Cyclic progesterone and spironolactone treatment for androgenic polycystic ovary syndrome

ISRCTN	ISRCTN99343883
DOI	https://doi.org/10.1186/ISRCTN99343883
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	H20-02824
Sponsor	Women's Health Research Institute
Funders	Women's Health Research Institute, Besins Healthcare International, Pure Integrative Pharmacy

Submission date: 29/08/2021
Registration date: 07/09/2021
Last edited: 27/01/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Polycystic ovary syndrome with higher than normal men's type hormone (called androgenic PCOS) occurs in 10% of women in the population. There are many potential causes. There is no durable treatment that deals with women's four main concerns: weight loss, regular cycles, fertility and hirsutism/acne and signs of high men's type hormones. The current treatment is combined hormonal contraception (The Pill) which results in some improvement but not all can take it and the benefits wear off after 6 months from stopping. The aim of this study is to perform a feasibility study of cyclic progesterone (given for 14 days to be similar to following egg release in a normal cycle) and spironolactone (a hormone that blocks men's hormone actions) over six cycles.

Who can participate?
Women or non-binary born female with physician-diagnosed androgenic PCOS, aged 19-40 years, living in Metro Vancouver, who do not have diabetes

What does the study involve?
Participants are treated with cyclic progesterone and spironolactone for 6 months. The primary outcome of the study is a change in the PCOS-specific quality of life. The researchers will assess safety with potassium measurements at the end of the study, and observe whether cyclic progesterone prevents spironolactone-related abnormal bleeding. The researchers will obtain women's reactions to taking these medicines. Participants will have two blood tests, collect first-morning saliva on 9 different days (stored in a home freezer), keep a daily menstrual cycle diary for 2 weeks on no treatment and for about 6 months on treatment, and answer questionnaires.

What are the possible benefits and risks of participating?
The benefits of participating are helping discover new treatments for PCOS, free access to cyclic progesterone (that is costly in Canada) and spironolactone, learning about yourself through diary-keeping, learning your own lab results, learning the results of the whole study (eventually). The researchers will also provide a free menstrual cup if interested (DivaCup), and the Prior book, Estrogen's Storm Season - stories of perimenopause. The risks of participating are a possible adverse reaction to either study medicine, an elevated potassium value from spironolactone, and abnormal bleeding from spironolactone. The researchers will avoid the risk of pregnancy on spironolactone by providing condoms and vaginal spermicide for women sexually active with a man.

Where is the study run from?
The Centre for Menstrual Cycle and Ovulation Research of the University of British Columbia (Canada)

When is the study starting and how long is it expected to run for?
January 2020 to November 2023

Who is funding the study?
1. Women's Health Research Institute (Canada)
2. Besins Healthcare International (Monaco)
3. Pure Integrative Pharmacy (Canada)

Who is the main contact?
1. Katie Nelson, kaitlin.nelson@ubc.ca
2. Dhani Kalidasan, dhani.kalidasan@ubc.ca
3. Dr Jerilynn C. Prior, jerilynn.prior@ubc.ca

Contact information

Dr Jerilynn C. Prior
Scientific

Suite 4111, 2775 Laurel Street.
Centre for Menstrual Cycle and Ovulation Research
Division of Endocrinology, Department of Medicine, Univ British Columbia
Vancouver
V5Z 1M9
Canada

ORCID ID	0000-0003-3232-0597
Phone	+1 (0)604 875 5927
Email	jerilynn.prior@ubc.ca

Ms Dhani Kalidasan
Public

Suite 4111, 2775 Laurel Street.
Centre for Menstrual Cycle and Ovulation Research
Division of Endocrinology, Department of Medicine, Univ British Columbia
Vancouver
V5Z 1M9
Canada

Phone	+1 (0)604 875 5927
Email	dhani.kalidasan@ubc.ca

Study information

Primary study design	Interventional
Study design	Single-centre single-arm interventional open-label 6-month therapy trial
Secondary study design	Non randomised study
Participant information sheet	ISRCTN99343883_PIS_ V1_28Sep2021.pdf
Scientific title	Phase II 6-month cyclic progesterone/spironolactone pilot therapy trial in polycystic ovary syndrome: pre-post, single-arm feasibility study
Study acronym	Cyclic P4/Sp in PCOS
Study objectives	Cyclic progesterone and spironolactone treatment over 6 months in women with androgenic polycystic ovary syndrome will significantly improve within-woman quality of life measured using the specific, validated PCOS-Q Health-Related Quality of Life instrument.
Ethics approval(s)	Approved 25/01/2020, Clinical Research Ethics Board of the University of British Columbia (UBC CREB Office, Room 210, Research Pavilion, 828 West 10th Avenue, Vancouver, BC V5Z 1L8, Canada; Tel: not available; pia.ganz@ors.ubc.ca), ref: H20-02824
Health condition(s) or problem(s) studied	Polycystic ovary syndrome (PCOS)
Intervention	This is a prospective, open-label, single-arm, pragmatic interventional feasibility study in premenopausal women without type 2 diabetes mellitus (off combined hormonal contraceptives and/or metformin for 1 month) with physician-diagnosed androgenic PCOS treated with oral micronized progesterone (biochemically the same as endogenous ovarian progesterone) for 14 days/month or menstrual cycle, at a dose of 300 mg at bedtime (CyclicP4). After the first full menstrual cycle on CyclicP4 (to avoid abnormal vaginal bleeding) the researchers will begin treating with the androgen- and mineralocorticoid-receptor blocker, spironolactone, at a dose of 200 mg at bedtime taken daily for 5 months.
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Progesterone, spironolactone
Primary outcome measure(s)	Health-related quality of life (HRQoL) change is measured within-woman with androgenic PCOS by the PCOS-Questionnaire© (PCOS-Q) instrument comparing the total score, and domain-specific scores between Phase 0 (screening, random cycle day) and the early follicular phase of Cycle 7 (study end) after 6-months’ treatment with cyclic progesterone (CyclicP4) and 5-months’ treatment with spironolactone (Sp) therapies
Key secondary outcome measure(s)	Current secondary outcome measures as of 29/12/2021: 1. Serum luteinizing hormone (LH) measured by conventional laboratory methods and salivary free testosterone (FreeT) measured by liquid chromatography/mass spectroscopy (LC/MS-MS) in a quantitative aliquot (derived from three separate mornings’ samples) given the pulsatility of hormones in saliva) changes are compared within-woman between Phase 0 and Cycle 7 2. Salivary FreeT change measured by liquid chromatography/mass spectroscopy (LC/MS-MS) is compared within-woman between Phase 0 and Cycle 1 early follicular phase after 14 days of CyclicP4 taken in late Phase 0 to bring on menstruation 3. Weight (kg, measured using balance beam), height (m, measured using weight scale stadiometer), waist circumference (cm, measured using NIH method), blood pressure (seated, automated mean of three readings), body mass index (kg/m²), blood HbA1c (measured using standard laboratory methods), tobacco and alcohol use measured using CaMos questionnaire, and physical activity changes within-woman assessed between Cycle 1 and Cycle 7 4. Menstrual cycle lengths, variability (predictability), flow (assessed by counts of soaked standard-sized pad/tampons or by menstrual cup semi-quantitative measures) and Menstrual Cycle Diary© (Diary) experience changes recorded within-woman are compared between Phase 0 data and the mean of experiences from Cycles 1-6, and also compared between Phase 0 and Cycle 6 5. Estradiol, progesterone, cortisol and DHEA saliva data within-woman changes measured using high-throughput liquid chromatography-tandem mass spectrometry from Phase 0 to Cycle 1 (after one 14-day CyclicP4 exposure) and from Phase 0 to Cycle 7 6. Women’s Perceived Change questionnaire on acne and sleep quality, scored on a Likert Scale (-5 to 0 to +5), assessed in the follicular phase of Cycle 7 7. Generic HRQoL changes assessed within-woman using the SF-36 instrument domain scores and mental and physical summary scores from Phase 0 to Cycle 7 8. SF-36 HRQoL domain and summary scores at Phase 0, and also at Cycle 7, are compared with most recent SF-36 data in age- and BMI range-similar local population-based women from the regional population-based BC Canadian Multicentre Osteoporosis Study (CaMos) cohort. 9. Serum C-reactive protein (hsCRP) and albumin (assessing inflammation) by local laboratory methods, Leukocyte Telomere Length (LTL) and mitochondrial DNA copy number (assessments of genetic aging, by UBC Cote lab-specific methods), and Anti-Mullerian Hormone (AMH, assessment of reproductive reserve) by the best method available (in archived serum stored at -70°C) in 2022-2023 changes will be measured and compared within-woman from Phase 0 to Cycle 7 10. Diary Phase 0, and also Cycle 6 records will be compared with similar-aged normative premenopausal data (archived from the 1-year Prospective Ovulation Cohort, n=53, Prior NEJM 1990) using non-parametric methods and principal components analysis 11. Changes within-woman in all measures between Phase 0 and Cycle 7 will be assessed using regression methods for an influence related to how long (in months, up to 1-year) since women in this trial stopped taking combined hormonal contraceptives (CHC) or metformin treatments 12. Serum potassium (K+) measured by standard laboratory methods at Cycle 7 and determined to be, or not be, within or less than 10% above the local laboratory reference range 13. Potential adverse effects of Sp assessed using the presence/absence of abnormal/unpredictable menstrual timing and flow in Cycle 2 14. Women’s willingness to continue taking CyclicP4/Sp therapy assessed using a 7-part Likert scale at Cycle 7; women’s preference assessed on a 7-part Likert scale for CHC vs CyclicP4/Sp therapy in women who had previously taken CHC as a PCOS treatment _____ Previous secondary outcome measures: 1. Serum luteinizing hormone (LH) measured by conventional laboratory methods and salivary free testosterone (FreeT) measured by liquid chromatography/mass spectroscopy (LC/MS-MS) in a quantitative aliquot (derived from three separate mornings’ samples) given the pulsatility of hormones in saliva) changes are compared within-woman between Phase 0 and Cycle 7 2. Salivary FreeT change measured by liquid chromatography/mass spectroscopy (LC/MS-MS) is compared within-woman between Phase 0 and Cycle 1 early follicular phase after 14 days of CyclicP4 taken in late Phase 0 to bring on menstruation 3. Weight (kg, measured using balance beam), height (m, measured using weight scale stadiometer), waist circumference (cm, measured using NIH method), blood pressure (seated, automated mean of three readings), body mass index (kg/m²), blood HbA1c (measured using standard laboratory methods), tobacco and alcohol use measured using CaMos questionnaire, and physical activity changes within-woman assessed between Cycle 1 and Cycle 7 4. Menstrual cycle lengths, variability (predictability), flow (assessed by counts of soaked standard-sized pad/tampons or by menstrual cup semi-quantitative measures) and Menstrual Cycle Diary© (Diary) experience changes recorded within-woman are compared between Phase 0 data and the mean of experiences from Cycles 1-6, and also compared between Phase 0 and Cycle 6 5. Estradiol, progesterone, cortisol and DHEA saliva data within-woman changes measured using high-throughput liquid chromatography-tandem mass spectrometry from Phase 0 to Cycle 1 (after one 14-day CyclicP4 exposure) and from Phase 0 to Cycle 7 6. Women’s Perceived Change questionnaire on acne and sleep quality, scored on a Likert Scale (-5 to 0 to +5), assessed in the follicular phase of Cycle 7 7. Generic HRQoL changes assessed within-woman using the SF-36 instrument domain scores and mental and physical summary scores from Phase 0 to Cycle 7 7. SF-36 HRQoL domain and summary scores at Phase 0, and also at Cycle 7, are compared with most recent SF-36 data in age- and BMI range-similar local population-based women from the regional population-based BC Canadian Multicentre Osteoporosis Study (CaMos) cohort. 8. Serum C-reactive protein (hsCRP) and albumen (assessing inflammation) by local laboratory methods, Leukocyte Telomere Length (LTL) and mitochondrial DNA (assessments of genetic aging, by UBC Cote lab-specific methods), and Anti-Mullerian Hormone (AMH, assessment of reproductive reserve) by the best method available (in archived serum stored at -70°C) in 2022-2023 changes will be measured and compared with-woman from Phase 0 to Cycle 7 9. Diary Phase 0, and also Cycle 6 records will be compared with similar-aged normative premenopausal data (archived from the 1-year Prospective Ovulation Cohort, n=53, Prior NEJM 1990) using non-parametric methods and principal components analysis 10. Changes within-woman in all measures between Phase 0 and Cycle 7 will be assessed using regression methods for an influence related to how long (in months, up to 1-year) since women in this trial stopped taking combined hormonal contraceptives (CHC) or metformin treatments 11. Serum potassium (K+) measured by standard laboratory methods at Cycle 7 and determined to be, or not be, within or less than 10% above the local laboratory reference range 12. Potential adverse effects of Sp assessed using the presence/absence of abnormal/unpredictable menstrual timing and flow in Cycle 2 13. Women’s willingness to continue taking CyclicP4/Sp therapy assessed using a 7-part Likert scale at Cycle 7; women’s preference assessed on a 7-part Likert scale for CHC vs CyclicP4/Sp therapy in women who had previously taken CHC as a PCOS treatment
Completion date	31/12/2023

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	19 Years
Upper age limit	40 Years
Sex	Female
Target sample size at registration	40
Total final enrolment	41
Key inclusion criteria	Current inclusion criteria as of 08/12/2022: 1. Community dwelling 2. Physician diagnosed with androgenic PCOS 3. Ages 19-40 years (we will screen those between the ages of 35-40 for very early perimenopause (Prior JC. (2005). Clearing confusion about perimenopause. BC Medical Journal 47(10): 534-538) 4. If applicable, 1 month off combined hormonal contraceptives 5. If applicable, 1 month off metformin therapy 6. Not at high risk for type 2 diabetes mellitus (T2DM) (based on HbA1c >6.4%) 7. Not seeking fertility in the next 6-7 months 8. Willing to use a barrier (condoms, provided) and an applicator full of vaginal spermicide if at risk for pregnancy (sexually active with a man) Previous inclusion criteria: 1. Community dwelling 2. Physician diagnosed with androgenic PCOS 3. Ages 19-35 years 4. If applicable, 1 month off combined hormonal contraceptives 5. If applicable, 1 month off metformin therapy 6. Not at high risk for type 2 diabetes mellitus (T2DM) (based on HbA1c >6.4%) 7. Not seeking fertility in the next 6-7 months 8. Willing to use a barrier (condoms, provided) and an applicator full of vaginal spermicide if at risk for pregnancy (sexually active with a man)
Key exclusion criteria	Current exclusion criteria as of 18/03/2022: 1. PCOS based only on oligomenorrhea and polycystic ovary morphology without androgen excess. 2. High risk for type 2 diabetes mellitus based on HbA1c of 6.4 or higher 3. Younger than 19 years or older than age 35 years 4. Unwilling to stop combined hormonal contraceptives (for 1 month before joining) or other hormonal contraception (such as DepoMPA for 6 months) and during the study 5. Unwilling to stop metformin (for 1 month before joining) and during the study 4. Unwilling to stop working toward fertility for 7 months 5. Unwilling to use a barrier method (condom) and a whole applicator of vaginal spermicide with each intercourse (if at risk for pregnancy) 6. Currently breastfeeding and have been for less than 6 months 7. History of migraines with aura and/or neurological signs and symptoms since this brain sensitivity may mean starting or stopping progesterone could trigger a migraine _____ Previous exclusion criteria: 1. PCOS based only on oligomenorrhea and polycystic ovary morphology without androgen excess. 2. High risk for type 2 diabetes mellitus based on HbA1c of 6.4 or higher 3. Younger than 19 years or older than age 35 years 4. Unwilling to stop combined hormonal contraceptives (for 1 month before joining) or other hormonal contraception (such as DepoMPA for 6 months) and during the study 5. Unwilling to stop metformin (for 1 month before joining) and during the study 4. Unwilling to stop working toward fertility for 7 months 5. Unwilling to use a barrier method (condom) and a whole applicator of vaginal spermicide with each intercourse (if at risk for pregnancy)
Date of first enrolment	29/10/2021
Date of final enrolment	02/03/2023

Locations

Countries of recruitment

Canada

Study participating centre

University of British Columbia Centre for Menstrual Cycle and Ovulation Research

2775 Laurel Street, Suite 4111
CeMCOR, UBC Division of Endocrinology
Vancouver
V5Z 1M9
Canada

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The researchers will share results privately with all participants as they become available through a password-protected section of the CeMCOR website (https://www.cemcor.ubc.ca). They will share the results more widely once the main paper has been published. The data officer for the Centre for Menstrual Cycle and Ovulation Research (currently Jerilynn C. Prior [Jerilynn.prior@ubc.ca]) is the contact for use of the data (alternate email Dharani Kalidasan [dhani.kalidasan@ubc.ca]). Per ethics regulations, all data will be de-identified before any sharing. The requesting, qualified scientists will be asked to provide a hypothesis and a primary objective for use of the data and will be required to work with CeMCOR scientists in further evaluation of these data.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	version 1	28/09/2021	29/12/2021	No	Yes
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol (other)		03/02/2022	08/09/2022	No	No
Thesis results		06/01/2025	27/01/2025	No	No

Additional files

ISRCTN99343883_PIS_ V1_28Sep2021.pdf: Participant information sheet

Editorial Notes

27/01/2025: The intention to publish date was changed from 31/12/2024 to 31/05/2025.
10/07/2024: The following changes were made:
1. The total final enrolment was changed from 39 to 41.
2. The intention to publish date was changed from 01/07/2024 to 31/12/2024.
19/12/2023: The following changes were made:
1. The overall end date was changed from 30/11/2023 to 31/12/2023.
2. The intention to publish date was changed from 01/06/2024 to 01/07/2024.
20/10/2023: The following changes were made to the trial record:
1. The overall end date was changed from 02/10/2023 to 30/11/2023.
2. The intention to publish date was changed from 01/03/2024 to 01/06/2024.
3. The plain English summary was updated to reflect these changes.
21/03/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/01/2023 to 02/03/2023.
2. The overall trial end date has been changed from 30/09/2023 to 02/10/2023 and the plain English summary updated accordingly.
3. Total final enrolment added.
08/12/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/12/2022 to 31/01/2023.
2. The overall trial end date has been changed from 01/08/2023 to 30/09/2023 and the plain English summary updated accordingly.
3. The inclusion criteria were updated.
08/09/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/09/2022 to 01/12/2022.
2. The overall trial end date has been changed from 01/05/2023 to 01/08/2023 and the plain English summary updated accordingly.
15/06/2022: The following changes have been made:
1. The recruitment end date has been changed from 30/06/2022 to 01/09/2022.
2. The overall trial end date has been changed from 01/03/2023 to 01/05/2023 and the plain English summary updated accordingly.
18/03/2022: The participant exclusion criteria have been changed.
07/03/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 15/03/2022 to 30/06/2022.
2. The overall trial end date was changed from 15/10/2022 to 01/03/2023.
3. The intention to publish date was changed from 15/10/2023 to 01/03/2024.
29/12/2021: The following changes have been made:
1. A participant information sheet has been added to the trial outputs.
2. The secondary outcome measures have been changed.
3. The recruitment start date has been changed from 15/09/2021 to 29/10/2021.
4. Katie Nelson's email address has been added to the plain English summary.
06/09/2021: Trial's existence confirmed by the Clinical Research Ethics Board of the University of British Columbia.