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

NCT00732693 | Completed Phase 4

• 1 other identifier: CLIC/Sargent-178000-R35464
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 2

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.

Conditions

Premature Ovarian Failure

Keywords

Premature ovarian failure; Sex hormone replacement; HRT; Blood pressure; Bone mineral density; Bone metabolism; Uterine function

Outcome Measures

Primary Outcomes (3)

• Change in 24 hour ambulatory blood pressure

  Before each washout period, then at 0, 3, 6 and 12 months of each treatment

• Bone mineral density measurements (DEXA)

  Baseline, 14 and 24 months

• 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

Secondary Outcomes (4)

• 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

• 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

• 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

• 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

Study Arms (2)

1

EXPERIMENTAL

Treatment with standard sex steroid replacement regimen

Drug: Ethinylestradiol / Norethisterone

2

EXPERIMENTAL

Treatment with physiologic sex steroid regimen

Drug: Estradiol / Progesterone

Interventions

Ethinylestradiol / Norethisterone DRUG

Oral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 "pill free" days

Also known as: Loestrin 30, Galen Ltd, UK

1

Estradiol / Progesterone DRUG

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

Also known as: Estraderm TTS, Novartis Pharmaceuticals UK Ltd, Cyclogest, Activis UK Ltd

2

Eligibility Criteria

• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Premature Ovarian Failure

You may not qualify if:

• Intercurrent illness

Sponsors & Collaborators

• University of Edinburgh: lead

Study Sites (2)

Royal Infirmary of Edinburgh

Edinburgh, EH16 4SA, United Kingdom

Location

Royal Hospital for Sick Children

Edinburgh, EH9 1LF, United Kingdom

Location

Related Publications (15)

• 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.

  PMID: 10609720 BACKGROUND

• 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.

  PMID: 2242365 BACKGROUND

• 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.

  PMID: 1622911 BACKGROUND

• 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. doi: 10.1111/j.1365-2265.1995.tb00544.x.

  PMID: 8736278 BACKGROUND

• 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. doi: 10.1200/JCO.1989.7.7.940.

  PMID: 2472472 BACKGROUND

• 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. doi: 10.1002/ijc.2910430309.

  PMID: 2538400 BACKGROUND

• 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. doi: 10.1046/j.1365-2265.1999.00654.x.

  PMID: 10396368 BACKGROUND

• 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. doi: 10.1046/j.1365-2265.1999.00891.x. No abstract available.

  PMID: 10594512 BACKGROUND

• 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. doi: 10.1159/000293307.

  PMID: 2185981 BACKGROUND

• Krolner 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.

  PMID: 6977427 BACKGROUND

• Mendelsohn 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.

  PMID: 10362825 BACKGROUND

• 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.

  PMID: 9373569 BACKGROUND

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

  PMID: 9685448 BACKGROUND

• 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.

  PMID: 8345029 BACKGROUND

• 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.

  PMID: 22343553 DERIVED

MeSH Terms

Conditions

Primary Ovarian Insufficiency

Interventions

Ethinyl Estradiol; Norethindrone; Estradiol; Progesterone

Condition Hierarchy (Ancestors)

Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Norpregnatrienes; Norpregnanes; Norsteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estrogenic Steroids, Alkylated; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Norpregnenes; Estrenes; Estranes; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners

Study Officials

• W Hamish B Wallace, MD

  NHS Lothian / University of Edinburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 11, 2008
• First Posted: August 12, 2008
• Study Start: February 1, 2002
• Primary Completion: November 1, 2006
• Study Completion: November 1, 2006
• Last Updated: August 12, 2008

Record last verified: 2008-08

Locations

GB (2)