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

Sponsor

University of Helsinki (Other)

Overall Status

Unknown status

CT.gov ID

NCT00543166

Collaborator

Göteborg University (Other), Uppsala University (Other)

107

Enrollment

Location

Arm

Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sjogren's Syndrome	Drug: dehydroepiandrosterone	Phase 4

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2003

Anticipated Study Completion Date :

Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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.	Drug: dehydroepiandrosterone 50 mg of dehydroepiandrosterone in the morning for 4 months in the treatment group. Other Names: DHEA

Arm

Intervention/Treatment

Placebo Comparator: 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.

Drug: dehydroepiandrosterone

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

Other Names:

DHEA

Outcome Measures

Primary Outcome Measures

Fatigue [prospective]

Secondary Outcome Measures

Quality of life [prospective]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Primary SS according to the American-European consensus criteria
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)
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:

Age <18 years or >80 years
prisoner
individuals not able to give their informed consent
history of breast cancer
history of uterus cancer
history of prostatic cancer
history of stroke or prothrombotic coagulation disorders
pregnant or lactating women
fertile patients without adequate prevention
difficult acne
a significant liver disease
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