Sex Steroids in Sjögren's Syndrome: Effect of Substitution Treatment on Fatigue

Sjogren's Syndrome Clinical Trial

Official title:

Sex Steroids in Sjögren's Syndrome: Effect of Substitution Treatment on Fatigue

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00543166
• Other study ID #: T101090002
• Status: Active, not recruiting
• Phase: Phase 4
• First received: October 9, 2007
• Last updated: November 2, 2007
• Start date: February 2003
• Est. completion date: December 2009

Study information

• Verified date: October 2007
• Source: Helsinki University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Finland: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Our research contributes to the understanding of some of the basic biology of the salivary glands. The etiology and many of the pathomechanisms of Sjögren's syndrome are unknown. In particular, reasons for the female dominance, late age of onset, fatigue and the prominent involvement of exocrine glands are unknown. We hypothesize, due to the disease characteristics, that the primary target hit by the disease process is the secretory acinar cell and that this cell is particularly damaged in women due to insufficient support, normally provided by dehydroepiandrosterone and its intracrine processing.

Description:

We hypothesize, due to the Sjögren's syndrome (SS) disease characteristics, that the primary target hit by the disease process is the secretory acinar cell and that this cell is particularly in women damaged due to insufficient support, normally provided by dehydroepiandrosterone and its intracrine processing. Dehydroepiandrosterone deficiency at the time of adrenopause seems to us as the more likely endocrine trigger than estrogen deficiency caused by menopause as androgens in general are considered to be protective against autoimmunity and estrogens to favor it. Acinar cell is normally responsible for the production of primary saliva. Acinar cell damage can lead to acinar cell apoptosis and loss. Normally this is compensated by division of the acinar cells in situ or, according to recent reports, perhaps rather by division and subsequent migration of one of the daughter cells into the acinar space and transdifferentiation of this intercalated ductal cell progenitor into mature acinar cell. In SS this remodeling seems to be impaired, perhaps for the same reason, which also leads to primary acinar cell damage. According to this hypothesis, the primary changes occur in the salivary glands and more specifically in the acinar cells, whereas immune activation and autoimmunity are secondarily activated against abnormally damaged acinar cells so that individuals with the "right" genetic background also produce SS-A and SS-B antibodies. The cause of the acinar cell damage may not be a direct, damaging stimulus, e.g. virus infection or irradiation damage, but rather lack of a supporting anabolic stimulus and inadequate maintenance of the acinar cell health leading to cytopathic acinar cell changes. In peri-menopausal women (who still produce some estrogens) this abnormal antigen release and processing from acinar cells, which reveals cryptic epitopes, together with autoimmunity enhancing effects of estrogens, may lead to the full picture of SS (Cutolo et al., 2004).

This neuroimmunoendocrine working hypothesis would explain many central disease characteristics, but does not provide a final answer to the mystery of this intriguing syndrome as the reasons for the insufficient production and generation of DHEA remain to be solved. We have done some preliminary studies to analyze this topic by mapping the signals of the extracellular matrix in the adrenal cortex, where the cells proliferate in the outer zone and subsequently migrate in a centripetal direction, during which phenotypic transition occurs from the outer zone (zona glomerulosa) cells producing aldosterone to the intermediate zone (zona fasciculata) cells producing glucocorticosteroids and finally to the inner zone (zona reticularis) cells producing DHEA. However, in this research project we have decided to totally focus on the salivary gland acinar cell-sex steroid interactions.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 107
• Est. completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Primary SS according to the American-European consensus criteria

2. General Fatigue =14 calculated from MFI-20 (Multiple fatigue inventory-20 questionnaire; the value was based on a pilot study of 239 members of the Finnish SS patient association)

3. subnormal serum S-DHEAS values (the reference values were calculated based on a pilot study of 81 healthy women and 57 healthy men).

Exclusion Criteria:

1. Age <18 years or >80 years

2. prisoner

3. individuals not able to give their informed consent

4. history of breast cancer

5. history of uterus cancer

6. history of prostatic cancer

7. history of stroke or prothrombotic coagulation disorders

8. pregnant or lactating women

9. fertile patients without adequate prevention

10. difficult acne

11. a significant liver disease

12. patients with changes in their systemic medication taken for SS during the previous three months 13) patients taking more than 10 mg prednisolone per day

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sjogren's Syndrome
• Syndrome

Intervention

Drug:
• dehydroepiandrosterone
50 mg of dehydroepiandrosterone in the morning for 4 months in the treatment group.

Locations

Country	Name	City	State
Finland	Department of Medicine, Helsinki University Central Hospital	Helsinki

Sponsors (3)

Lead Sponsor	Collaborator
Helsinki University	Göteborg University, Uppsala University

Country where clinical trial is conducted

Finland, 

References & Publications (4)

Konttinen YT, Tensing EK, Laine M, Porola P, Törnwall J, Hukkanen M. Abnormal distribution of aquaporin-5 in salivary glands in the NOD mouse model for Sjögren's syndrome. J Rheumatol. 2005 Jun;32(6):1071-5. — View Citation

Laine M, Porola P, Udby L, Kjeldsen L, Cowland JB, Borregaard N, Hietanen J, Ståhle M, Pihakari A, Konttinen YT. Low salivary dehydroepiandrosterone and androgen-regulated cysteine-rich secretory protein 3 levels in Sjögren's syndrome. Arthritis Rheum. 20 — View Citation

Laine M, Virtanen I, Salo T, Konttinen YT. Segment-specific but pathologic laminin isoform profiles in human labial salivary glands of patients with Sjogren's syndrome. Arthritis Rheum. 2004 Dec;50(12):3968-73. — View Citation

Valtysdóttir ST, Wide L, Hällgren R. Low serum dehydroepiandrosterone sulfate in women with primary Sjögren's syndrome as an isolated sign of impaired HPA axis function. J Rheumatol. 2001 Jun;28(6):1259-65. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fatigue		prospective
Secondary	Quality of life		prospective