Clinical trial NCT00732693: Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Premature Ovarian Failure
Keywords: Premature ovarian failure
Sex hormone replacement
HRT
Blood pressure
Bone mineral density
Bone metabolism
Uterine function
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
First posted: 2008-08-12
Enrollment: 42
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: Inclusion Criteria:

* Premature Ovarian Failure

Exclusion Criteria:

* Intercurrent illness

Primary outcomes:
measure: Change in 24 hour ambulatory blood pressure
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
measure: Bone mineral density measurements (DEXA)
timeFrame: Baseline, 14 and 24 months
measure: Uterine ultrasound scan to assess uterine volume, endometrial thickness, and uterine artery blood flow
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment
Secondary outcomes:
measure: Central arterial blood pressure and arterial stiffness measured using peripheral arterial tonometry
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
measure: Biochemical evidence of activity on the renin-angiotensin system, including plasma renin activity, angiotensin II, aldosterone, creatinine, urea and electrolyte concentrations.
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
measure: Serum markers of collagen turnover and bone matrix formation
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
measure: Hormonal assays for gonadotrophins, FSH, LH and sex steroids estrogen and progesterone
timeFrame: Before each washout period, then at 0, 3, 6 and 12 months of each treatment phase
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
Study officials:
affiliation: NHS Lothian / University of Edinburgh
name: W Hamish B Wallace, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. doi: 10.1111/j.1471-0528.1990.tb02574.x.
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. doi: 10.1111/j.1471-0528.1992.tb13755.x.
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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. doi: 10.1007/BF01623776.
citation: Rubin K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics. 1998 Aug;102(2 Pt 3):481-5.
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. doi: 10.1210/jcem.77.2.8345029. No abstract available.
citation: O'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.