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

NCT ID: NCT00543166

Last Updated: 2007-11-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-02-28
• Study Completion Date: 2009-12-31

Brief 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.

Detailed 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.

Conditions

Sjogren's Syndrome

Keywords

Sjögren's syndrome; fatigue; salivary gland; dehydroepiandrosterone

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

2

180 patients divided to two separate groups (each containing 90 patients). This study has a cross-over, wash-out design, which consists of two 4 month treatment period separated by a one month long wash-out period. During one treatment period the patient gets placebo and during one of the treatment periods the patient gets 50mg of dehydroepiandrosterone (DHEA) in the morning.

Group Type: PLACEBO_COMPARATOR

dehydroepiandrosterone

Intervention Type: DRUG

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

Interventions

dehydroepiandrosterone

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

Intervention Type: DRUG

Other Intervention Names

DHEA

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Göteborg University

OTHER

Sponsor Role: collaborator

Uppsala University

OTHER

Sponsor Role: collaborator

University of Helsinki

OTHER

Sponsor Role: lead

Principal Investigators

Yrjö Konttinen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Helsinki University Central Hospital, Helsinki, Finland

Locations

Department of Medicine, Helsinki University Central Hospital

Helsinki, Helsinki, Finland

Countries

Finland

References

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. doi: 10.1002/art.20730.

Reference Type: BACKGROUND

PMID: 15593200 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 15940770 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 11409117 (View on PubMed)

Laine M, Porola P, Udby L, Kjeldsen L, Cowland JB, Borregaard N, Hietanen J, Stahle M, Pihakari A, Konttinen YT. Low salivary dehydroepiandrosterone and androgen-regulated cysteine-rich secretory protein 3 levels in Sjogren's syndrome. Arthritis Rheum. 2007 Aug;56(8):2575-84. doi: 10.1002/art.22828.

Reference Type: RESULT

PMID: 17665393 (View on PubMed)

Virkki LM, Porola P, Forsblad-d'Elia H, Valtysdottir S, Solovieva SA, Konttinen YT. Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA-deficient patients with primary Sjogren's syndrome. Arthritis Care Res (Hoboken). 2010 Jan 15;62(1):118-24. doi: 10.1002/acr.20022.

Reference Type: DERIVED

PMID: 20191499 (View on PubMed)

Other Identifiers

T101090002

Identifier Type: -

Identifier Source: org_study_id