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Polycystic Ovary Syndrome

Hyperandrogenism

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Ovarian Diseases

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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46, XX Disorders of Sex Development

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21-hydroxylase Deficiency

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Natriuretic Agents

Androgens

Spironolactone

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Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

16 weeks without medication, then 16 weeks with medication, then 12 months without medication; spironolactone 50 mg tablets: 50-100 mg orally twice daily (1.7-3.3 mg/kg/24 hr)

Spironolactone is an androgen-receptor commonly used (off-label) for hyperandrogenism in girls and women. It is used in this study to determine if androgen blockade can improve ovulation rates in girls with androgen excess, who often have low rates of ovulation in the years following menarche. The spironolactone dose will be as follows: If ≤ 60 kg, 50 mg twice daily; if \> 60 kg, 100 mg twice daily.

Melissa Gilrain, BS

Christine Burt Solorzano, MD

Melissa Gilrain

Adolescent girls with androgen excess have a higher rate of irregular periods and decreased ovulation rates compared to normal girls, and are considered at-risk for developing polycystic ovary syndrome (PCOS). This pilot study will look at whether giving spironolactone might improve ovulation rates in girls with androgen excess, ages 13-19. If this is true, spironolactone treatment to young girls might prevent PCOS from developing and avoid future infertility.

This is a non-randomized, clinical pilot study testing whether 16 weeks of spironolactone improves ovulation rates in post-menarcheal girls with androgen excess. The investigators will recruit girls ages 13-19 with clinical or biochemical androgen excess (defined as hirsutism and/or elevated Tanner stage-specific free testosterone concentrations) who are 4 to 6 years post-menarche. Girls will keep a menstrual diary and collect twice weekly saliva samples for progesterone and estradiol for 16 weeks before and for 16 weeks during spironolactone (if ≤ 60 kg, 50 mg twice daily; if \> 60 kg, 100 mg twice daily \[1.7-3.3 mg/kg/24 hr\]) use. Girls will be asked to continue to collect saliva twice weekly for progesterone and estradiol testing for an additional 16 weeks after discontinuation of spironolactone and to continue menstrual diaries off of study medication for 12 additional months to assess persistence of any spironolactone effect. Ovulation events will be counted per 100 days based on definitive rises in salivary progesterone. The primary outcome will be changes in ovulation rate during spironolactone use compared to baseline. Changes in menstrual regularity via inter-menstrual interval will also be assessed as a secondary outcome of spironolactone administration. Another secondary outcome will be changes in acne and/or hirsutism.

non-randomized cross-sectional, before and after intervention

Does Treatment of Androgen Excess Using Spironolactone Improve Ovulatory Rates in Girls With Androgen Excess?

Ovulation rate during and after spironolactone compared to before medication. Ovulation will be counted based on salivary progesterone levels. The rate of ovulation will be defined as the number of ovulatory cycles per 100 days of follow-up.

Menstrual length during and after spironolactone compared to before medication. Changes in menstrual regularity will be assessed using inter-menstrual interval (IMI)

Changes in acne before vs. after spironolactone treatment assessed using the Global Acne Grading System

Changes in hirsutism before vs. after spironolactone assessed using a modified Ferriman-Gallwey scoring system

Waterloo Foundation

University of Virginia

Associate Professor of Pediatrics

Anti-Infective Agents

Anti-Bacterial Agents

Doxycycline

Antibiotics, Antitubercular

Matrix Metalloproteinase Inhibitors

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Subjects randomized to receive doxycycline for a period of 12 weeks. A 12-week period thereafter will occur off study medication. The dose of doxycycline to be used in this study is 200mg/day in divided doses of 100mg twice daily. The dose of doxycycline being used in this study is 100mg because it is the standard approved dose.

The administered placebo is to be continued for a period of 12 weeks. A 12-week period thereafter will occur off placebo control

200mg/day in divided doses of 100mg twice daily

doxycycline

Sugar Pill

Kathleen M Hoeger, MD, MPH

Stephen Hammes, MD

The purpose of this study is to study the effect of a commonly used antibiotic, doxycycline, on the production of ovarian hormones and menstrual cycles in women with Polycystic Ovarian Syndrome (PCOS).

Polycystic ovarian syndrome (PCOS) is one of the leading causes of female infertility, affecting 5-10% of reproductive-age women . This heterogeneous disorder is characterized by anovulatory infertility, androgen excess, an increase in the ratio of LH to FSH, and morphologic polycystic changes to the ovaries. Obesity and insulin resistance are also metabolic factors associated with PCOS that further increase the morbidity in these patients. Inducing fertility in patients with PCOS can be a challenge, as it most often involves ovulation induction that can lead to ovarian enlargement, hyperstimulation, and multiple-birth pregnancies. This study is designed to determine novel effective strategies to promote normal cycling in this patient population.

Effect of a Commonly Used Antibiotic, Doxycycline, in Women With Polycystic Ovarian Syndrome

The Use of an MMP Inhibitor, Doxycycline, to Reduce Ovarian Androgen Production and Restore Normal Cycling in Women With Polycystic Ovarian Syndrome

We will determine total serum testosterone levels in all participating subjects at week 24.

We will determine total serum testosterone levels in all participating subjects at week 12.

Serum progesterone levels will be obtained on a weekly basis to assess ovulation. We will then perform statistical analysis on this data to determine the effectiveness of doxycycline in this study population.

The total number of ovulations per group. Ovulation was defined as elevation of serum progesterone and or urinary pregnanediol glucuronide followed by documented menstrual bleeding within 2 weeks of elevation.

University of Rochester

Professor

Subjects randomized to receive doxycycline for a period of 12 weeks. A 12-week period thereafter will occur off study medication. The dose of doxycycline to be used in this study is 200mg/day in divided doses of 100mg twice daily. The dose of doxycycline being used in this study is 100mg because it is the standard approved dose.

doxycycline: 200mg/day in divided doses of 100mg twice daily

The administered placebo is to be continued for a period of 12 weeks. A 12-week period thereafter will occur off placebo control

Sugar Pill: 1 pill twice a day

Total

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

total serum testosterone

free serum testosterone

serum hormone binding globulin (SHBG)

This study was underpowered due to reduced enrollment. Targeted enrollment was 40 and actual enrollment was 10.

Kathleen Hoeger MD MPH

in the sugar pill arm one participant dropped out at week 12

Total Serum Testosterone

This measurement was not completed, because the number of ovulations was measured in its place and better indicates the effect of the treatment. See outcome measure number 8.

Serum Progesterone Levels in Blood

Free Testosterone in Serum

in the sugar till arm, one participant dropped out at week 12

Serum Hormone Binding Globulin (SHBG)

in the sugar pill arm, one participant withdrew at week 12

In the sugar pill arm, one participant withdrew at week 12.

Total Number of Ovulations

Overall Study

Metabolic Diseases

Antineoplastic Agents

Bicalutamide

Androgen Antagonists

Adult females with polycystic ovary syndrome (PCOS) and evidence of clinical or biochemical androgen excess will be recruited.

Bicalutamide at a dose of 50mg once daily for 28 days.

Bicalutamide 50 mg

Polycystic ovary syndrome (PCOS) affects 10% of all women, and it usually co-exists with high levels of sex hormones called androgens, such as testosterone. Women with PCOS are at increased risk of metabolic complications such as diabetes, non-alcoholic fatty liver disease, high blood pressure and heart disease. However, very little is understood about how androgen excess may drive the metabolic complications observed in women with PCOS.

Skeletal muscle is an important site of energy metabolism; increasingly, it is suspected that skeletal muscle energy balance is adversely impacted by androgens, thereby driving metabolic complications. To take this theory forward, we want to investigate the effects of androgens on muscle energy metabolism. We will perform detailed metabolic testing (including blood tests and muscle biopsies) in women with PCOS before and after taking tablets that block the action of testosterone for 28 days. In addition, we will be using a gold standard technique to see how women with PCOS metabolise fat and other nutrients by measuring markers in blood and breath samples after a breakfast test meal. This clinical research will increase our understanding of the complex relationships between hormonal abnormalities and metabolic disease in women with PCOS.

Background:

Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder affecting 10-13% of all women and is associated with major healthcare and economic burden, estimated at $8 billion annually the US in 2020. Traditionally considered a reproductive disorder only, it is now increasingly clear that PCOS is associated with severe metabolic health consequences across the entire life course of women. There is a two-fold increased risk of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease, and emerging evidence of increased cardiovascular disease (CVD) incidence. There are no disease-specific therapies to mitigate or treat metabolic risk in women with PCOS. This is consistently highlighted as the priority concern amongst PCOS patient advocacy groups.

Androgen excess is a cardinal feature of PCOS, and circulating androgen burden is closely correlated with metabolic complications. In women with PCOS, the risk of developing metabolic dysfunction is above that conferred by simple obesity, suggesting that androgen excess is a key player; however, a distinct mechanistic role for androgens in this process remains to be elucidated. Androgen excess is associated with metabolically deleterious visceral fat accumulation and circulating testosterone levels correlate directly with the risk of T2DM and NAFLD. Muscle is a critical metabolic target tissue that plays a central role in energy metabolism through processes such as glucose uptake and oxidation, as well as oxidation of fatty acids to generate ATP in the mitochondria. Recent mechanistic data have shown that androgen excess is associated with changes in the transcriptional profile of skeletal muscle genes linked with metabolism and energy balance. Therefore, skeletal muscle is likely to represent an important site of crosstalk between androgen excess, disturbances in energy metabolism and risk of metabolic disease in PCOS.

Defective skeletal muscle glucose uptake is a key early step in the pathogenesis of insulin resistance in PCOS, and an early predictor of progression to overt type 2 diabetes mellitus. Impaired mitochondrial oxidation of free fatty acids in skeletal muscle and other disturbances in skeletal muscle mitochondrial function, such as oxidative phosphorylation, are increasingly implicated in the pathogenesis of metabolic disease such as T2DM. Abnormalities in skeletal muscle mitochondrial function have also been identified in small-scale studies in women with PCOS, and were associated with impaired fatty acid oxidation, weight gain and an increased risk of diabetes.

We hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a major role in the pathogenesis of metabolic disease in women with PCOS.

Study description:

We propose to test our hypothesis utilising state-of-the-art metabolic phenotyping tools in two study visits. We will examine systemic fatty acid oxidation, muscle proteomics and targeted and non-targeted metabolomics in women with PCOS before and after pharmacological androgen receptor blocade. In addition, a subset of ex vivo muscle biopsies will undergo in vitro experiments to measure skeletal muscle mitochondrial morphology and function.

After study visit 1, all recruited participants will receive 50mg of an oral androgen receptor antagonist (bicalutamide), resulting in pharmacological AR blockade, before undertaking an identical study visit for repeat assessment.

Women with a confirmed diagnosis of polycystic ovary syndrome with androgen excess on clinical or biochemical grounds

The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (REFUEL PCOS) Study 2

Change in whole body fatty acid oxidation on stable isotope breath after 28 days of androgen receptor (AR) blockade compared to baseline

Changes in metabolomic pathways relating to energy balance and mitochondrial function in serum and muscle after AR blockade

Changes in mitochondrial morphology ex vivo post AR blockade

Differences in mitochondrial oxygen consumption and oxidative phosphorylation using Seahorse technology pre and post AR blockade

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Does Treatment of Androgen Excess Using Spironolactone Improve Ovulatory Rates in Girls With Androgen Excess?	NCT04075149	Polycystic Ovar... Puberty Disorde... Ovulation Disor...	Spironolactone	13 Years - 19 Years	University of Virginia
Effect of a Commonly Used Antibiotic, Doxycycline, in Women With Polycystic Ovarian Syndrome	NCT01788215	Polycystic Ovar... Irregular Menst... Androgen Excess	doxycycline Sugar Pill	18 Years - 40 Years	University of Rochester
The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (REFUEL PCOS) Study 2	NCT05647356	Polycystic Ovar... Androgen Excess Metabolic Disea...	Bicalutamide 50...	18 Years - 40 Years	Royal College of Surgeons, Ireland
Does Treatment of Androgen Excess Using Spironolactone Improve Ovulatory Rates in Girls With Androgen Excess?	NCT04075149	Polycystic Ovar... Puberty Disorde... Ovulation Disor...	Spironolactone	13 Years - 19 Years	University of Virginia

Spots Global Cancer Trial Database for androgen excess