Estrogen metabolism in systemic lupus erythematosus. Patients and family members

Abstract

Systemic l u p u s erythematosus (SLE) i s commonly observed i n females a f t e r p u b e r t y a t a h i g h r a t i o o f 9:l (1).The d i s e a s e i s a l s o observed i n monozygotic t w i n s (2), f i r s t degree r e l a t i v e s ( 3 ) , and more r e c e n tl y among c e r t a i n male f a m i l i e s ( 4 ) . I n a d d i t i o n , i t i s uncommon i n t h e p r e p u b e r t a l y e a r s ( 5 ) and a f t e r menopause (6). The reason f o r t h e preponderance o f SLE i n s i n g l e f a m i l i e s remains unknown, b u t r e c e n t work on t h e imnunogenetics of t h e HLA-D h a p l o t y p e s has suggested concurrence o f disease w i t h t h e s e h a p l o t y p e s (7). The r o l e o f sex hormones i n t h e pathogenesis and m o r b i d i t y o f SLE i s c u r r e n t l y b e i n g e l u c i d a t e d (10).The reason f o r t h e h i g h female p r e v a l e n c e i s n o t known.However, i t i s c l e a r t h a t e s t r o n e i s p r e f e r e n t i a l l y h y d r o x y l a t e d a t t h e C-16 p o s i t i o n i n p a t i e n t s w i t h SLE r e s u l t i n g i n t h e accumulation o f . s u b s t a n c e s which have a h i g h degree o f e s t r o g e n i c a c t i v i t y (8,9) ( F i g u r e 1). One s t u d y has shown t h a t t h e compound 16 a -h y d r o x ye s t r o n e i s u n i q u e l y e s t r o g e n i c (10). P a t i e n t s w i t h K l i I n t h i s paper we p r e s e n t d a t a showing i n c r e a s e d 16 a -h y d r o x y l a t i o n o f e s t r o n e t o m e t a b o l i t e s havinge s t r o g e n i c p r o p e r t i e s , and i l l u s t r a t e t h e e x t e n t o f h y d r o x y l a t i o n i n f i r s t degree r e l a t i v e s o f SLE pat i e n t s . F i r s t degree r e l a t i v e s o f patients w i t h SLE were hospitalized a t t h e Rockefeller UniversityHospital.Written informed consent was obtained and a l l procedures were approved by t h e Human Research Committee. The same c r i t e r i a applied t o these r e l a t i v e s as was applied t o the selection o f t h e patients above.Measurement o f estrogenic u r i n a r y metabolites was performed as previously described (8).B r i e f 1 3 the technique involved the i n j e c t i o n I V o f e s t r a d i o l 6, 7-H and a four day collect i o n o f urine. The u r i n e was subsequently fractionated by c e l i t e p a r t i t i a n chromatography and the metabolites were isolated. Q u a n t i t a t i o n o f the metabolites was done i n each case by reverse isotope d i l u t i o n . Determination o f Elevated Urinary Metabolites.Extent o f Reaction. The extent o f 16 hydroxylation was determined as Dreviouslv described (9,121.A b e t t e r method o f accurately 'measuring hydroxylation a t C-16 was accomplished by g i v i n g each p a t i e n t an I V i n j e c t i o n of e s t r a d i o l labeled a t carbon atom C-16. The t o t a l body water o f each p a t i e n t was measured a t the outset using a 24 hour c r e a t in i n e value and t h e percent excess deuterium (D 0) a f t e r . a n administered o r a l dose.Fr...

Modulation of Rat Peritoneal Mast Cell and Human Basophil Histamine Release by Estrogens

“…Estrogens have been involved in the pathol ogy of many autoimmune disorders probably through a regulatory influence on the immune system [4][5][6]. Mast cells are known to have a central role in the al lergic reaction, but they have also been more exten sively involved in a variety of chronic inflammatory processes [15].…”

“…The ef fect of steroids and cytokines in a local inflammatory site for therapeutic intervention is of enormous inter est. Sex steroids have also been involved in the modu lation of the immune system [4] and might play a role in the pathogenesis and treatment of some (autoim mune disorders [5]. Several studies suggested the in vivo and in vitro effect of sex steroids on T and B cell [6], although the influence of sex steroids on the mod ulation of mast cells and basophils is not yet precisely defined.…”

Effects of altered prenatal hormonal environment on expression of autoimmune disease in NZB/NZW mice.

“…Systemic lupus erythematosus (SLE) is a The predilection of SLE for women of chronic and incurable disease charac-reproductive age (1), association between terized by formation of autoantibodies disease flares and pregnancy (2), aberrant and immune-mediated damage to key pattern of estrogen metabolism (3), target organs such as the kidney (1 Matings between New Zealand Black (NZB) and New Zealand White (NZW) mice produce F1 NZB/NZW hybrids, which develop a disease analogous to SLE. These animals produce antibodies directed against double-stranded DNA (anti-DNA) and die prematurely with glomerulonephritis and renal failure (5).…”

Rheumatic manifestations of pituitary tumors

“…Flares of SLE have been reported after initiation of oral contraceptives [50][51][52]. Conversely, there is evidence to suggest that the use of oral contraceptives may reduce the incidence of RA [53,54] or modify the disease and prevent the progression to more severe forms [49,55].…”