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

Overview

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.

Full Title of Study: “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

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 2006

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.

Interventions

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

Arms, Groups and Cohorts

  • Experimental: 1
    • Treatment with standard sex steroid replacement regimen
  • Experimental: 2
    • Treatment with physiologic sex steroid regimen

Clinical Trial Outcome Measures

Primary Measures

  • 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

Secondary Measures

  • 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

Participating in This Clinical Trial

Inclusion Criteria

  • Premature Ovarian Failure Exclusion Criteria:

  • Intercurrent illness

Gender Eligibility: Female

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Edinburgh
  • Provider of Information About this Clinical Study
    • Dr W Hamish B Wallace, Consultant/Reader in Paediatric Oncology, NHS Lothian / University of Edinburgh
  • Overall Official(s)
    • W Hamish B Wallace, MD, Principal Investigator, NHS Lothian / University of Edinburgh

References

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.

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.

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.

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.

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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.

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.

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.

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.

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.

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.

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.

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

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.

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