Hormone Therapy for Polycystic Ovary Syndrome

(CRM010 Trial)

Overseen By Melissa Gilrain, BS

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Virginia

Must not be taking: Systemic corticosteroids

Disqualifiers: Diabetes, Liver abnormalities, Cancer, others

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the medication flutamide, a hormone therapy, can improve specific hormone functions in women with polycystic ovary syndrome (PCOS). PCOS often causes issues like irregular periods and excess male hormones, leading to symptoms such as unwanted hair growth. Participants will be randomly assigned to receive either flutamide or a placebo to determine if flutamide enhances the hormone response when combined with progesterone. Women experiencing PCOS symptoms like irregular periods and excess hair growth, who are otherwise healthy, may be suitable for this study. As an Early Phase 1 trial, this research focuses on understanding how flutamide works in people, offering participants a chance to contribute to groundbreaking 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. However, if you have stable and adequately treated hypothyroidism, you can continue your thyroid medication.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that flutamide is usually safe in low doses for treating polycystic ovary syndrome (PCOS). One study found that low-dose flutamide can help reduce belly fat and slow fat buildup in women with PCOS. However, some safety concerns exist. Long-term use of flutamide has been linked to liver damage and birth defects. Specifically, one study highlighted severe liver damage as a major concern. Participants should be aware of these risks when considering joining a trial involving flutamide. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PCOS?

Flutamide is unique for treating polycystic ovary syndrome (PCOS) because it targets androgen receptors directly, unlike typical treatments focused on hormonal regulation, such as birth control pills or Metformin. By focusing on androgen receptors, Flutamide aims to reduce the excess male hormones often found in women with PCOS, potentially addressing symptoms like unwanted hair growth and acne more effectively. Researchers are excited about this approach as it offers a new pathway to manage PCOS symptoms by tackling the hormone imbalance at its source.

What evidence suggests that flutamide might be an effective treatment for PCOS?

Research has shown that flutamide, a medication that blocks testosterone, can assist women with polycystic ovary syndrome (PCOS) in several ways. In this trial, some participants will receive flutamide, which studies have found can help women with PCOS who aren't ovulating to start releasing eggs again. It also improves blood flow to the uterus, benefiting reproductive health. Additionally, flutamide may help reduce abdominal fat in women with PCOS. Overall, early evidence suggests that flutamide might help manage some hormonal and physical symptoms of PCOS. ^{6 7 8 9 10}

Who Is on the Research Team?

Christopher M McCartney, MD

Principal Investigator

Univsersity of Virginia

Are You a Good Fit for This Trial?

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.

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.

I am committed to using non-hormonal birth control methods during the study.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Flutamide
• Micronized progesterone

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Eulexin for:

• Prostate cancer

Approved in European Union as Flutamide for:

• Prostate cancer

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+

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

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

Citations

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Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E2 and FSH in PCOS patients, which were lower. Of note, flutamide ...

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The most important result of the present study was that flutamide restored ovulation in anovulatory PCOS patients.

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In patients with PCOS treated with flutamide, a significant increase in uterine perfusion (P<.05) was observed during treatment (Fig. 1), while no difference ...

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Conclusion. Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated ...

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pubmed.ncbi.nlm.nih.gov

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Drugs commonly used to treat PCOS appear to be associated with very low risk of severe adverse effects although data are extrapolated from other populations.

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12036725/

Randomized Clinical Trial: Effect of Low-Dose Flutamide on ...

Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation.

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fertstert.org

fertstert.org/article/S0015-0282(22)02036-2/fulltext

Polycystic ovarian syndrome: a second-take on flutamide

In addition, the long-term safety of flutamide is also in question owing to the risk of hepatotoxicity and teratogenicity. What it should be is ...

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academic.oup.com

academic.oup.com/jcem/article/98/12/4646/2834080

Adverse Effects of the Common Treatments for Polycystic ...

The major concern with flutamide use is its association with severe hepatotoxicity and secondary death. A prospective cohort (22) of 214 hyperandrogenic ...

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sciencedirect.com

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Randomized clinical trial: effect of low-dose flutamide on ...

To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates ...