Polycystic Ovary Syndrome
Conditions
Keywords
Hyperandrogenism, Oral Contraceptive Pills
Brief summary
The mainstay treatment for females with Polycystic Ovary Syndrome (PCOS) has long been a combination of an oral contraceptive pill or OCP (containing both estrogen and progestin) along with an anti-androgen medication (such as Spironolactone) to not only prevent chronic anovulation but also suppress elevated testosterone levels and its clinical effects on the body. While there are multiple OCPs available on the market today and several studies that look at different progestins and their anti-androgenicity, not much is known about whether the length of active pills in OCP therapy (3 weeks versus 6 months) has any further benefit in continued suppression of testosterone and subsequently improvement in clinical findings of hyperandrogenism in the PCOS population. In this pilot randomized open label clinical trial, females between the ages of 16 and 35 years diagnosed with PCOS based on the Rotterdam Criteria, and not currently on medical therapy with an OCP will be enrolled in the study and randomized to either a continuous 6 month OCP or cyclical 21 day active OCP therapy. Our aim is to conduct a pilot randomized clinical trial to determine the effect of 6 months of active monophasic OCPs on testosterone levels and cutaneous findings of hyperandrogenism (hirsutism and acne) as compared to a traditional 21 day active/7 day placebo OCP in women with PCOS. These findings will be compared over a 6 month period.
Detailed description
Those who meet criteria to take part in the study (women between the ages of 16-35 years, diagnosed with PCOS and have findings of hyperandrogenism either by serum testosterone levels above the normal reference range or by their modified Ferriman Gallwey score of \>8, and are recommended to start an oral contraceptive pill for therapy) and give consent, will be randomized into either of two oral contraceptive (OCP) treatment groups: 1. Ethinyl estradiol 30 mcg-Drospirenone 3 mg (Yasmin): 168 days of active hormone pills (no placebo pills) for 6 months. 2. Ethinyl estradiol 30 mcg-Drospirenone 3mg (Yasmin): 21 days of active + 7 days of placebo pills for 6 months Participants will be given the OCP Yasmin with instructions to take the medication at the same time each day for the length of the study (6 months). On the 4th, 12th and 24th week of therapy (roughly the 1st, 3rd and 6th month), blood work will be drawn and is detailed below. At 1 month into therapy, (near the end of the 4th week on an OCP) both treatment groups will be expected to get blood work (total and free testosterone, SHBG, estradiol, LH, and FSH levels will be checked). At the time of the blood draw, subjects in the cyclical group should be on placebo/sugar pills and those in the continuous group on active hormone pills. At 3 months into therapy, participants will come back to the PCOS clinic for routine care follow up and be seen by a Reproductive Endocrinology and Fertility specialist. This visit is considered standard of care and not specific to the study. However, during this visit a study investigator will also touch base briefly with the participants to see how they are doing. An online survey (through REDCap) will also be sent to participants that addresses if they have missed any doses of their medication and assess their acne quality of life. In addition, participants will once again get blood work (including total and free testosterone, SHBG, estradiol, LH, FSH, fasting lipid panel, fasting serum glucose, insulin, and HbA1c). As before, the cyclical group should be on placebo/sugar pills at the time of blood draw and the continuous group on active hormone pills. At 6 months into therapy, participants will come in for a study visit (this is not considered routine care) in which they will have their vitals taken, a physical exam that includes a re-evaluation of their mFG score, and an in-clinic pelvic ultrasound to assess ovarian volume and follicle counts. They will also be emailed a post-study survey through REDCap, that includes a quality of life questionnaire for both acne and hirsutism, and includes questions regarding satisfaction with current therapy and any missed doses of their medication. Lastly, participants will again be expected to get blood work (total and free testosterone, SHBG, estradiol, LH, FSH).
Interventions
DRUGYasmin
Participants in each treatment arm will receive the medication Yasmin. However only the Cyclical OCP Therapy arm will take the sugar pills designated each month in the pill packs and the Continuous OCP Therapy arm will not.
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
To be included in this study, participants must be: 1. Female, within 15-40 years of age 2. Diagnosed with Polycystic Ovary Syndrome based on the 2003 Rotterdam Criteria (must meet 2 out of 3 criteria): 1. evidence of either biochemical or clinical hyperandrogenism (elevated free and or total testosterone level above the normal reference range for assay, and/or an modified Ferriman-Gallwey hirsutism score \>8) 2. Oligo- or anovulation 3. Polycystic ovary morphology on ultrasound 3. Adolescents should be at least 2 years out from menarche (first menstrual period). 4. Participants must not be on an oral contraceptive pill (OCP) at the start of the study and or Spironolactone therapy (an anti-androgen medication), but recommended by their physician to start OCP therapy.
Exclusion criteria
1. Females with Polycystic Ovary Syndrome (PCOS) who do not have either biochemical (elevated total or free testosterone levels) or clinical (modified Ferriman-Gallwey hirsutism score \<8) findings of hyperandrogenism will not be included in the study as this is one of the primary outcome measures. 2. Females with PCOS who are already on and currently using a form of contraceptive (oral, vaginal ring, or patch) 3. Females that are concurrently using or plan to use an anti-androgenic medication such as Spironolactone in the next 6 months. 4. Females currently or are planning to obtain permanent hair removal (ex. laser hair removal, electrolysis) in the concurrent 6 months of starting oral contraceptive (OCP) therapy will also be excluded from the study 5. Women who are pregnant or have contraindications for starting an OCP, including active smokers, history of clotting disorders, history of deep vein thrombosis or blood clots, neoplasia, vascular disease, migraines, hypertension, or have renal/hepatic disease will be excluded from the study as OCP therapy would not be indicated or approved in this population. 6. Females with elevated potassium levels above the normal reference range for age.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Biochemical Hyperandrogenism From Baseline to 1 Month Post Yasmin Initiation | measured at baseline and 1 month into therapy | Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 1 month post Yasmin initiation. |
| Change in Biochemical Hyperandrogenism From Baseline to 3 Month Post Yasmin Initiation | measured at baseline and 3 month into therapy | Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 3 month post Yasmin initiation. |
| Change in Biochemical Hyperandrogenism From Baseline to 6 Month Post Yasmin Initiation | measured at baseline and 6 month into therapy | Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 6 month post Yasmin initiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Findings of Hyperandrogenism - Hirsutism | Baseline and at 6 months into therapy | Participants will be examined by a physician and scored using the modified Ferriman-Gallwey Hirsutism score (mFG). This scoring system is considered the standard scoring system that defines hirsutism (excess male pattern hair growth on the body) quantitatively. There are 9 body areas measured on a scare of 0-4, with higher values indicative of significant hair growth. All subscales are combined for a total score, with a minimum score of 0 and max of 36. A total score of \>/=8 is considered diagnostic for hirsutism. The difference in score values from baseline to 6 months was then calculated. |
| Metabolic Changes With OCP Therapy | Baseline and at 3 months into therapy | Diabetes risk will be assessed and compared in both treatment arms by measuring HOMA-IR (calculated as \[glucose\*insulin\]/405) at both baseline and 3 months visits and calculating the change in HOMA-IR value. Higher HOMA-IR values indicate more severe insulin resistance, with the ranges being as follows: HOMA \<2: Normal, HOMA 2-4: Mild Insulin Resistance, and HOMA \>4: Moderate-Severe Insulin Resistance. |
Countries
United States
Participant flow
Recruitment details
Enrollment occurred between April 2019 and January 2022 at the UCSF Center for Reproductive Health's PCOS multidisciplinary clinic.
Participants by arm
| Arm | Count |
|---|---|
| Continuous OCP Therapy Participants randomly assigned to this arm will receive 8 packs of a 21 day oral contraceptive pills (OCP) called Yasmin (3 mg Drospirenone/0.03 mg Ethinyl estradiol) which comes in a formulation of 21 days of active hormone and 7 days of sugar pills. In this arm, participants will only be expected to take active hormone pills (colored pills) for the 6 months straight without stopping or taking the sugar pills in each pack.
Yasmin: Participants in each treatment arm will receive the medication Yasmin. However only the Cyclical OCP Therapy arm will take the sugar pills designated each month in the pill packs and the Continuous OCP Therapy arm will not. | 26 |
| Cyclical OCP Therapy Participants randomly assigned to this arm will receive 6 packs of a 21 day oral contraceptive pill (OCP) called Yasmin (3 mg Drospirenone/0.03 mg Ethinyl estradiol) which has 21 days of active hormone and 7 days of sugar pills. Participants will take one pill daily for 6 months and be expected to take the sugar pills at the end of each monthly pack prior to starting a new pack.
Yasmin: Participants in each treatment arm will receive the medication Yasmin. However only the Cyclical OCP Therapy arm will take the sugar pills designated each month in the pill packs and the Continuous OCP Therapy arm will not. | 25 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Unable to attend visit(s) due to contracting COVID | 2 | 1 |
| Overall Study | Unable to attend visit(s) due to UCSF pandemic policies restricting non-essential visits | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Continuous OCP Therapy | Cyclical OCP Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 25 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 17 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Modified Ferriman-Gallwey (mFG) score | 13 units on a scale STANDARD_DEVIATION 5 | 14 units on a scale STANDARD_DEVIATION 7 | 13.49 units on a scale STANDARD_DEVIATION 4.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 5 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 6 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 16 Participants | 10 Participants | 26 Participants |
| Region of Enrollment United States | 26 participants | 25 participants | 51 participants |
| Serum Total Testosterone | 32.4 ng/dl STANDARD_DEVIATION 15.3 | 29.5 ng/dl STANDARD_DEVIATION 18.5 | 30.97 ng/dl STANDARD_DEVIATION 16.94 |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 0 / 26 | 0 / 25 |
| serious Total, serious adverse events | 0 / 26 | 1 / 25 |
Outcome results
Primary
Change in Biochemical Hyperandrogenism From Baseline to 1 Month Post Yasmin Initiation
Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 1 month post Yasmin initiation.
Time frame: measured at baseline and 1 month into therapy
Population: Analysis exclusions: 1 non-compliant initially with taking continuous dose, 1 unable to promptly obtain yasmin from pharmacy, 1 unresponsive to appointment scheduling reminders, 6 insufficient specimen volume to run assay and unable to calculate change value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 1 Month Post Yasmin Initiation | -15.38 ng/dl | Standard Deviation 13.15 |
| Cyclical OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 1 Month Post Yasmin Initiation | -8.54 ng/dl | Standard Deviation 17.66 |
Primary
Change in Biochemical Hyperandrogenism From Baseline to 3 Month Post Yasmin Initiation
Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 3 month post Yasmin initiation.
Time frame: measured at baseline and 3 month into therapy
Population: Analysis exclusions: 3 unable to attend appointment due to COVID, 3 participants elected to drop out of study as desired to switch to another brand of OCP, 3 participants were unresponsive to communications to schedule appointment. 4 contracted COVID or unable to attend visit due to UCSF restriction on non-essential visits during COVID lockdown
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 3 Month Post Yasmin Initiation | -17.05 ng/dl | Standard Deviation 17.13 |
| Cyclical OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 3 Month Post Yasmin Initiation | -4.58 ng/dl | Standard Deviation 16.46 |
Primary
Change in Biochemical Hyperandrogenism From Baseline to 6 Month Post Yasmin Initiation
Positive or negative change in blood serum Total Testosterone value (units: ng/dl) from baseline to 6 month post Yasmin initiation.
Time frame: measured at baseline and 6 month into therapy
Population: Analysis exclusions (16): 3 voluntarily dropped out of study for personal reasons, 3 unresponsive to appointment scheduling reminders,1 broke fast and unable to draw, 1 specimen hemolyzed and unable to run assay, 4 contracted COVID or unable to attend visit due to UCSF restriction on non-essential visits during COVID lockdown,4 insufficient specimen volume to run 6 month assay and unable to calculate change value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 6 Month Post Yasmin Initiation | -13.53 ng/dl | Standard Deviation 19.25 |
| Cyclical OCP Therapy | Change in Biochemical Hyperandrogenism From Baseline to 6 Month Post Yasmin Initiation | -9.36 ng/dl | Standard Deviation 13.29 |
Secondary
Change in Clinical Findings of Hyperandrogenism - Hirsutism
Participants will be examined by a physician and scored using the modified Ferriman-Gallwey Hirsutism score (mFG). This scoring system is considered the standard scoring system that defines hirsutism (excess male pattern hair growth on the body) quantitatively. There are 9 body areas measured on a scare of 0-4, with higher values indicative of significant hair growth. All subscales are combined for a total score, with a minimum score of 0 and max of 36. A total score of \>/=8 is considered diagnostic for hirsutism. The difference in score values from baseline to 6 months was then calculated.
Time frame: Baseline and at 6 months into therapy
Population: Analysis exclusions: 8 of the 35 participants who attended the 6 month visit declined the physical exam necessary for physician mFG scoring and thus changes in mFG scores from baseline to 6 months could not be calculated for these participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous OCP Therapy | Change in Clinical Findings of Hyperandrogenism - Hirsutism | -3.14 numerical change in score on a scale | Standard Deviation 2.85 |
| Cyclical OCP Therapy | Change in Clinical Findings of Hyperandrogenism - Hirsutism | -1.62 numerical change in score on a scale | Standard Deviation 3.36 |
Secondary
Metabolic Changes With OCP Therapy
Diabetes risk will be assessed and compared in both treatment arms by measuring HOMA-IR (calculated as \[glucose\*insulin\]/405) at both baseline and 3 months visits and calculating the change in HOMA-IR value. Higher HOMA-IR values indicate more severe insulin resistance, with the ranges being as follows: HOMA \<2: Normal, HOMA 2-4: Mild Insulin Resistance, and HOMA \>4: Moderate-Severe Insulin Resistance.
Time frame: Baseline and at 3 months into therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous OCP Therapy | Metabolic Changes With OCP Therapy | 0.007 HOMA-IR value | Standard Deviation 0.13 |
| Cyclical OCP Therapy | Metabolic Changes With OCP Therapy | 0.071 HOMA-IR value | Standard Deviation 0.269 |