphene citrate and letrozole in ovulation induction for women with polycystic ovary syndrome (PCOS): a randomized controlled clinical trial. Al-Thuwaynee, S., Swadi, AAJ.[2023]

In a study of 18 women with polycystic ovaries, it was found that an estradiol/testosterone ratio of 0.09 or higher significantly improved the chances of inducing ovulation when using Clomiphene Citrate.

The research suggests that maintaining a baseline estrogen plasma concentration of 50 pg/ml may be important for achieving the desired antiestrogenic effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The polycystic ovary. I. Estradiol/testosterone ratio and the use of antiestrogens. Cortés-Gallegos, V., Legarreta, ME., Aranda, IS., et al.[2013]

The low estrogen-containing oral contraceptive Loestrin effectively normalized hormone levels in 25 women with polycystic ovary disease, reducing elevated luteinizing hormone and testosterone levels while increasing testosterone binding globulin.

Treatment with Loestrin led to noticeable improvements in symptoms, such as reduced hair growth and better complexion, within 12 to 16 weeks, with minimal side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normalization of testosterone levels using a low estrogen-containing oral contraceptive in women with polycystic ovary syndrome. Raj, SG., Raj, MH., Talbert, LM., et al.[2019]

Letrozole is as effective as clomiphene citrate for inducing ovulation in women with PCOS, with both treatments achieving follicle maturation in similar time frames.

However, letrozole resulted in a significantly thicker endometrial lining and a higher pregnancy rate after intrauterine insemination, while producing fewer follicles, which may reduce the risk of multiple pregnancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole versus Clomiphene Citrate for Induction of Ovulation in Patients with Polycystic Ovarian Syndrome Undergoing Intrauterine Insemination. Hendawy, SF., Samaha, HE., Elkholy, MF.[2021]

Letrozole is as effective as human menopausal gonadotropin (HMG) in inducing ovulation and achieving pregnancy in patients with polycystic ovary syndrome (PCOS) who are resistant to clomiphene citrate, with similar ovulation rates (53.6% for letrozole vs 64.7% for HMG).

Letrozole has a lower incidence of ovarian hyperstimulation syndrome (2 cases) compared to HMG (12.5% incidence), making it a safer option for inducing ovulation in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole and human menopausal gonadotropin for ovulation induction in clomiphene resistance polycystic ovary syndrome patients: A randomized controlled study. Shi, S., Hong, T., Jiang, F., et al.[2022]

Letrozole significantly outperformed clomiphene citrate in inducing ovulation, with a risk ratio of 1.14, and also showed higher rates of clinical pregnancies (RR 1.48) and live births (RR 1.49) in a systematic review of 29 randomized controlled trials involving 3,952 women with PCOS.

The study suggests that letrozole is a more effective option for ovulation induction in women with infertility and PCOS compared to clomiphene citrate, although the overall quality of the evidence was mixed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole Compared With Clomiphene Citrate for Polycystic Ovarian Syndrome: A Systematic Review and Meta-analysis. Liu, Z., Geng, Y., Huang, Y., et al.[2023]

The combination pill of ethinyl estradiol (EE) and desogestrel (DSG) significantly improved hyperandrogenic symptoms, such as reduced Ferriman-Gallwey scores and lower serum testosterone levels, in women with polycystic ovary syndrome (PCOS) during the first 6 months of treatment.

However, after 12 months, no further improvements were observed, and the treatment did not adversely affect insulin sensitivity or body weight, indicating that while effective initially, the benefits may plateau over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ethinyl estradiol and desogestrel on clinical and metabolic parameters in Indian patients with polycystic ovary syndrome. Bhattacharya, SM., Ghosh, M., Basu, R.[2013]

In a study of 80 infertile women with polycystic ovarian syndrome, letrozole was found to improve endometrial thickness compared to clomiphene citrate, suggesting better conditions for implantation.

While clomiphene citrate resulted in higher levels of dominant follicles and oestradiol, letrozole showed lower resistance and pulsatility indices, indicating a potentially more favorable environment for pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of letrozole versus clomiphene citrate on endometrial receptivity in Iraqi women with polycystic ovarian syndrome. Al-Obaidi, MT., Ali, ZH., Al-Saadi, WI., et al.[2022]

In a study of 20 women with polycystic ovary syndrome (PCO) treated with desogestrel and ethinylestradiol for 3 months, 70% experienced weight loss, but there were only moderate changes in lipid levels, including increased triglycerides and cholesterol.

The treatment did not significantly improve lipid profiles compared to healthy controls, indicating that while it may help with weight management, it does not provide additional benefits for lipid health in women with PCO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid metabolic studies in women with a polycystic ovary syndrome during treatment with a low-dose desogestrel-ethinylestradiol combination. Cullberg, G., Hamberger, L., Mattsson, LA., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6439127/

Transdermal versus oral estrogen: clinical outcomes in ... Authors concluded that transdermal estrogen showed better results than oral estrogen and can be used safely in patients with a high risk of deep ...

2. worldscientific.com worldscientific.com/doi/full/10.1142/S2661318224500117?srsltid=AfmBOooEg2bcgw7BfCf5RA6sOCER0K4Jl6Jqlq0xE3wHInR_9BJ9CGHi

Clinical Outcomes of Oral vs. Transdermal Estrogen for ... These results suggest that transdermal estrogen may be more effective in promoting endometrial growth for FET in HRT-FET cycles than oral estrogen. The use of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8022087/

Effect of transdermal estrogen dose regimen for ... There was no difference in clinical pregnancy rate (28.9% vs 28.2%, P =.837) and live birth rate (17.3% vs 21.4%, P =.201) between the ID and CD groups.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666396125000147

The last update on polycystic ovary syndrome(PCOS) ... Additionally, the effectiveness of these creams and other topical treatments may be diminished by side effects such as burning sensations and folliculitis ...

5. withpower.com withpower.com/trial/early-phase-1-syndrome-10-2017-4ab03

Estradiol for Polycystic Ovary Syndrome (CRM009 Trial) Letrozole is as effective as human menopausal gonadotropin (HMG) in inducing ovulation and achieving pregnancy in patients with polycystic ovary syndrome (PCOS) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4842240/

A Comparison of the Effects of Transdermal Estradiol and ... The purpose of this study was to determine the optimal endometrial preparation protocol by comparing the clinical outcome of two methods of endometrial ...

7. medcentral.com medcentral.com/endocrinology/hormones/polycystic-ovary-syndrome-pcos-clinical-challenges-in-screening-and-diagnosis

PCOS Treatment Update Disparities in disease presentation can lead to missed diagnosis and delays in treatment, adversely impacting long term health outcomes.

8. worldscientific.com worldscientific.com/doi/full/10.1142/S2661318224500117?srsltid=AfmBOor0nMHe50JX1WkeOzOl09qJ30eZB1ipd8o0WLjTjgN4yorH6L0P

Clinical Outcomes of Oral vs. Transdermal Estrogen for ... The meta-analysis showed that the endometrial thickness was significantly higher in the transdermal estrogen group than in the oral estrogen group. These ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05282277?intr=RACLOPRIDE&aggFilters=studyType:int&viewType=Table&rank=6

Examining the Effects of Estradiol on Neural and Molecular ... This project will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis using simultaneous positron emission ...