Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure

Premature Ovarian Failure Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00732693
• Other study ID #: CLIC/Sargent-178000-R35464
• Status: Completed
• Phase: Phase 4
• First received: August 11, 2008
• Last updated: August 11, 2008
• Start date: February 2002
• Est. completion date: November 2006

Study information

• Verified date: August 2008
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: National Health ServiceUnited Kingdom: Research Ethics CommitteeUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: November 2006
• Est. primary completion date: November 2006
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Premature Ovarian Failure

Exclusion Criteria:

• Intercurrent illness

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Menopause, Premature
• Premature Birth
• Premature Ovarian Failure
• Primary Ovarian Insufficiency

Intervention

Drug:
• Ethinylestradiol / Norethisterone
Oral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 "pill free" days
• Estradiol / Progesterone
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

Locations

Country	Name	City	State
United Kingdom	Royal Hospital for Sick Children	Edinburgh
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh

Sponsors (1)

Lead Sponsor	Collaborator
University of Edinburgh

Country where clinical trial is conducted

United Kingdom, 

References & Publications (14)

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. — View Citation

Critchley 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. — View Citation

Critchley 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. — View Citation

Davies 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. — View Citation

Hansen 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. — View Citation

Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation. Int J Cancer. 1989 Mar 15;43(3):399-402. — View Citation

Hoorweg-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. — View Citation

Howell 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. — View Citation

Kaneko 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. Review. — View Citation

Krølner 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. — View Citation

Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999 Jun 10;340(23):1801-11. Review. — View Citation

Register 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. — View Citation

Rubin K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics. 1998 Aug;102(2 Pt 3):481-5. Review. — View Citation

Saenger 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. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 24 hour ambulatory blood pressure		Before each washout period, then at 0, 3, 6 and 12 months of each treatment	No
Primary	Bone mineral density measurements (DEXA)		Baseline, 14 and 24 months	No
Primary	Uterine ultrasound scan to assess uterine volume, endometrial thickness, and uterine artery blood flow		Before each washout period, then at 0, 3, 6 and 12 months of each treatment	No
Secondary	Central arterial blood pressure and arterial stiffness measured using peripheral arterial tonometry		Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase	No
Secondary	Biochemical evidence of activity on the renin-angiotensin system, including plasma renin activity, angiotensin II, aldosterone, creatinine, urea and electrolyte concentrations.		Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase	No
Secondary	Serum markers of collagen turnover and bone matrix formation		Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase	No
Secondary	Hormonal assays for gonadotrophins, FSH, LH and sex steroids estrogen and progesterone		Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase	No