*3.2.1 Diabetes mellitus 1*

Cases of diabetes mellitus 1 have been described in SLE. In a cohort of SLE patients in the UK the prevalence of diabetes mellitus 1 was investigated [80]. The coexistence of diabetes mellitus 1, SLE and celiac disease has been described in a young female patient [81]. It appears that diabetes mellitus 1 is rare among SLE patients. However, the risk of developing renal disease, retinal disease and peripheral neuropathy requires careful follow up of the patients. It is also important for the physician to decide which complication is due to lupus or diabetes as the management is different.

## *3.2.2 Diabetes mellitus 2*

Diabetes mellitus type 2 is reported with increasing frequency nowadays [82]. Hence, diabetes mellitus 2 has been reported in patients with SLE. In their cohort of 485 SLE patients Cortes et al. [80] reported 4 patients with diabetes mellitus 2

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*Endocrine Manifestations of Systemic Lupus Erythematosus*

and two considered to have steroid induced diabetes mellitus. Thus, it appears that diabetes mellitus 2 is infrequent within lupus patients. This may be due to the fact, that lupus develops in a younger age than diabetes mellitus 2 [14]. The relationship between SLE and gestational diabetes has been studied in a meta-analysis [83]. It was found that SLE does not seem to increase the risk of gestational diabetes. However, steroid use in SLE may increase the risk of gestational diabetes.

Primary hyperparathyroidism is frequently recognized nowadays due to the routine measurement of serum calcium levels. Primary hyperparathyroidism has been reported in patients with lupus. However, there are just a few case reports in the literature of patients with SLE and primary hyperparathyroidism. Primary hyperparathyroidism due to the presence of a parathyroid adenoma in a 47-year old female patient with SLE has been described [84]. Hypercalcemia resolved in this patient after removal of the adenoma. Primary hyperparathyroidism due to a cystic parathyroid adenoma has also been described in a 62-year old female patient with SLE [85]. In their cohort of 708 lupus patients Munoz and Isenberg [14] also identified 5 (0.70%) patients with hyperparathyroidism, 1 with primary hyperparathyroidism and 4 patients with secondary hyperparathyroidism in the context of chronic renal failure due to lupus nephritis. Hyperparathyroidism presented after

Addison's disease has been reported in patients with SLE. However, there are only a few case reports of Addison's disease in patients with SLE. The case of a 29-year old female patient who presented with Addisonian crisis in the presence of SLE and responded therapeutically to corticosteroids, both as far as Addison's and lupus is concerned has been described [86]. In their cohort of lupus patients Munoz and Isenberg [14] did not identify any patient with Addison's disease. It appears that

The occurrence of Cushing's syndrome due to an adrenal adenoma in patients

Cushing's syndrome who developed lupus has been described [87]. The patient was successfully treated by surgical removal of the adrenal adenoma. A case of a 51-year old woman with SLE who developed Cushing's syndrome and was found to have a left adrenal adenoma has been described [88]. The patient was successfully man-

Reproductive function of young female patients with SLE is commonly perturbed by various pathophysiologic mechanisms [89]. Ovarian reserve is diminished even in the presence of mild lupus suggesting a direct effect of the disease

with SLE is rare. The case of an 18-year old female patient with subclinical

Addison's disease is a rare occurrence in lupus patients.

*DOI: http://dx.doi.org/10.5772/intechopen.97363*

**3.3 Parathyroid disease in SLE**

*3.3.1 Hyperparathyroidism*

lupus in all cases described.

**3.4 Adrenal disease in SLE**

*3.4.1 Addison's disease*

*3.4.2 Cushing's syndrome*

**4. Ovarian function**

aged by laparascopic left adrenalectomy.

*Endocrine Manifestations of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97363*

and two considered to have steroid induced diabetes mellitus. Thus, it appears that diabetes mellitus 2 is infrequent within lupus patients. This may be due to the fact, that lupus develops in a younger age than diabetes mellitus 2 [14]. The relationship between SLE and gestational diabetes has been studied in a meta-analysis [83]. It was found that SLE does not seem to increase the risk of gestational diabetes. However, steroid use in SLE may increase the risk of gestational diabetes.

## **3.3 Parathyroid disease in SLE**

### *3.3.1 Hyperparathyroidism*

*Lupus - Need to Know*

both diseases.

*3.1.4 Graves' disease*

*3.2.1 Diabetes mellitus 1*

agement is different.

*3.2.2 Diabetes mellitus 2*

profile and disease activity as well as cumulative organ damage in this group was also investigated. In a group of 301 SLE patients and 141 controls TSH levels, T4 levels, antiTg antibodies and antiTPO antibodies were measured by chemiluminescence and immunometric methods. The serological and clinical profile of the patients was reviewed. SLE disease activity was measured using the SLEDAI index. The prevalence of Hashimoto's thyroiditis was 12.6% in SLE as opposed to 5.6% in controls, the difference being statistically significant. A lower prevalence of malar rash and a higher prevalence of anti-Sm was noted in lupus patients with Hashimoto's thyroiditis. No association was noted between Hashimoto's thyroiditis and disease activity of cumulative organ damage. In conclusion, a two-fold increased risk of Hashimoto's thyroiditis was noted in lupus patients. In a study performed in China 63 cases of lupus patients who also had Hashimoto's thyroiditis were studied [75]. Lupus patients were classified in four groups, those in remission, those with low disease activity, those with moderate and those with high disease activity. Free T3 levels were found to be negatively correlated with disease activity. In an effort to find a way to treat effectively Hashimoto's thyroiditis and SLE a group of scientists [76] injected human amniotic epithelial cells in murine models of Hashimoto's thyroiditis and SLE. They observed that levels of antiTg, antiTPO antibodies and TSH levels decreased as well as evidence of tissue destruction within the thyroid decreased. Additionally, the injection of human amniotic epithelial cells induced the disappearance of antidsDNA antibodies and ANA in mice with SLE and improved immunoglobulin profiles. It downregulated the ratio of Th17/Treg cells in both Hashimoto thyroiditis and SLE mice and upregulated the proportion of B10 cells. Human epithelial amniotic cells suppressed the levels of pro-inflammatory cytokines, IL-17A and IFN-γ and enhanced TGF-β in the murine models of

Hashimoto's thyroiditis and SLE, thus suggesting a common pathogenic substrate in

Graves' disease is a systemic autoimmune disease with multiple manifestations, affecting the thyroid, the eyes and the skin [77]. Cases of Graves' disease have been described in patients with SLE [78]. The case of a patient with Graves' disease who

Cases of diabetes mellitus 1 have been described in SLE. In a cohort of SLE patients in the UK the prevalence of diabetes mellitus 1 was investigated [80]. The coexistence of diabetes mellitus 1, SLE and celiac disease has been described in a young female patient [81]. It appears that diabetes mellitus 1 is rare among SLE patients. However, the risk of developing renal disease, retinal disease and peripheral neuropathy requires careful follow up of the patients. It is also important for the physician to decide which complication is due to lupus or diabetes as the man-

Diabetes mellitus type 2 is reported with increasing frequency nowadays [82]. Hence, diabetes mellitus 2 has been reported in patients with SLE. In their cohort of 485 SLE patients Cortes et al. [80] reported 4 patients with diabetes mellitus 2

later developed SLE has been described in the literature [79].

**3.2 Pancreatic dysfunction in SLE pathogenesis and form**

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Primary hyperparathyroidism is frequently recognized nowadays due to the routine measurement of serum calcium levels. Primary hyperparathyroidism has been reported in patients with lupus. However, there are just a few case reports in the literature of patients with SLE and primary hyperparathyroidism. Primary hyperparathyroidism due to the presence of a parathyroid adenoma in a 47-year old female patient with SLE has been described [84]. Hypercalcemia resolved in this patient after removal of the adenoma. Primary hyperparathyroidism due to a cystic parathyroid adenoma has also been described in a 62-year old female patient with SLE [85]. In their cohort of 708 lupus patients Munoz and Isenberg [14] also identified 5 (0.70%) patients with hyperparathyroidism, 1 with primary hyperparathyroidism and 4 patients with secondary hyperparathyroidism in the context of chronic renal failure due to lupus nephritis. Hyperparathyroidism presented after lupus in all cases described.

#### **3.4 Adrenal disease in SLE**

#### *3.4.1 Addison's disease*

Addison's disease has been reported in patients with SLE. However, there are only a few case reports of Addison's disease in patients with SLE. The case of a 29-year old female patient who presented with Addisonian crisis in the presence of SLE and responded therapeutically to corticosteroids, both as far as Addison's and lupus is concerned has been described [86]. In their cohort of lupus patients Munoz and Isenberg [14] did not identify any patient with Addison's disease. It appears that Addison's disease is a rare occurrence in lupus patients.

#### *3.4.2 Cushing's syndrome*

The occurrence of Cushing's syndrome due to an adrenal adenoma in patients with SLE is rare. The case of an 18-year old female patient with subclinical Cushing's syndrome who developed lupus has been described [87]. The patient was successfully treated by surgical removal of the adrenal adenoma. A case of a 51-year old woman with SLE who developed Cushing's syndrome and was found to have a left adrenal adenoma has been described [88]. The patient was successfully managed by laparascopic left adrenalectomy.

## **4. Ovarian function**

Reproductive function of young female patients with SLE is commonly perturbed by various pathophysiologic mechanisms [89]. Ovarian reserve is diminished even in the presence of mild lupus suggesting a direct effect of the disease itself on ovarian function [90, 91] (**Figure 4**). It is possible that the underlying process is autoimmune oophoritis [92–94]. The clinical manifestations of these abnormalities are menstrual irregularity, amenorrhea, or premature ovarian failure. Menstrual irregularities are frequently observed in patients with SLE, and many of them are associated with the activity of the disease [95]. SLE itself induces dysfunction in the hypothalamic–pituitary-ovarian axis and elevates serum prolactin [35, 96, 97]. A study compared the levels of anti–müllerian hormone (AMH) as a marker of ovarian reserve between SLE patients and control subjects and found that SLE patients had significantly lower AMH levels than did the control subjects. No correlation was observed between disease activity and AMH levels [91]. Female SLE patients may have subfertility issues due to active disease, the use of immunosuppressive medications and delayed childbearing [98]. These findings show that SLE itself has a negative influence on ovarian reserve and function.

SLE patients presenting with severe manifestations of the disease are treated with the alkylating agent cyclophosphamide [99, 100]. Cyclophosphamide is toxic to the ovaries [101–103]. SLE patients exposed to cyclophosphamide have a much higher risk of developing premature ovarian failure and infertility as compared to those receiving less toxic agents [91, 95, 104]. Cyclophosphamide leads to a decrease in reproductive life span and possibly premature ovarian failure. If the loss of ovarian function develops during or shortly after the completion of therapy, it is termed acute ovarian failure. For those who retain ovarian function after the completion of chemotherapy, a subset will go on to develop premature menopause before the age of 40 [105]. The clinical manifestations of ovarian damage in women at reproductive age vary from temporary irregular menses to amenorrhea, infertility, and premature ovarian failure depending on the magnitude of the damage. The probability of developing permanent ovarian failure depends on the following factors: patient's age and the type, dose, and duration of the treatment. If the patient is older and her ovarian reserve is low, they are less likely to retain or regain menstrual function than younger ones. Studies have documented that cyclophosphamide administration is the most significant risk factor for ovarian failure and that AMH is a sensitive and reliable marker of ovarian reserve and damage after exposure to cyclophosphamide in female patients with SLE [106–108]. In the case of cyclophosphamide administration in lupus patients fertility preservation may be attempted [108]. Currently, embryo or oocyte freezing are the established methods used for fertility preservation in patients receiving gonadotoxic treatment [109–111]. Other

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**Author details**

**5. Conclusion**

Ifigenia Kostoglou-Athanassiou1

provided the original work is properly cited.

and Panagiotis Athanassiou3

\*, Lambros Athanassiou2

1 Department of Endocrinology, Asclepeion Hospital, Voula, Athens, Greece

2 Department of Rheumatology, Asclepeion Hospital, Voula, Athens, Greece

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

3 Department of Rheumatology, St. Paul's Hospital, Thessaloniki, Greece

\*Address all correspondence to: ikostoglouathanassiou@yahoo.gr

*Endocrine Manifestations of Systemic Lupus Erythematosus*

options are ovarian tissue freezing and the use of gonadotropin-releasing (GnRH)

In conclusion, the reproductive function of female SLE patients can be adversely affected by various mechanisms such as, the chronic inflammatory state, autoimmune ovarian disease in the form of autoimmune oophoritis, lupus flares associated with hyperprolactinemia, which may interfere with ovulation and may modulate immune activity and temporary or even permanent premature ovarian failure as a

SLE is a systemic autoimmune disease which affects all organ systems and occurs frequently in female patients in the reproductive period. Estrogens appear to modulate the immune response, induce loss of self-tolerance, alter the Th1/Th2 balance in favor of the Th2 process, induce the survival of T and B lymphocytes and the production of autoantibodies. Estrogens appear to be involved in the pathogenesis of SLE. In SLE neuroendocrine system function is affected by the autoimmune process, the neuroendocrine system affecting in turn the disease process. Stress appears to affect disease expression in lupus patients. In SLE hypothyroidism occurs oftener than in the general population, hyperthyroidism occurs in the same rate as in the general population and Hashimoto's thyroiditis is present oftener than in a control population. Diabetes mellitus 1 occurs sometimes, diabetes mellitus 2 occurs less frequently than in the general population. Hyperparathyroidism has been observed in lupus patients. Addison's disease is extremely rare in lupus patients. Cushing's disease occurs infrequently in lupus patients. The ovarian function is affected in female SLE patients. Primary ovarian failure may occur due to autoimmune oophoritis. Cyclophosphamide in SLE is used and its use may be accompanied by the development of premature ovarian failure. The recognition of endocrine disease is important in SLE as symptoms may be similar to those of lupus, however management may be different. The recognition and treatment of an endocrine problem in SLE may guide treatment and lead to symptom amelioration and proper patient management.

hormone agonist treatment concurrently with chemotherapy [112, 113].

result of the administration of cytotoxic agents such as cyclophosphamide.

*DOI: http://dx.doi.org/10.5772/intechopen.97363*

**Figure 4.** *Factors adversely affecting ovarian function in systemic lupus erythematosus.*

#### *Endocrine Manifestations of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97363*

options are ovarian tissue freezing and the use of gonadotropin-releasing (GnRH) hormone agonist treatment concurrently with chemotherapy [112, 113].

In conclusion, the reproductive function of female SLE patients can be adversely affected by various mechanisms such as, the chronic inflammatory state, autoimmune ovarian disease in the form of autoimmune oophoritis, lupus flares associated with hyperprolactinemia, which may interfere with ovulation and may modulate immune activity and temporary or even permanent premature ovarian failure as a result of the administration of cytotoxic agents such as cyclophosphamide.
