Hormone Therapy for Polycystic Ovary Syndrome

(CRM010 Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Christopher M McCartney, MD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: University of Virginia

Must not be taking: Systemic corticosteroids

Disqualifiers: Diabetes, Liver abnormalities, Cancer, others

Trial Summary

What is the purpose of this trial?

This trial is testing if flutamide, which blocks testosterone, can help women with PCOS improve their hormone regulation. The study aims to see if this medication can enhance the body's response to progesterone. Flutamide has been used to treat high levels of male hormones in women with PCOS, but its use is limited by potential liver damage and cost.

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, if you have stable and adequately treated hypothyroidism, you can continue your thyroid medication.

What data supports the effectiveness of the drug for treating polycystic ovary syndrome?

Research shows that flutamide, one of the drugs in the treatment, significantly reduces hirsutism (excessive hair growth) in women with polycystic ovary syndrome (PCOS) without major side effects. Additionally, oral micronized progesterone, another component, is effective in hormonal replacement therapy, which may help manage symptoms of PCOS. ^{1 2 3 4 5}

Is micronized progesterone safe for use in humans?

Micronized progesterone is considered safe and well-tolerated, with no reported side effects on lipids, blood pressure, or coagulation factors, making it suitable for various hormonal therapies. ^{3 6 7 8 9}

How does the drug flutamide with micronized progesterone differ from other treatments for polycystic ovary syndrome?

This drug combination is unique because flutamide, an antiandrogen, effectively reduces hirsutism (excessive hair growth) in women with polycystic ovary syndrome without significant side effects, while micronized progesterone provides hormonal balance without the rapid liver inactivation seen in other forms of progesterone. ^{1 2 3 5 10}

Research Team

Christopher M McCartney, MD

Principal Investigator

Univsersity of Virginia

Eligibility Criteria

This trial is for post-pubertal women aged 18-30 with PCOS, showing signs of excess male hormones and irregular periods. Participants must be in good health, not pregnant or lactating, avoid pregnancy during the study, and have no liver issues or significant medical history like diabetes or cancer. They should weigh over 110 pounds without severe blood disorders.

Inclusion Criteria

You are generally healthy, but being overweight, having obesity, hyperandrogenism, PCOS, or treated hypothyroidism is okay.

I am a woman aged 18-30 and have been menstruating for over 4 years.

You have signs of a condition called PCOS, which includes having high levels of male hormones and irregular menstrual cycles, and there are no other reasons for these symptoms.

Exclusion Criteria

I might have Cushing's syndrome, adrenal insufficiency, or acromegaly based on my symptoms or doctor's exam.

You have very low platelet or white blood cell counts.

I have diabetes or my blood sugar/A1c levels are high.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pretreatment

Participants are pretreated with transdermal estradiol for 3 days before CRU admission

3 days

1 visit (in-person)

Treatment

Participants undergo two assessments of progesterone positive feedback after 4 weeks of pretreatment with flutamide or placebo

4 weeks

2 visits (in-person)

Washout

A washout period of at least 2 months to ensure adequate clearance of flutamide

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Flutamide (Antiandrogen)
• Micronized progesterone (Progestin)

Trial Overview The study tests if flutamide can improve pituitary function in women with PCOS when pre-treated with estradiol and given progesterone. It's a randomized, placebo-controlled double-blinded crossover study to see if flutamide enhances FSH release.

Participant Groups

Group I: Flutamide Experimental Treatment 3 Interventions

Prior to the first or second admission (randomly determined), subjects will be pretreated for 4 weeks with Flutamide (250 mg twice daily)

Group II: Placebo Placebo Group 3 Interventions

Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with placebo (twice daily).

Flutamide is already approved in Canada, Japan for the following indications:

Approved in Canada as Flutamide for:

• Prostate cancer

Approved in Japan as Flutamide for:

• Prostate cancer

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

James E. Ryan

University of Virginia

Chief Executive Officer since 2018

J.D. from Harvard Law School

Nikki Hastings

University of Virginia

Chief Medical Officer since 2018

Ph.D. in Biomedical Engineering from University of Virginia

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Dr. Diana W. Bianchi

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Chief Executive Officer since 2016

MD from Stanford University

Dr. Alison Cernich

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Chief Medical Officer since 2020

PhD in Clinical Psychology from University of Maryland

Findings from Research

In a study of 25 women with severe hirsutism due to polycystic ovary syndrome (PCOS), treatment with the antiandrogen flutamide for 24 months resulted in a significant reduction in hirsutism, as measured by the Ferriman-Gallwey score.

The treatment was well-tolerated, with no significant hormonal changes or side effects reported, indicating that flutamide can be a safe and effective long-term option for managing hirsutism in women with PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged treatment of hirsutism with flutamide alone in patients affected by polycystic ovary syndrome. Pucci, E., Genazzani, AD., Monzani, F., et al.[2019]

In a study of women with polycystic ovarian disease not seeking pregnancy, treatment with a combination of 50 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate for six months significantly reduced levels of gonadotropins, testosterone, and androstenedione.

The treatment also increased sex hormone binding globulin (SHBG), resulting in a net decrease in the calculated free testosterone index, which may help mitigate androgenic effects on the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a cyproterone-containing oral contraceptive on hormonal levels in polycystic ovarian disease. Calaf-Alsina, J., Rodriguez-Espinosa, J., Cabero-Roura, A., et al.[2013]

Oral micronized progesterone effectively reproduces the natural hormone's anti-estrogenic and anti-mineralocorticoid effects at a daily dose of 200 mg, making it a viable option for various hormonal therapies.

This preparation has shown no adverse effects on lipid profiles, coagulation factors, or blood pressure, indicating its safety for use in postmenopausal therapy, premenstrual syndrome, and pregnancy maintenance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. Sitruk-Ware, R., Bricaire, C., De Lignieres, B., et al.[2019]

A systematic review of 9 studies involving 2289 patients found that the Progestin-primed ovarian stimulation (PPOS) protocol does not significantly reduce the risk of ovarian hyperstimulation syndrome (OHSS) or improve live birth rates compared to traditional GnRH analogue protocols in women with PCOS undergoing IVF or ICSI.

While PPOS required a higher dose of gonadotropins, it showed potential benefits in improving implantation, clinical pregnancy, and ongoing pregnancy rates compared to the GnRH agonist short protocol, although the overall evidence quality was low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. Yang, L., Liang, F., Yuan, Y., et al.[2023]

Low-dose flutamide combined with metformin is an effective treatment for normalizing symptoms of polycystic ovary syndrome (PCOS) in nonobese adolescents and young women.

To enhance safety, it is recommended to use flutamide-metformin alongside a contraceptive method, such as an oral or transdermal estroprogestagen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in nonobese adolescents and women. Ibáñez, L., de Zegher, F.[2013]

A single oral dose of 300 mg micronized progesterone in eight healthy postmenopausal women showed effective absorption, achieving serum concentrations that mimic natural luteal phase levels.

The study found that absorption of micronized progesterone varied significantly among individuals and increased with age, suggesting it may be a promising alternative to synthetic progestins without negatively affecting lipoprotein profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral administration of micronized progesterone: a review and more experience. McAuley, JW., Kroboth, FJ., Kroboth, PD.[2013]

Micronized progesterone provides a new oral option for hormone therapy in pre- and postmenopausal women, effectively overcoming absorption issues associated with traditional progesterone.

It is functionally equivalent to synthetic progestogens for treating conditions like secondary amenorrhea, but offers a more natural metabolic profile, making it potentially safer for long-term use in hormone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: a new therapeutic option. Langer, RD.[2013]

Oral micronized progesterone has enhanced bioavailability, making it effective for various therapeutic uses, including treating secondary amenorrhea and as part of hormone replacement therapy for postmenopausal women.

Research supports its potential benefits for premenopausal bleeding disorders and luteal phase dysfunction, indicating a broad clinical application for this formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: clinical indications and comparison with current treatments. Fitzpatrick, LA., Good, A.[2019]

Oral micronized progesterone (MP) is a newly FDA-approved treatment that offers a safer and more effective alternative to traditional synthetic progestational agents, which often have adverse effects.

The article highlights the importance of individualized treatment plans and patient compliance, as demonstrated through five case studies, to achieve the best therapeutic outcomes with MP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micronized progesterone: a new option for women's health care. Wetzel, W.[2013]

A low-dose combination therapy of flutamide, metformin, and ethinylestradiol-drospirenone effectively reduced total and abdominal fat, improved lean mass, and normalized certain blood markers in young women with ovarian hyperandrogenism, based on a study of 40 participants over 3 months.

The addition of low-dose flutamide significantly enhanced the treatment's effects on cholesterol, inflammation markers, and ovarian blood flow, suggesting it plays a crucial role in managing symptoms of polycystic ovary syndrome, challenging the notion that drospirenone alone provides significant antiandrogen benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. Ibáñez, L., Valls, C., Cabré, S., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Prolonged treatment of hirsutism with flutamide alone in patients affected by polycystic ovary syndrome. [2019]

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

Effects of a cyproterone-containing oral contraceptive on hormonal levels in polycystic ovarian disease. [2013]

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

Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. [2023]

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

Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in nonobese adolescents and women. [2013]

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

Oral administration of micronized progesterone: a review and more experience. [2013]

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

Micronized progesterone: a new therapeutic option. [2013]

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

Micronized progesterone: clinical indications and comparison with current treatments. [2019]

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

Micronized progesterone: a new option for women's health care. [2013]

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

Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. [2013]