Hormonal approaches for the treatment of rheumatoid arthritis

[madman]

Fig. 1 Mechanism of onset of rheumatoid arthritis

* Hormones such as estrogen, progesterone, and testosterone have been shown to impact immune function and have anti-inflammatory properties, suggesting their involvement in the development and management of RA.




Abstract

Rheumatoid Arthritis (RA) is an autoimmune, chronic, systemic inflammatory disease that causes redness, swelling, stiffness, and joint pain. It is a long-lasting disease that can have a widespread impact on the body, often affecting the hands, feet, and wrists. The immune cells, such as dendritic cells, T cells, B cells, macrophages, and neutrophils, play a significant role in bone degradation and inflammation. Several cytokines, including TNF-α and IL-17A, play a significant role in causing bone erosion, cartilage deterioration, and joint inflammation. Progesterone and estrogen have a crucial impact on the pathophysiology of RA, influencing the immune system. Research has demonstrated that hormone replacement therapy (HRT) can effectively reduce inflammation, improve disease activity, enhance joint health, alleviate pain, and promote bone strength. Treatments such as tamoxifen and raloxifene, known as selective estrogen receptor modulators (SERMs), are effective against chronic inflammatory illnesses like RA. The treatment with Gonadotropin-releasing hormone (GnRH) has an impact on the hypothalamic–pituitary–gonadal axis, which in turn affects the activity of RA illness. These alternative treatments hold promise in enhancing well-being and alleviating joint pain for individuals with RA.








Conclusion

In conclusion, RA is an autoimmune disease characterized by joint deterioration, inflammation, presence of ACPAs and RF. Hormones such as estrogen, progesterone, and testosterone have been shown to impact immune function and have anti-inflammatory properties, suggesting their involvement in the development and management of RA. HRT and SERMs have demonstrated potential benefts in managing RA in postmenopausal women. Additionally, complementary therapies such as herbal treatments, Swedish massage, and balneotherapy have shown promising effect in managing RA symptoms. Further investigation is needed to understand the roles of hormones and complementary therapies in regulating immunological responses and inflammation in RA. Additionally, exploring novel therapeutic targets like cytokines could lead to more personalized and effective treatments for RA.

 

[madman]

Effects of sex hormones on rheumatoid arthritis

Estrogen

These are steroid molecules that originate from cholesterol. There are four types of estrogens that have been identified: 17β-estradiol (E2), Estrone (E1), Estriol (E3),and Estetrol (E4), its impact and working in rheumatoid arthritis as shown in Fig. 2. In females, the hormone estradiol (E2) is produced in the ovaries from the onset of puberty until the onset of menopause. E2 plays a crucial role in the development of both primary and secondary sexual characteristics in women. However, it is also created in men through the process of aromatization, where testosterone is converted into estradiol. Approximately 20% of estradiol production in males occurs in the testes, while the remaining 80% takes place in peripheral tissues (Noirrit-Esclassan et al. 2021). Estrogens have a crucial role in regulating skeletal growth, maintenance and have several physiological effects, such as promoting the development plus maturation of the reproductive system, skeleton, immunological, neurological, and cardiovascular systems (Islander et al. 2011).




Fig. 2 Impact and functions of estrogen concerning the occurrence of Rheumatoid Arthritis

 

[madman]

Effects of sex hormones on rheumatoid arthritis

Androgen

There are four androgen hormones, namely dihydrotestosterone (DHT), testosterone (T), androstenedione (ASD), and dehydroepiandrosterone (DHEA), which are all produced from cholesterol in the gonads and adrenal glands. Out of the four androgens, only DHT cannot be transformed into estrogens. Therefore, research that uses DHT is the most straightforward to analyze. Adrenal (ASD & DHEA) and gonadal androgens (T & DHT) have anti-inflammatory characteristics by inhibiting the release of pro-infammatory substances such as IL-1β, IL-6, TNF, etc. (Gubbels Bupp and Jorgensen 2018; Schmidt et al. 2005). The direct and indirect anti-inflammatory effects of androgen lead to a lower risk of developing autoimmune rheumatic diseases in men compared to women.



Fig. 3 The Role of Androgens in the Prevalence of Rheumatoid Arthritis

 

[madman]

Effects of sex hormones on rheumatoid arthritis

Progesterone

It is a naturally occurring steroid hormone that is primarily synthesized by the adrenal cortex and the gonads, which include the ovaries and testes. Progesterone is produced by the ovarian corpus luteum in the initial ten weeks of pregnancy and later by the placenta throughout the latter stages of pregnancy (Cable JK and Grider MH 2021). It is an immunoregulatory hormone that suppresses the immune system and has an unknown impact on the immunological pathways associated with RA as shown in Fig. 4. Progesterone exerts its influence on cellular function by direct interaction with membrane-bound and intracellular (cytosol and nuclear) receptors, triggering signaling cascades (Cutolo2000). Progesterone exerts extensive anti-inflammatory effects by inhibiting activation-induced cytidine deaminase (AID), TH1, and TH17 immune responses, as well as the activity of NK cells, neutrophils, and macrophages. It also stimulates the TH2 immune response by increasing the production of IL-4 and IL-10 in human T cells (Raine and Giles 2022).



Fig. 4 Exploring the impact of progesterone on rheumatoid arthritis

 

[madman]

Fig. 5 Effects of menopause in rheumatoid arthritis

 

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Table 1 In vivo and In vitro studies on hormonal effect on RA