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Cited by 111Hypothalamic control of reproductive hormonesHormonal and reproductive studiesAdrenal Hormones and Disorders

Dose-Dependent Effects of Recombinant Human Interleukin-6 on the Pituitary-Testicular Axis

Tsigos, Constantine, Papanicolaou, Dimitris A., Kyrou, Ioannis, Raptis, Sotirios A., Chrousos, George P.·1999·Journal of Interferon & Cytokine Research
DOI 10.1089/107999099312948
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Abstract

Inflammatory cytokines are soluble mediators of immune function that also regulate intermediate metabolism and several endocrine axes. To examine the effects of interleukin-6 (IL-6), the main circulating cytokine, on the hypothalamic-pituitary-testicular axis in men, we performed dose-response studies of recombinant human IL-6 (rHuIL-6) in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 microg/kg body weight) were injected subcutaneously into 15 healthy male volunteers (3 at each dose) in the morning. We measured the circulating levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) at baseline and then at 24 h, 48 h, and 7 days after the IL-6 injection. LH and FSH levels were also measured half-hourly for the first 4 h after the IL-6 injection. All IL-6 doses were tolerated well and produced no significant adverse effects. Mean peak plasma IL-6 levels achieved after IL-6 administration were 8 +/- 1, 22 +/- 5, 65 +/- 22, 290 +/- 38, and 4050 +/- 149 pg/ml, respectively for the five doses. We observed no significant changes in plasma testosterone levels after the two smaller IL-6 doses. The three higher IL-6 doses, however, caused significant decreases in testosterone levels by 24 h, which persisted at 48 h and returned to baseline by 7 days. The higher testosterone suppression was after the 3.0 microg/kg dose, making the dose-response curve bell-shaped. There also appeared to be small but not significant increases in LH levels after the three higher IL-6 doses, which were not acute and seemed to follow temporally the testosterone decreases. The concurrent plasma levels of FSH and SHBG were not appreciably affected by any IL-6 dose. In conclusion, subcutaneous IL-6 administration, which caused acute elevations in circulating IL-6 levels of a similar magnitude to those observed in severe inflammatory and noninflammatory stress, induced prolonged suppression in testosterone levels in healthy men without apparent changes in gonadotropin levels. This suggests that IL-6 might induce persistent testicular resistance to LH action or suppression of Leydig cell steroidogenesis or both, with potential adverse effects on male reproductive function.

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  • In aging and chronic inflammatory diseases, the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction.

    “the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction (responses shown for low IL-6 serum concentrations in ref. [42, 43]).”

    From Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology (2012) · cites this paper as [43]

  • In aging and chronic inflammatory diseases, circulating cytokine levels can be 5 to 10 times higher than normal (e.g., IL-6 from 2 pg/ml to 10-20 pg/ml).

    “In these settings, circulating cytokine levels can be 5 to 10 times higher than normal (e.g., IL-6 from 2 pg/ml to 10–20 pg/ml), and the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction (responses shown for low IL-6 serum concentrations in ref. [42, 43]).”

    From Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology (2012) · cites this paper as [43]

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Authors
Tsigos, C., Papanicolaou, D. A., Kyrou, I., Raptis, S. A., & Chrousos, G. P.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Journal of Interferon & Cytokine Research
Publisher
SAGE Publications
Published
1999-11
Volume
19
Issue
11
Pages
1271-1276
ISSN
  • 1079-9907 (ISSN-L)
  • 1557-7465
DOI
10.1089/107999099312948
OpenAlex
W2015294286
Cited by
111
References
31
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 1 · 2015: 9 · 2014: 4 · 2013: 3 · 2012: 5
FWCI
2.06
Type
journal article
Language
en
Open access
closed
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Journal of Interferon & Cytokine Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
interleukin-6, hypothalamic-pituitary-testicular axis, testosterone suppression, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, Leydig cell steroidogenesis, dose-response relationship, inflammatory cytokines, gonadotropin secretion, male reproductive endocrinology, healthy men, subcutaneous injection
MeSH terms
Adult, Dose-Response Relationship, Drug, Follicle Stimulating Hormone, Humans, Luteinizing Hormone, Male, Pituitary Gland, Recombinant Proteins, Reference Values, Sex Hormone-Binding Globulin, Testis, Testosterone, Interleukin-6

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