Premature Ovarian FailurePhase 4NCT00732693
Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
A Phase 4 study testing Ethinylestradiol / Norethisterone and Estradiol / Progesterone in people with Premature Ovarian Failure, run by University of Edinburgh at 2 sites in United Kingdom.
Trial summary
The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens. Read more about this study
- Who is it for?
- Any age, women only
- Conditions the study is for
- Premature Ovarian Failure
- What is being tested?
- Ethinylestradiol / Norethisterone and Estradiol / Progesterone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Feb 2002to Nov 2006
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Premature Ovarian Failure
Who cannot join
- Intercurrent illness
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
Royal Infirmary of Edinburgh
Edinburgh, EH16 4SA
Royal Hospital for Sick Children
Edinburgh, EH9 1LF
About this study
Official title: Comparison of Standard and Physiologic Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure and the Assessment of Skeletal, Cardiovascular and Reproductive Parameters
The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.
Read the detailed description
Premature ovarian failure, defined as the onset of the menopause before the age of 40 years, is a relatively common problem that affects 1% of women. There are a variety of aetiologies underlying premature ovarian failure including Turner syndrome and those with idiopathic onset, however with the increasing success of intensive treatment for childhood cancer, there are increasing numbers of young survivors, with a variety of late effects of treatment, including premature ovarian failure.
Evidence is required for the optimal management of young women with premature ovarian failure, either as a result of childhood cancer treatment or for other reasons. These women are currently offered combined sex steroid replacement in the convenient form of the oral contraceptive pill, or hormone replacement therapy, designed for older women after the menopause. These preparations are not designed to achieve physiological replacement of oestrogen or progesterone, either in dosage or in biochemical structure - many preparations using synthetic derivatives. These younger women who have differing metabolic and psychological requirements are looking to a future of 30 or more years of replacement. The optimal mode of SSR is not known for young women with premature ovarian failure, however there is concern that current regimens may be inadequate for optimal skeletal and cardiovascular health.
Current preliminary data demonstrates that use of physiological sex steroid replacement improves uterine parameters. Evidence is required to determine whether optimising sex steroid replacement can also significantly improve parameters of skeletal and cardiovascular health. Young women with ovarian failure face several decades of hormone replacement, so small improvements in management may make large differences to later morbidity and mortality.
The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.
- Conditions
- Premature Ovarian Failure
- Being tested
- Ethinylestradiol / Norethisterone, Estradiol / Progesterone
- Keywords
- Premature ovarian failure, Sex hormone replacement, HRT, Blood pressure, Bone mineral density, Bone metabolism, Uterine function
- Medical subject headings
- Primary Ovarian Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ethinylestradiol / NorethisteroneDrug
Also called Loestrin 30, Galen Ltd, UK
Oral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 "pill free" days
Estradiol / ProgesteroneDrug
Also called Estraderm TTS, Novartis Pharmaceuticals UK Ltd, Cyclogest, Activis UK Ltd
Transdermal estradiol 100mcg daily for week 1, then 150mcg daily for weeks 2-4; and vaginal progesterone pessaries 200mg twice daily for weeks 3-4
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Treatment with standard sex steroid replacement regimen Receives: Drug: Ethinylestradiol / Norethisterone |
| 2 | Experimental | Treatment with physiologic sex steroid regimen Receives: Drug: Estradiol / Progesterone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in 24 hour ambulatory blood pressure
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
Bone mineral density measurements (DEXA)
Measured: Baseline, 14 and 24 months
Uterine ultrasound scan to assess uterine volume, endometrial thickness, and uterine artery blood flow
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
Secondary outcomes (4)
Central arterial blood pressure and arterial stiffness measured using peripheral arterial tonometry
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Biochemical evidence of activity on the renin-angiotensin system, including plasma renin activity, angiotensin II, aldosterone, creatinine, urea and electrolyte concentrations.
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Serum markers of collagen turnover and bone matrix formation
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Hormonal assays for gonadotrophins, FSH, LH and sex steroids estrogen and progesterone
Measured: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Aug 2008 (estimated)
- Study startFeb 2002
- Primary completionNov 2006
- Study completionNov 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Premature Ovarian FailureStudies of the same condition, open and under way.
- More trials run by University of EdinburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Edinburgh
- Sponsor type
- University, hospital or other
- Investigators
- W Hamish B Wallace, MD, Principal investigator, NHS Lothian / University of Edinburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00732693
- Sponsor's protocol ID
- CLIC/Sargent-178000-R35464
- Status last verified
- Aug 2008
- First submitted
- 11 Aug 2008
- Last updated
- 12 Aug 2008
- Results posted
- No
- Data monitoring committee
- No
Publications
Bath LE, Critchley HO, Chambers SE, Anderson RA, Kelnar CJ, Wallace WH. Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement. Br J Obstet Gynaecol. 1999 Dec;106(12):1265-72. doi: 10.1111/j.1471-0528.1999.tb08180.x.
PubMed 10609720Critchley HO, Buckley CH, Anderson DC. Experience with a 'physiological' steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure. Br J Obstet Gynaecol. 1990 Sep;97(9):804-10. doi: 10.1111/j.1471-0528.1990.tb02574.x.
PubMed 2242365Critchley HO, Wallace WH, Shalet SM, Mamtora H, Higginson J, Anderson DC. Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstet Gynaecol. 1992 May;99(5):392-4. doi: 10.1111/j.1471-0528.1992.tb13755.x.
PubMed 1622911Davies MC, Gulekli B, Jacobs HS. Osteoporosis in Turner's syndrome and other forms of primary amenorrhoea. Clin Endocrinol (Oxf). 1995 Dec;43(6):741-6. doi: 10.1111/j.1365-2265.1995.tb00544.x.
PubMed 8736278Hansen SW, Olsen N. Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin for germ cell cancer: measurement of vasoconstrictor response to cold. J Clin Oncol. 1989 Jul;7(7):940-2. doi: 10.1200/JCO.1989.7.7.940.
PubMed 2472472Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation. Int J Cancer. 1989 Mar 15;43(3):399-402. doi: 10.1002/ijc.2910430309.
PubMed 2538400Hoorweg-Nijman JJ, Kardos G, Roos JC, van Dijk HJ, Netelenbos C, Popp-Snijders C, de Ridder CM, Delemarre-van de Waal HA. Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol (Oxf). 1999 Feb;50(2):237-44. doi: 10.1046/j.1365-2265.1999.00654.x.
PubMed 10396368Howell SJ, Shalet SM. Aetiology-specific effect of premature ovarian failure on bone mass - is residual ovarian function important? Clin Endocrinol (Oxf). 1999 Nov;51(5):531-4. doi: 10.1046/j.1365-2265.1999.00891.x. No abstract available.
PubMed 10594512Kaneko N, Kawagoe S, Hiroi M. Turner's syndrome--review of the literature with reference to a successful pregnancy outcome. Gynecol Obstet Invest. 1990;29(2):81-7. doi: 10.1159/000293307.
PubMed 2185981Krolner B, Pors Nielsen S. Bone mineral content of the lumbar spine in normal and osteoporotic women: cross-sectional and longitudinal studies. Clin Sci (Lond). 1982 Mar;62(3):329-36. doi: 10.1042/cs0620329.
PubMed 6977427Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999 Jun 10;340(23):1801-11. doi: 10.1056/NEJM199906103402306. No abstract available.
PubMed 10362825Register TC, Jayo MJ, Jerome CP. Oral contraceptive treatment inhibits the normal acquisition of bone mineral in skeletally immature young adult female monkeys. Osteoporos Int. 1997;7(4):348-53. doi: 10.1007/BF01623776.
PubMed 9373569Rubin K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics. 1998 Aug;102(2 Pt 3):481-5.
PubMed 9685448Saenger P. Clinical review 48: The current status of diagnosis and therapeutic intervention in Turner's syndrome. J Clin Endocrinol Metab. 1993 Aug;77(2):297-301. doi: 10.1210/jcem.77.2.8345029. No abstract available.
PubMed 8345029O'Donnell RL, Warner P, Lee RJ, Walker J, Bath LE, Kelnar CJ, Wallace WH, Critchley HO. Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen. Hum Reprod. 2012 Apr;27(4):1130-8. doi: 10.1093/humrep/des004. Epub 2012 Feb 16.
PubMed 22343553
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Standard and Physiologic Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure and the Assessment of Skeletal, Cardiovascular and Reproductive Parameters
- ClinicalTrials.gov ID
- NCT00732693
- Acronym / sponsor ID
- CLIC/Sargent-178000-R35464
- Conditions
- Premature Ovarian Failure
- Keywords
- Premature ovarian failure, Sex hormone replacement, HRT, Blood pressure, Bone mineral density, Bone metabolism, Uterine function
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- University of EdinburghUniversity, hospital or other
- Study start
- Feb 2002
- Primary completion
- Nov 2006 (actual)
- Study completion
- Nov 2006 (actual)
- First posted
- 12 Aug 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.
Detailed description
Premature ovarian failure, defined as the onset of the menopause before the age of 40 years, is a relatively common problem that affects 1% of women. There are a variety of aetiologies underlying premature ovarian failure including Turner syndrome and those with idiopathic onset, however with the increasing success of intensive treatment for childhood cancer, there are increasing numbers of young survivors, with a variety of late effects of treatment, including premature ovarian failure.
Evidence is required for the optimal management of young women with premature ovarian failure, either as a result of childhood cancer treatment or for other reasons. These women are currently offered combined sex steroid replacement in the convenient form of the oral contraceptive pill, or hormone replacement therapy, designed for older women after the menopause. These preparations are not designed to achieve physiological replacement of oestrogen or progesterone, either in dosage or in biochemical structure - many preparations using synthetic derivatives. These younger women who have differing metabolic and psychological requirements are looking to a future of 30 or more years of replacement. The optimal mode of SSR is not known for young women with premature ovarian failure, however there is concern that current regimens may be inadequate for optimal skeletal and cardiovascular health.
Current preliminary data demonstrates that use of physiological sex steroid replacement improves uterine parameters. Evidence is required to determine whether optimising sex steroid replacement can also significantly improve parameters of skeletal and cardiovascular health. Young women with ovarian failure face several decades of hormone replacement, so small improvements in management may make large differences to later morbidity and mortality.
The aim of the study is to determine whether physiological sex steroid replacement improves parameters of skeletal, cardiovascular and reproductive health of women treated with current sex steroid replacement regimens.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Ethinylestradiol / NorethisteroneTreatment with standard sex steroid replacement regimen |
| 2 | Experimental | Drug: Estradiol / ProgesteroneTreatment with physiologic sex steroid regimen |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- Premature Ovarian Failure
Key exclusion criteria (1 listed)
- Intercurrent illness
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ethinylestradiol / NorethisteroneAlso: Loestrin 30, Galen Ltd, UKOral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 "pill free" days | Drug | 1 |
| Estradiol / ProgesteroneAlso: Estraderm TTS, Novartis Pharmaceuticals UK Ltd, Cyclogest, Activis UK LtdTransdermal estradiol 100mcg daily for week 1, then 150mcg daily for weeks 2-4; and vaginal progesterone pessaries 200mg twice daily for weeks 3-4 | Drug | 2 |
Primary outcome
Change in 24 hour ambulatory blood pressure
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
Bone mineral density measurements (DEXA)
Time frame: Baseline, 14 and 24 months
Uterine ultrasound scan to assess uterine volume, endometrial thickness, and uterine artery blood flow
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
4 secondary outcomes
Central arterial blood pressure and arterial stiffness measured using peripheral arterial tonometry
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Biochemical evidence of activity on the renin-angiotensin system, including plasma renin activity, angiotensin II, aldosterone, creatinine, urea and electrolyte concentrations.
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Serum markers of collagen turnover and bone matrix formation
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Hormonal assays for gonadotrophins, FSH, LH and sex steroids estrogen and progesterone
Time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2008.
- Background: PubMed 10609720Bath LE, Critchley HO, Chambers SE, Anderson RA, Kelnar CJ, Wallace WH. Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement. Br J Obstet Gynaecol. 1999 Dec;106(12):1265-72. doi: 10.1111/j.1471-0528.1999.tb08180.x.
- Background: PubMed 2242365Critchley HO, Buckley CH, Anderson DC. Experience with a 'physiological' steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure. Br J Obstet Gynaecol. 1990 Sep;97(9):804-10. doi: 10.1111/j.1471-0528.1990.tb02574.x.
- Background: PubMed 1622911Critchley HO, Wallace WH, Shalet SM, Mamtora H, Higginson J, Anderson DC. Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstet Gynaecol. 1992 May;99(5):392-4. doi: 10.1111/j.1471-0528.1992.tb13755.x.
- Background: PubMed 8736278Davies MC, Gulekli B, Jacobs HS. Osteoporosis in Turner's syndrome and other forms of primary amenorrhoea. Clin Endocrinol (Oxf). 1995 Dec;43(6):741-6. doi: 10.1111/j.1365-2265.1995.tb00544.x.
- Background: PubMed 2472472Hansen SW, Olsen N. Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin for germ cell cancer: measurement of vasoconstrictor response to cold. J Clin Oncol. 1989 Jul;7(7):940-2. doi: 10.1200/JCO.1989.7.7.940.
- Background: PubMed 2538400Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation. Int J Cancer. 1989 Mar 15;43(3):399-402. doi: 10.1002/ijc.2910430309.
- Background: PubMed 10396368Hoorweg-Nijman JJ, Kardos G, Roos JC, van Dijk HJ, Netelenbos C, Popp-Snijders C, de Ridder CM, Delemarre-van de Waal HA. Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol (Oxf). 1999 Feb;50(2):237-44. doi: 10.1046/j.1365-2265.1999.00654.x.
- Background: PubMed 10594512Howell SJ, Shalet SM. Aetiology-specific effect of premature ovarian failure on bone mass - is residual ovarian function important? Clin Endocrinol (Oxf). 1999 Nov;51(5):531-4. doi: 10.1046/j.1365-2265.1999.00891.x. No abstract available.
- Background: PubMed 2185981Kaneko N, Kawagoe S, Hiroi M. Turner's syndrome--review of the literature with reference to a successful pregnancy outcome. Gynecol Obstet Invest. 1990;29(2):81-7. doi: 10.1159/000293307.
- Background: PubMed 6977427Krolner B, Pors Nielsen S. Bone mineral content of the lumbar spine in normal and osteoporotic women: cross-sectional and longitudinal studies. Clin Sci (Lond). 1982 Mar;62(3):329-36. doi: 10.1042/cs0620329.
- Background: PubMed 10362825Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999 Jun 10;340(23):1801-11. doi: 10.1056/NEJM199906103402306. No abstract available.
- Background: PubMed 9373569Register TC, Jayo MJ, Jerome CP. Oral contraceptive treatment inhibits the normal acquisition of bone mineral in skeletally immature young adult female monkeys. Osteoporos Int. 1997;7(4):348-53. doi: 10.1007/BF01623776.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
W Hamish B Wallace, MD principal investigator
NHS Lothian / University of Edinburgh
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ethinylestradiol / Norethisterone and Estradiol / Progesterone in people with Premature Ovarian Failure, run by University of Edinburgh at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Aug 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in 24 hour ambulatory blood pressure (time frame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00732693, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2008.