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

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ClinicalTrials.gov Identifier: NCT00732693

Recruitment Status : Completed

First Posted : August 12, 2008

Last Update Posted : August 12, 2008

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Sponsor:

Information provided by:

University of Edinburgh

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Premature Ovarian Failure	Drug: Ethinylestradiol / Norethisterone Drug: Estradiol / Progesterone	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	42 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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 Start Date :	February 2002
Actual Primary Completion Date :	November 2006
Actual Study Completion Date :	November 2006

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Primary Ovarian Insufficiency

Drug Information available for: Estradiol Estradiol benzoate Ethinylestradiol Progesterone Estradiol cypionate Estradiol valerate Estradiol acetate Estradiol hemihydrate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1 Treatment with standard sex steroid replacement regimen	Drug: Ethinylestradiol / Norethisterone Oral ethinylestradiol 30mcg and norethisterone 1.5mg daily for weeks 1-3, followed by 7 "pill free" days Other Name: Loestrin 30, Galen Ltd, UK
Experimental: 2 Treatment with physiologic sex steroid regimen	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 Other Names: Estraderm TTS, Novartis Pharmaceuticals UK Ltd Cyclogest, Activis UK Ltd

Outcome Measures

Primary Outcome 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 Outcome 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 ]

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Premature Ovarian Failure

Exclusion Criteria:

Intercurrent illness

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00732693

Locations

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United Kingdom
Royal Infirmary of Edinburgh
Edinburgh, United Kingdom, EH16 4SA
Royal Hospital for Sick Children
Edinburgh, United Kingdom, EH9 1LF

Sponsors and Collaborators

University of Edinburgh

Investigators

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Principal Investigator:	W Hamish B Wallace, MD	NHS Lothian / University of Edinburgh

More Information

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Dr W Hamish B Wallace, Consultant/Reader in Paediatric Oncology, NHS Lothian / University of Edinburgh
ClinicalTrials.gov Identifier:	NCT00732693
Other Study ID Numbers:	CLIC/Sargent-178000-R35464
First Posted:	August 12, 2008 Key Record Dates
Last Update Posted:	August 12, 2008
Last Verified:	August 2008

Keywords provided by University of Edinburgh:


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

Additional relevant MeSH terms:

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Premature Birth Primary Ovarian Insufficiency Menopause, Premature Obstetric Labor, Premature Obstetric Labor Complications Pregnancy Complications Ovarian Diseases Adnexal Diseases Gonadal Disorders Endocrine System Diseases Ethinyl Estradiol Norethindrone Norethindrone Acetate Estradiol	Progesterone Estrogens Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Contraceptive Agents, Hormonal Contraceptive Agents Reproductive Control Agents Contraceptive Agents, Female Progestins Contraceptives, Oral, Hormonal Contraceptives, Oral Contraceptives, Oral, Synthetic

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