Predictors of Hyperandrogenism for Polycystic Ovary Syndrome

(SHK001 Trial)

Overseen By Melissa G Gilrain, BS

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: University of Virginia

Must not be taking: Oral contraceptives, Metformin

Disqualifiers: Diabetes, Cushing's syndrome, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1 day

144 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The objective of the study is to determine the relative contributions of four established predictors of hyperandrogenism (luteinizing hormone \[LH\] secretion, ovarian response to recombinant human chorionic gonadotropin \[r-hCG\] administration, adrenal response to adrenocorticotropic hormone \[ACTH\] administration, and hyperinsulinemia) in older vs. young women with Polycystic Ovary Syndrome (PCOS) in a cross-sectional, physiological study. The investigators hypothesize that hyperinsulinemia is a stronger independent predictor of free testosterone (T) in older reproductive aged (vs. young) women with PCOS.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that affect the reproductive system, such as birth control pills, metformin, and certain mood stabilizers, at least 2 months before screening and 3 months before the study.

Is the treatment safe for humans?

The treatment, including recombinant human chorionic gonadotropin (rhCG), was found to be safe and well-tolerated in a study involving 84 healthy men and women. This suggests it is generally safe for human use. ^{1 2 3 4 5}

How does this treatment for PCOS differ from other treatments?

This treatment for PCOS is unique because it focuses on understanding and predicting hyperandrogenism (excess male hormones) by examining adrenal androgen secretion and novel androgen pathways, which are not well understood in current treatments. This approach may offer new insights into managing PCOS by targeting specific hormonal imbalances. ^{6 7 8 9 10}

What data supports the effectiveness of the drug ACTH (Adrenocorticotropic hormone) for treating hyperandrogenism in polycystic ovary syndrome?

The research indicates that there is heightened adrenal androgen activity in polycystic ovary syndrome, suggesting that treatments targeting adrenal function, like ACTH, could potentially influence androgen levels. However, the studies do not directly assess the effectiveness of ACTH in treating hyperandrogenism in PCOS. ^{6 8 11 12 13}

Who Is on the Research Team?

Chris McCartney, MD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

This trial is for women aged 20-30 and 40-49 with PCOS, showing signs of excess male hormones and irregular periods. They must not be at risk of pregnancy, willing to follow the study plan, and have no history of severe health issues like heart disease or diabetes. Women close to menopause or with certain hormonal disorders are excluded.

Inclusion Criteria

I have PCOS with signs of high male hormones and irregular periods.

I am committed to preventing pregnancy using non-hormonal methods during the study.

Subjects must be willing and able to provide written informed consent

Exclusion Criteria

Your total testosterone level is higher than 150 ng/dL.

I understand what the study involves and why it's being done.

Prisoners

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline measurements including free testosterone, LH concentrations, and glucose tolerance test

1 day

1 visit (in-person)

Treatment

Administration of ACTH and rhCG to assess hormonal responses

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ACTH
• rhCG

Trial Overview The study aims to understand how different factors contribute to high male hormone levels in younger vs. older women with PCOS by testing their responses to rhCG (a fertility drug) and ACTH (a hormone that stimulates adrenal glands).

How Is the Trial Designed?

Group I: ACTH (Cosyntropin), rhCG (Ovidrel) Experimental Treatment 2 Interventions

ACTH (Cosyntropin) administered 250 mcg IV; rhCG (Ovidrel) administered 250 mcg IV

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Published Research Related to This Trial

Both 'classic' polycystic ovary syndrome (PCO) patients and 'PCO-like' patients show elevated adrenal androgen responses, specifically androstenedione and dehydroepiandrosterone (DHEA), when stimulated with corticotropin-releasing factor (CRF).

Basal levels of DHEA sulfate (DHEA-S) do not effectively predict adrenal responses to CRF, indicating that DHEA-S may not be a reliable marker for adrenal hyperactivity in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pituitary-adrenal responses to ovine corticotropin-releasing factor in polycystic ovary syndrome and in other hyperandrogenic patients. Carmina, E., Lobo, RA.[2019]

In a study of 30 women with polycystic ovary syndrome (PCOS), 70% had elevated levels of DHEA sulfate and 53% had elevated 11 beta-hydroxyandrostenedione, indicating significant adrenal androgen excess in this population.

After 3 to 6 months of GnRH agonist therapy, the number of women with elevated DHEA sulfate decreased to 37%, suggesting that the therapy can effectively reduce adrenal androgen levels, particularly in those with initially high levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome. Carmina, E., Gonzalez, F., Chang, L., et al.[2018]

In a study of 187 non-obese women aged 18-35, higher serum Anti-Müllerian hormone (AMH) levels were significantly associated with menstrual disturbances, indicating that AMH could be a useful biomarker for diagnosing PCOS-related menstrual issues.

Women with serum AMH levels greater than 60 pmol/L had a 28.5-fold increased likelihood of experiencing menstrual disturbances compared to those with lower AMH levels, highlighting the potential of AMH in identifying women at risk for PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome. Abbara, A., Eng, PC., Phylactou, M., et al.[2021]

In a study of 45 women with polycystic ovary syndrome (PCOS) compared to 27 controls, significant increases in serum androstenedione, total and free testosterone were observed, confirming a hyperandrogenic state in PCOS patients.

The study also revealed overactivity of the hypothalamic-pituitary-adrenal axis in PCOS, indicated by increased urinary free cortisol and decreased corticosteroid-binding globulin, suggesting that urinary free cortisol is not a reliable marker to differentiate PCOS from Cushing's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased urinary free cortisol and decreased serum corticosteroid-binding globulin in polycystic ovary syndrome. Invitti, C., Pecori Giraldi, F., Dubini, A., et al.[2019]

In women with polycystic ovary syndrome (PCOS), a low dose ACTH stimulation test (1 microg) revealed adrenal hyperactivity, particularly shown by increased levels of dehydroepiandrosterone sulfate (DHEAS).

The study found that at a standard dose of ACTH (250 microg), women with PCOS had significantly higher responses of 17-hydroxyprogesterone, androstenedione, and DHEAS compared to healthy women, indicating dysregulation of adrenal hormone production in PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome. Colak, R., Keleştimur, F., Unlühizarci, K., et al.[2022]

The novel recombinant human chorionic gonadotropin (rhCG; CG beta) was found to be safe and well-tolerated in a first-in-human trial involving 84 healthy subjects, indicating its potential for further clinical development.

CG beta demonstrated higher pharmacokinetic (PK) exposure compared to CG alfa, with a longer half-life and greater serum testosterone response, suggesting that it may be effective at lower therapeutic doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human trial assessing the pharmacokinetic-pharmacodynamic profile of a novel recombinant human chorionic gonadotropin in healthy women and men of reproductive age. Broksø Kyhl, LE., Hesse, C., Larsson, P., et al.[2022]

In a study comparing 24 unexplained infertile women to 13 fertile women, the infertile group showed significantly higher baseline testosterone levels, indicating that their elevated testosterone likely originated from ovarian sources.

Despite the higher testosterone levels, 46.66% of the infertile women who received follow-up treatment successfully conceived after ovulation induction therapy, suggesting that elevated testosterone may not preclude successful fertility treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adrenal response to adrenocorticotropin stimulation in unexplained infertile women. Cohen, I., Blanstein, J., Ben-Michael, R., et al.[2019]

In a study of 12 women with polycystic ovary syndrome (PCOS), it was found that their response to corticotropin-releasing hormone (CRH) was significantly greater than that of age- and weight-matched controls, indicating a heightened adrenal response.

The prolonged secretion of ACTH and cortisol in PCOS patients suggests a hyperfunction of the hypothalamic-pituitary-adrenal axis, which may contribute to the complex symptoms associated with PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. Lanzone, A., Petraglia, F., Fulghesu, AM., et al.[2019]

In a study comparing 13 women with polycystic ovary syndrome (PCOS) to 15 healthy women, both groups showed similar increases in androgen levels during an ACTH infusion, indicating that the adrenal response to ACTH is not impaired in women with PCOS.

The findings suggest that the hyperandrogenemia seen in PCOS may result from dysregulated steroid production in both the adrenal glands and ovaries, as individual responses to ACTH and hCG were significantly correlated in women with PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Androgen responses to adrenocorticotropic hormone infusion among individual women with polycystic ovary syndrome. Maas, KH., Chuan, S., Harrison, E., et al.[2018]

In lean women with polycystic ovary syndrome (PCOS), there is increased production of cortisol and androgens, indicating a dysregulation of steroid metabolism, which may involve enhanced activity of the enzyme 5alpha-reductase (5alpha-R) and reduced activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).

Insulin levels were found to positively correlate with the activity of 5alpha-R in PCOS, suggesting that insulin may enhance the conversion of steroids, but this was not linked to elevated cortisol production rates, indicating that the dysregulation of steroid metabolism is complex and not the primary cause of PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. Tsilchorozidou, T., Honour, JW., Conway, GS.[2022]

In a study involving 42 women with polycystic ovary syndrome (PCOS) and 42 matched healthy controls, it was found that women with PCOS had significantly higher levels of androgens across four different steroid biosynthetic pathways, indicating a complex hormonal imbalance associated with the condition.

The research revealed that while PCOS women exhibited elevated serum testosterone levels and metabolites from various androgen pathways, no specific diagnostic pattern was identified in their steroid profiles, suggesting that PCOS may not have a unique biochemical signature compared to other conditions affecting steroid biosynthesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The serum steroid signature of PCOS hints at the involvement of novel pathways for excess androgen biosynthesis. Altinkilic, EM., du Toit, T., Sakin, Ö., et al.[2023]

In a study of 1741 women with polycystic ovary syndrome (PCOS), obesity was linked to higher levels of testosterone, which increased the risk of symptoms like hirsutism, infertility, and menstrual cycle disturbances.

The research found that elevated luteinizing hormone (LH) levels above 10 IU/l were associated with infertility, suggesting that weight loss could improve symptoms and that treatment should be tailored based on hormone levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Balen, AH., Conway, GS., Kaltsas, G., et al.[2022]

In a study of 204 women with PCOS, using gold standard methods for measuring free testosterone (FT) revealed that 70.6% were hyperandrogenemic, while routine assays significantly misclassified 29.4% of patients, affecting their clinical phenotype assignment.

The findings suggest that relying on routine testosterone assays can lead to incorrect classifications of PCOS phenotypes and metabolic risk, highlighting the importance of using accurate measurement techniques for better diagnosis and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of Androgen Assay Accuracy in the Phenotyping of Women With Polycystic Ovary Syndrome. Tosi, F., Fiers, T., Kaufman, JM., et al.[2022]

Citations

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

Pituitary-adrenal responses to ovine corticotropin-releasing factor in polycystic ovary syndrome and in other hyperandrogenic patients. [2019]

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

Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome. [2021]

4. Denmark pubmed.ncbi.nlm.nih.gov

Increased urinary free cortisol and decreased serum corticosteroid-binding globulin in polycystic ovary syndrome. [2019]

5. England pubmed.ncbi.nlm.nih.gov

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome. [2022]

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

First-in-human trial assessing the pharmacokinetic-pharmacodynamic profile of a novel recombinant human chorionic gonadotropin in healthy women and men of reproductive age. [2022]

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

Adrenal response to adrenocorticotropin stimulation in unexplained infertile women. [2019]

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

Corticotropin-releasing hormone induces an exaggerated response of adrenocorticotropic hormone and cortisol in polycystic ovary syndrome. [2019]

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

Androgen responses to adrenocorticotropic hormone infusion among individual women with polycystic ovary syndrome. [2018]

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

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. [2022]

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

The serum steroid signature of PCOS hints at the involvement of novel pathways for excess androgen biosynthesis. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. [2022]

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

Implications of Androgen Assay Accuracy in the Phenotyping of Women With Polycystic Ovary Syndrome. [2022]