Influence by hypothyroidism on the level of sex hormones in blood and their intracrine content in the tumor in rats with Guerin's carcinoma

Oleg I. Kit, Valeriya A. Bandovkina, Elena M. Frantsiyants, Irina V. Kaplieva, Alla I. Shikhlyarova, Ekaterina I. Surikova, Irina V. Nesku-bina, Natalia D. Cheryarina, Yulia A. Pogorelova, Lidia K. Trepit-aki, Alina Y. Arakelova, Natalia A. Maksimova, Yury A. Poryvaev, Maria G. Ilchenko. Influence by hypothyroidism on the level of sex hormones in blood and their intracrine content in the tumor in rats with Guerin’s carcinoma. Cardiometry; Issue No. 27; May 2023; p. 20-25; DOI: 10.18137/cardiometry.2023.27.2025; Available from: influence-hypothyroidism-level-sex-hormones

The regulation of the reproductive status by thyroid hormones (TH) in mammals is quite complex [1]. TH can affect sex steroids in several ways: by acting directly on the gonads, through their interaction with estradiol (E2), progesterone (P4), testosterone (T), FSH, LH and prolactin (PRL), or on the production of GnRH-releasing hormone in the hypothalamus pituitary-gonadal axis (HPG) [2, 3].

Both thyroid and steroid hormones are able to bind directly to nuclear receptors and act as transcription factors, mediating intracellular effects. In this case, continuous intracellular crosstalk is possible, which is induced by the combined action of TH and steroid hormones on target cells [4, 5]. It is known that the DNA binding site of the estrogen receptors is similar to the same binding site of the thyroid receptors: they both have the same DNA-binding sequence AGGTCA. As a result, cross-talk between the steroid hormone receptors (including the estrogen, progesterone, androgen receptors, and glucocorticoid receptors) and the thyroid hormones through incomplete elements of the hormonal response or coactivators is possible that leads to activation or inhibition of the gene transcription that implies the proper biological effect produced by steroid and thyroid hormones, their genomic effect [1].

It turned out that the TH dysregulation in rat models with hypothyroidism does not always induce a decrease in the level of serum sex hormones, similarly to that when their increase is not always can be detected in hyperthyroidism [6].

Steroid metabolism in peripheral tissues (intracri-nology) is now considered as the key way by which tissues can use hormones to respond to local physiological needs and “fine tuning” in steroid activation or inhibition as hormone receptor-dependent processes [7].

A number of studies have shown that changes in the level of hormones in the blood serum do not reflect their local content in the peripheral glands, in the tumor and its microenvironment [8]. That is, the local, or intracrine, biosynthesis and the action of sex steroids in the tumor are independent of the availability and the synthesis in other tissues and thus ensure that there is no regulation by the body.

The aim of our research work was to study the level of sex steroids in blood, the tumor and the perifocal zone in rats of both sexes with Guerin’s carcinoma against the background of hypothyroidism.

The experiment was performed in white outbred rats of both sexes weighing 150–180 g. The animals were delivered by the Federal State Budgetary Institution Scientific Center for Biomedical Technologies at the Federal Medical and Biological Agency (Andreev-ka Branch, Moscow Region). The laboratory animals were kept under natural light conditions with free access to water and food. Work with animals was carried out in accordance with the rules of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Directive 86/609/EEC), as well as in accordance with the International Guiding Principles for Biomedical Research Involving Animals and Order No. 267 “Approval of the rules of laboratory practice” dated June 19, 2003, issued by the Ministry of Health of Russia. Animals were manipulated in a box in compliance with the generally accepted rules of asepsis and antisepsis. Reference: Record No. 25/129 dated 10/27/2021 prepared by our Ethics Committee.

We used in our research work a strain of Guerin’s carcinoma, delivered by the Federal State Budgetary Institution “The Russian Cancer Research Center named after N.N. Blokhin” at the Ministry of Health of Russia. Material for transplantation was obtained from donor rats on days 12-16 of the tumor growth. Transplantation of Guerin’s carcinoma to animals was carried out by standard subcutaneous injection of a tumor suspension under the skin of the right shoulder blade in a volume of 0.5 ml of cell suspension diluted 1:10 in saline.

The white outbred rats of both sexes received for 30 days pharmacopoeial thyreostatic drug Merkazolil (“Akrikhin” Russia) at a daily dose of 2.5 mg/100 g of body weight (the total dose was 75 mg/100 g of body weight). The animals did not refuse to eat, gained weight, and no deterioration in the appearance of the skin and the hairline, no lethargy or drowsiness were recorded. Hypothyroidism in animals was confirmed by determining the content of total thyroxine and thyroid-stimulating hormone in the blood serum, by radioimmunoassay using standard kits (Immunotech, Czech Republic) 30 days after the thyreostatic agent medication. The animals of each sex were divided into groups comprising 15 females and 15 males: The main group was composed by the rodents after persistent hypothyroidism, and the animals therein were subcutaneously transplanted with Guerin’s carcinoma.