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Laqueur E, Hart PC, de Jongh SE. Ueber weibliches Sexualhormon (Menformon), das Hormon des östrischen Zyklus III. Dtsch Med Wochenschr. 1926;30:1247-1250

Korenchevsky V, Dennison M, Schalit R. CLVI. The response of castrated male rats to the injection of testicular hormone. Biochem J. 1932;26:1306-1314

The idea

The two author groups of The Netherlands (Laqueur et al., Amsterdam, pharmacotherapeutic laboratory of the university) and England (Korenchevsky et al., London, Lister Institute) were interested in methods of testing the activity and strength of estrogenic (1) and testicular hormones (2). At the time, without knowing the exact nature of the tested hormones, biological test methods were very common. Biological test methods allowed for isolation of increasingly pure test substances, which finally led to the description of the authentic sex hormones and their exact molecular structure (3-4).

The discovery

In a multitude of investigations, the two author groups recognized that the hormone preparations significantly influenced the thymus – the location of naïve T lymphocytes, as we know it today. Indeed, the hormonal preparations, whether estrogenic or testicular, lead to thymus involution / shrinkage. The authors did not know the exact function of the thymus, but they clearly showed the first influence of sex hormones on a lymphoid organ. Later, it was also recognized that estrogens/testosterone has a strong influence on the B lymphocyte equivalent of the thymus, where naïve B lymphocytes are produced, the Bursa Fabricius of birds (5).

Discussion

Many groups have supported the concept of thymus involution with the appearance of gonadal hormones, also in humans. Before, and during the process of puberty, the thymus markedly shrinks. Real readout parameters of the immune system appeared later in the history of immunology in the form of antigen-specific antibodies, and it was demonstrated that the antibody response is sex-dependent, and that orchiectomy increased the specific antibody response (6). The later information speaks for the immunoinhibitory role of testosterone.

Thymus involution remains an enigma in immunology, but we know that it happens in all vertebrates and, thus, it is likely an evolutionary conserved program. From an evolutionary standpoint, strong early thymus activity allows for a diverse T cell repertoire to fight infections, particularly in the young. During the early years, a fixed T cell repertoire is established which serves the immune system for most of the available infections in a given local environment. Since the maintenance of thymus function is energy consuming, some believe that shrinkage of the thymus is necessary to devote energy to other physiological processes (7). In addition, the force of natural selection declines with age. Until maturity and reproduction, this force of natural selection is strongest but, thereafter, it shrinks, and involution of the thymus just happened independent of selection.

Since many autoimmune disease are more prevalent in women than men, the immunostimulatory nature of estrogens (mainly on B lymphocytes) and the immunoinhibitory influence of androgens was often reviewed in the context of autoimmune diseases (8-11).

Sex hormone regulation of immune reactions stood the test of time, and Neuroimmunomodulation published some relevant experiments (12-16, and many more).

References

1. Laqueur E, Hart PC, de Jongh SE. Ueber weibliches Sexualhormon (Menformon), das Hormon des östrischen Zyklus III. Dtsch Med Wochenschr. 1926;30:1247-1250
2. Korenchevsky V, Dennison M, Schalit R. CLVI. The response of castrated male rats to the injection of testicular hormone. Biochem J. 1932;26:1306-1314
3. David K, Dingemanse E, Freud J, Laqueur E. Über krystallinisches männliches Hormon aus Hoden (Testosteron), wirksamer als aus Harn oder aus Cholesterin bereitetes Androsteron. Biol Chem. 1935;233:281–283
4. Butenandt A, Hanisch G. Über Testosteron. Umwandlung des Dehydroandrosterons in Androstendiol und Testosteron; ein Weg zur Darstellung des Testosterons aus Cholesterin. Biol Chem. 1935;237:89–97
5. Selye H. Morphological changes in the fowl following chronic overdosage with various steroids. J Morphol 1943;73:401-421
6. Batchelor JR, Chapman BA. The influence of sex upon the antibody response to an incompatible tumour. Immunology 1965;9:553-564
7. Shanley DP, Aw D, Manley NR, Palmer DB. An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol. 2009;30:374-381
8. Cohn DA. High sensitivity to androgens as a contributing factor in sex differences in the immune Response. Arthritis Rheum 1979;22:1218-1233
9. Ansar Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol. 1985;121:531-551
10. Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT. Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 1995;13:217-226
11. Cutolo M, Straub RH. Sex steroids and autoimmune rheumatic diseases: state of the art. Nat Rev Rheumatol. 2020;16:628-644
12. Suescun M, Chisari AN, Carino M, Hadid R, Gaillard RC, Spinedi E. Sex steroid regulation of the hypothalamo-pituitary-adrenal axis activity in middle-aged mice during endotoxic shock. Neuroimmunomodulation. 1994;1:315-320
13. Di Santo E, Foddi MC, Ricciardi-Castagnoli P, Mennini T, Ghezzi P. DHEAS inhibits TNF production in monocytes, astrocytes and microglial cells. 1996;3:285-288
14. Shelat SG, Aird F, Redei E. Exposure to dehydroepiandrosterone in utero affects T-cell function in males only. Neuroimmunomodulation. 1997;4:154-162
15. Nanamiya W, Takao T, Asaba K, De Souza EB, Hashimoto K. Effect of orchidectomy on the age-related modulation of IL-1beta and IL-1 receptors following lipopolysaccharide treatment in the mouse. Neuroimmunomodulation. 2000;8:13-19
16. Macció DR, Calfa G, Roth GA. Oral testosterone in male rats and the development of experimental autoimmune encephalomyelitis. Neuroimmunomodulation. 2005;12:246-254

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