SLE is predominantly a female disease.15
First onset of SLE before puberty and after menopause16
is uncommon. The female predilection becomes less pronounced outside the reproductive age range. In addition, patients with Klinefelter’s syndrome, characterised by hypergonadotrophic hypogonadism, are prone to the development of SLE.17
These observations suggest a role for endogenous sex hormones in disease predisposition.
Abnormal oestrogen metabolism has been demonstrated in patients with SLE of both sexes, with an increase in 16α hydroxylation of oestrone, resulting in significantly raised 16α hydroxyestrone concentrations.18
The 16α metabolites are more potent and feminising oestrogens. Women with SLE also have low plasma androgens, including testosterone, dihydrotestosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate.19,20
This abnormality might be explained by increased testosterone oxidation at C-1721
or increased tissue aromatase activity.22
The concentrations of androgens correlate inversely with disease activity.20
Low concentrations of plasma testosterone and raised luteinising hormone (LH) values23,24
have been found in some men with SLE. Thus, excessive oestrogenic but inadequate androgenic hormonal activity in both men and women with SLE might be responsible for the alteration of the immune responses.
Table 2 summarises the actions of oestrogens on various cell types of the immune system. Both physiological and supraphysiological concentrations of oestrogens facilitate humoral responses, leading to increased B cell proliferation and antibody production.25–28
On the contrary, high doses of oestrogens inhibit T cell responses, such as proliferation and IL-2 production.29,30
Oestrogens also increase calcineurin mRNA levels and enhance the cell surface expression of CD40 ligand (CD40L) in cultured T cells from patients with SLE.31,32
These effects appear to be unique to patients with SLE, indicating that lupus T cells are more sensitive to oestrogens. Taken together, oestrogens may aggravate SLE by prolonging the survival of autoimmune cells, increasing T helper type 2 (Th2) cytokine production, and stimulating B cells to produce autoantibodies. The inhibition of the Th1 response and the enhancement of CD40L expression on lupus T cells may indirectly promote the Th2 response and lead to further B cell hyperactivity.
The effect of androgens on lymphocyte functions has been less well studied. Testosterone reduces immunoglobulin production from peripheral blood mononuclear cells of both normal subjects and patients with SLE.33,34
DHEA has been shown to be associated with enhancement of Th1 and inhibition of Th2 immune responses in both humans and mice.35,36
The opposite effects of oestrogens and androgens on the immune system, coupled with unbalanced oestrogenic and androgenic hormonal activity in patients with SLE, may help explain some of the immune aberrations seen in this disease.
Epidemiological studies reveal an association between the use of exogenous oestrogens and the onset of SLE. In a large cohort of nurses as part of the Nurses’ Health Study, it was shown that both the past use of oral contraceptive (OC) pills and hormonal replacement therapy (HRT) was associated with a slightly increased risk of SLE development.37,38
Moreover, a proportional increase in the risk of SLE related to the duration of HRT was seen. A more recent case–control study also reported an increased risk of the development of SLE or discoid lupus in women receiving HRT for more than two years when compared with non-users.39
There is evidence that endogenous oestrogen concentrations may influence disease activity and prognosis in human SLE. In the presteroid era, improvement of SLE was noted in individual patients who had undergone menopause or oophorectomy.40
Flares of SLE are well known to occur during periods of rapid hormonal changes. These include pregnancy, puerperium, ovulation stimulation during in vitro fertilisation, and exogenous oestrogen administration.41–44
Lupus activity tends to be reduced when patients undergo menopause.45
It has also been noted that in many women disease flares are more common during the second half of the menstrual cycle, after the midcycle surge of oestrogen.46
The administration of exogenous oestrogens in the form of OC pills and HRT may exacerbate the disease in patients with existing lupus.47–49
Furthermore, late onset SLE, defined as first onset of disease after the age of 50, was reported have a more benign disease course, with less serious organ involvement.50
Patients with SLE who have low female sex hormone values at disease onset were found to have a lower relative mortality risk when compared with age matched controls.51
Prolactin has recently been found to be an immunostimulatory hormone.52
The main origin is the anterior pituitary, but lymphocytes are also capable of producing prolactin, which serves as an autocrine or paracrine mediator.53
Chronic hyperprolactinaemia induced by syngeneic pituitary gland implantation stimulates primary humoral antibody responses in rats,54
and accelerates autoimmune phenomena in lupus prone mice.55
Recent data suggest that the stimulatory actions of oestrogens on autoreactive B cells require the presence of prolactin.56
Hyperprolactinaemia has been demonstrated in a proportion of patients with SLE of both sexes.57–64
Prolactin concentrations correlate with disease activity in some studies.58,64
Bromocriptine, a dopamine agonist that selectively inhibits prolactin secretion from the pituitary, has been shown to be useful in the treatment of non-life threatening SLE.65,66
However, the exact role of prolactin in SLE requires further work because a positive correlation between lupus activity and prolactin values cannot be demonstrated consistently.59,62–64
“There is evidence that endogenous oestrogen concentrations may influence disease activity and prognosis in human systemic lupus erythematosus”
Gonadotrophin releasing hormone (GnRH), a decapeptide produced by the hypothalamus, regulates the release of LH and follicle stimulating hormone from the anterior pituitary. Recent animal studies show that GnRH is immunostimulatory.67
In lupus prone mice, GnRH has been shown to exacerbate lupus, but the effect appears to be sexually dimorphic.68,69
However, the role of GnRH in human SLE requires further evaluation.
The hypothalamo–pituitary–adrenal (HPA) axis is the chief component of the stress system. The stress induced increase in serum concentrations of glucocorticoids is essential for the prevention of autoreactive or unrestrained amplification of the immune response, which results in self injury and autoimmunity. A defective HPA axis may confer susceptibility to autoimmune disorders. Female Lewis (LEW/N) rats, characterised by a defective hypothalamic corticotrophin releasing hormone (CRH) response to several immunological activators, including IL-1,70
are highly susceptible to a wide variety of experimental autoimmune disorders.
There is preliminary evidence that a defective HPA axis is present in both murine and human lupus. A significantly lower increase in plasma corticosterone concentrations upon stimulation by recombinant IL-1 is seen in lupus prone (MRL/lpr) mice.71
Aging of MRL/lpr mice, which is accompanied by an increase in autoantibody production, is associated with a decrease in hypothalamic CRH mRNA expression.72
Studies on the function of the HPA axis in patients with SLE are limited and often confounded by the effect of concomitant glucocorticoid treatment. A study on a group of active untreated female patients with SLE reports that the cortisol response to induced hypoglycaemia is significantly lower in patients than in healthy controls, indicating that some degree of HPA axis dysfunction does exist.73
The dysregulated HPA axis in SLE may be responsible for disease susceptibility and progression.
Table 3 summarises the role of hormones in the pathogenesis of SLE. Hormones may not have a direct causative role in SLE, but a milieu consisting of different values of hypothalamo–pituitary and gonadal hormones may create an endogenous environment for susceptible individuals to develop the disease. Changes in the concentrations of sex steroids, coupled with certain yet undiscovered environmental factors, may lead to disease flares and serve to explain the “wax and wane” nature of the disease.
Role of hormones in human SLE