Hormone Regulation Therapy for Polycystic Ovary Syndrome

(CRM008 Trial)

Overseen By Christopher R McCartney, M.D.

Age: < 18

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Virginia

Must be taking: Spironolactone

Must not be taking: Oral contraceptives, Metformin

Disqualifiers: Diabetes, Pregnancy, Cancer, others

Compensation: Varies

Number of Visits: 2

32 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if, in mid- to late pubertal girls with hyperandrogenism, androgen-receptor blockade (spironolactone) improves the ability of progesterone to acutely reduce waking luteinizing hormone pulse frequency (primary endpoint).

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that affect the reproductive system, glucose metabolism, lipid metabolism, or blood pressure at least 2 months before the screening visit and 3 months before starting the study medications. This includes oral contraceptives, progestins, metformin, systemic glucocorticoids, some antipsychotics, and stimulants like methylphenidate.

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

Research shows that spironolactone, a component of the treatment, significantly reduces hirsutism (excessive hair growth) and helps regulate menstrual cycles in women with polycystic ovary syndrome. It also improves insulin resistance when combined with metformin, another common treatment for this condition. ^{1 2 3 4 5}

Is hormone regulation therapy for PCOS safe for humans?

Micronized progesterone, a form of hormone regulation therapy, is generally considered safe for humans, with no reported side effects on lipid profiles, blood clotting, or blood pressure. It is well-tolerated and has been approved by the FDA for use in various women's health conditions. ^{6 7 8 9 10}

How does the drug for PCOS differ from other treatments?

This treatment for PCOS combines micronized progesterone and spironolactone, which are both enhanced for better absorption and effectiveness. Micronized progesterone provides anti-estrogenic and anti-mineralocorticoid effects without affecting blood pressure, while micronized spironolactone effectively reduces hirsutism and regulates menstrual cycles without significant side effects. ^{2 5 6 7 11}

Research Team

Christopher R McCartney, M.D.

Principal Investigator

University of Virginia Center for Research in Reproduction

Eligibility Criteria

This trial is for mid to late pubertal girls with hyperandrogenism, which can be related to conditions like Polycystic Ovary Syndrome. Participants must not be pregnant, avoid pregnancy during the study, and should generally be in good health without significant medical issues affecting their heart, lungs or metabolism.

Inclusion Criteria

I am generally healthy, though I may be overweight or have treated thyroid issues.

I, or my guardian, can and will agree to participate in the study.

I am a girl in the middle to late stages of puberty, not more than 2 years after my first period.

Exclusion Criteria

I have signs of increased male traits like more body hair, deeper voice, or enlarged clitoris.

My prolactin levels are more than 20% above the normal limit.

Your liver test results are consistently abnormal, except for mild elevations in bilirubin due to Gilbert's syndrome, or mild elevations in transaminases due to obesity, hypothyroidism, or polycystic ovary syndrome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pretreatment

Participants are pretreated for 2 weeks with either spironolactone or placebo prior to the first CRU admission

2 weeks

CRU Admission 1

Participants undergo an 18-hour Clinical Research Unit admission with blood sampling and polysomnography

18 hours

1 visit (in-person)

Washout Period

A washout period of at least 2 months between CRU admissions to comply with blood withdrawal limits

At least 2 months

CRU Admission 2

Participants undergo a second 18-hour Clinical Research Unit admission with crossover treatment

18 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Micronized progesterone
• Placebo
• Spironolactone

Trial Overview The study tests if spironolactone (which blocks androgen receptors) helps progesterone reduce waking luteinizing hormone pulse frequency in adolescent girls with high levels of male hormones. The effectiveness of this combination treatment is compared against a placebo.

Participant Groups

Group I: Spironolactone Experimental Treatment 2 Interventions

Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with spironolactone (50 mg twice daily).

Group II: Placebo Placebo Group 2 Interventions

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

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

Approved in United States as Progesterone for:

• Menstrual disorders
• Infertility
• Endometriosis
• Polycystic ovary syndrome (PCOS)
• Menopausal hormone therapy

Approved in European Union as Progesterone for:

• Menstrual disorders
• Infertility
• Endometriosis
• Polycystic ovary syndrome (PCOS)
• Menopausal hormone therapy

Approved in Canada as Progesterone for:

• Menstrual disorders
• Infertility
• Endometriosis
• Polycystic ovary syndrome (PCOS)
• Menopausal hormone therapy

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+

Findings from Research

In a study of 82 young women with polycystic ovary syndrome (PCOS), both spironolactone and metformin improved menstrual cycle frequency and reduced hirsutism, but spironolactone was more effective in these areas.

Spironolactone was associated with fewer adverse events compared to metformin, making it a safer option for managing symptoms of PCOS, while both medications improved insulin sensitivity and hormonal levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. Ganie, MA., Khurana, ML., Eunice, M., et al.[2013]

In a study of 34 women with polycystic ovary syndrome, three months of spironolactone treatment led to a significant reduction in hirsutism and helped restore regular menstrual patterns, although the cycles remained anovulatory.

The treatment was safe, with no observed side effects, and it effectively lowered levels of testosterone and other androgens without affecting luteinizing hormone or follicle-stimulating hormone levels, making it a recommended initial therapy for managing symptoms of polycystic ovary syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effects of spironolactone in polycystic ovary syndrome. Milewicz, A., Silber, D., Kirschner, MA.[2013]

In a study of 48 hirsute women treated with spironolactone for 3 to 12 months, both facial and body hair growth improved by 30-40%, leading to a significant reduction in the need for hair removal methods like waxing or shaving.

While plasma testosterone levels decreased by 30% during treatment, this reduction did not directly correlate with the improvement in hirsutism, indicating that spironolactone's mechanism of action may involve factors beyond just lowering testosterone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome. Evans, DJ., Burke, CW.[2020]

In a study of 189 women with polycystic ovarian syndrome (PCOS), the combination of low-dose spironolactone and metformin significantly reduced insulin resistance (HOMA-IR) more than either drug alone after 12 weeks of treatment.

While both metformin and spironolactone were effective in lowering insulin resistance and other hormonal markers, the combined therapy showed superior results, indicating a potential benefit of using both medications together for managing PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Low-Dose Spironolactone Combined with Metformin or Either Drug Alone on Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Pilot Study. Long, T., Zhang, Y., Zeng, C., et al.[2022]

A review of five studies indicates that spironolactone may be an effective treatment for hirsutism in women with polycystic ovary syndrome (PCOS), showing a positive trend in outcomes.

The research highlights that while various treatment options exist for hirsutism, spironolactone has demonstrated promising results in addressing this common issue associated with PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone for hirsutism in polycystic ovary syndrome. Christy, NA., Franks, AS., Cross, LB.[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]

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]

In a study involving 57 women with early menopause and premature ovarian insufficiency, micronised progesterone (MP) combined with transdermal oestradiol (t-E2) showed significant improvements in traditional cardiovascular disease markers, including increased cardiac output and reduced diastolic blood pressure after 12 months.

In contrast, medroxyprogesterone acetate (MPA) combined with t-E2 did not result in significant changes in these traditional cardiovascular parameters, although neither treatment significantly altered the carotid-femoral pulse wave velocity (cfPWV), a key biomarker for cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial. Mittal, M., McEniery, C., Supramaniam, PR., et al.[2022]

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 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 spironolactone tablets, with a smaller particle size of 2.21 micrometers, showed significantly higher bioavailability compared to standard spironolactone tablets with a particle size of 78.8 micrometers after a 200-mg dose in healthy men.

The pharmacologic activity of micronized spironolactone was also significantly greater, as indicated by a higher Na/K ratio in 24-hour urine samples, highlighting the importance of particle size in enhancing the effectiveness of spironolactone treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of micronization on the bioavailability and pharmacologic activity of spironolactone. McInnes, GT., Asbury, MJ., Ramsay, LE., et al.[2019]

References

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

Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. [2013]

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

Therapeutic effects of spironolactone in polycystic ovary syndrome. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome. [2020]

4. Egypt pubmed.ncbi.nlm.nih.gov

Effects of Low-Dose Spironolactone Combined with Metformin or Either Drug Alone on Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Pilot Study. [2022]

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

Spironolactone for hirsutism in polycystic ovary syndrome. [2013]

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

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

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

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

8. Ireland pubmed.ncbi.nlm.nih.gov

Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial. [2022]

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

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

11. England pubmed.ncbi.nlm.nih.gov

Effect of micronization on the bioavailability and pharmacologic activity of spironolactone. [2019]