Abnormal Anterior Pituitary Hormone Levels and Possible Neuroendocrine Relationships in Females With Hand Osteoarthritis: A Pilot Study.

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Abnormal Anterior Pituitary Hormone Levels and Possible Neuroendocrine Relationships in Females With Hand Osteoarthritis: A Pilot Study.

https://doi.org/10.21203/rs.3.rs-5013072/v1

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Background. Hand Osteoarthritis (HOA) presents genetic and hereditary characteristics and related to menopause with inflammatory symptoms.

Aim. To evaluate the anterior pituitary and sexual hormonal profiles of climacteric women with HOA and identify the probable link with hypothalamic commitment of GnRH (Gonadotropin Releasing Hormone) and TRH (Thyrotropin Releasing Hormone).

Methodology. A retrospective, controlled trial on climacteric females patients with HOA compared to healthy women, and all submitted to hormonal evaluation by RIA for estradiol (E2), progesterone (PRG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), parathyroid stimulating hormone (PTH), growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH).

Results. The groups were homogeneously related to age, menopause onset, and expected climacteric levels of E2, PRG, FSH, ACTH, GH, and PTH; the HOA group, without black patients (p<0.000), presented more abnormal tests than the controls (<0.0000) in 86.4% (95%CI67,2-96.4) of the sample, and related to low levels of LH in 40.9%(95%CI22.1-61.9) and FSH in 9.09%(CI95%1.5-26.9), 45.4%(CI95%25.8-60.1) patients with increased levels of TSH (p<0.000) and 31.8%(CI95%15.1-53.0) with high PRL levels (p = 0.04). The analysis of hypothalamic dependence demonstrated that 50.0% (CI95% 29.7-70.2) of the sample presented low LH/FSH levels related to GnRH and 77.2%(CI95%56.5-01.1) with TSH/PRL levels associated with TRH.

Conclusion. The HOA patients exhibit more hormonal abnormalities than the control group, and trend to sub-clinical syndromes of hypothyroidism, hyperprolactinemia, and hypogonadism hypogonadotropic only related to LH and ovarian hormones, and these findings demonstrated a probable neuroendocrine participation in HOA physiopathology.

General Practice

Hand Osteoarthritis

pituitary hormones

sexual hormones

neuroendocrine

inflammation

osteoarthritis

Hands Osteoarthritis (HOA) is an idiopathic manifestation of cartilage degeneration related to menopause with inflammatory signs, and genetic and hereditary profiles, and unrelated to trauma or articular overload without systemic commitment, presented several major histocompatibility complex antigens, and characterized by the development of acute initial interphalangeal arthritis, mucinous and bone cysts, sclerosis, hyperostosis [1, 2, 3]. Previous studies demonstrated the relationship of 28:1

between females and males, and that females developed with high levels of estrogen, and presented significant prevalence of myoma, hysterectomy, dysfunctional gynecological hemorrhages, breast complaints, and overproduction of aggressive enzymes and inflammatory molecules [4, 5, 6, 7, 8, 9, 10]. The excess of estrogen harms the hypothalamic neurons and compromises the TRH (thyrotropin-releasing hormone) and GnRH (gonadotropin-releasing hormones) surges, and modifies the production of dopamine, gonadotropins, TSH, prolactin (PRL), harms the hypothalamic/ pituitary axis, and this neuroendocrine disturbance affects the tissular metabolism and predisposes to inflammatory development [10, 11, 12].

Our concern about this theme started with anecdotal observation in 1992 with a 52-year-old female with exacerbated clinical signs of menopause, anxiety, acute HOA symptoms, breast secretion, hyperprolactinemia without pituitary adenoma, and all symptoms improved after seven days of treatment with bromocriptine. Supported by this evidence, the authors elaborated a pilot project with menopausal women with HOA, compared to homogeneous healthy group, to study the pituitary and sexual hormone profiles and search for probable neuroendocrine abnormalities and the link with unexpected hormonal levels and sub-clinical endocrinological syndromes which participate for the degenerative and inflammatory syndrome without systemic commitment.

Study design and patients.

A retrospective controlled trial with the data from the registry of female outpatients with HOA compared to a homogeneous healthy group to evaluate the pituitary and gonad hormonal profiles. The project approved by the Research Ethics Committee, and all participants signed the written informed consent participants, and to be included in the project must followed the criteria for the HOA diagnose from the American College of Rheumatology diagnostic criteria, and typical articular inflammatory signs, natural menopause for more than one year, and clinical and radiological characteristics [13]. The exclusion criteria include menstruation, inflammatory rheumatic diseases, metabolic diseases, degenerative diseases, trauma, systemic clinical diseases, and the use of medications that interfere on the hormonal profile. The control group performed with healthy women without HOA, who filled the exclusion criteria and freely agreed to participate in the trial. The data collected and registered in routine care from January 1993 to March 1994 and extracted in 2022.

Clinical and laboratory collection.

The demographic data included sex, age, disease length, menopause age, HOA onset, and ethnicity. The hormonal levels measurement made in fasting blood samples obtained at 7:00 AM, performed through radio-immune assays (RIA) tests with monoclonal antibody CIS-RIA (Dosage Immunradiométrique - CIS bio international 1993), to evaluate the levels of estradiol (E2), progesterone (PRG), and anterior pituitary follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), parathyroid stimulating hormone (PTH), growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH) [14, 15]. The abnormal tests defined by increased values above the highest limits of E2, PGR, TSH, PRL, GH, ACTH, PTH and decreased values below the FSH and LH lower limits obtained from laboratory analysis compared to the method’s expected normal hormonal ranges for climacteric women: estradiol (E2) from 0 to 60pg / ml; progesterone (PRG) from 0 to 73 pg/ml; luteinizing hormone (LH) from 13 to 122 µUI / ml; follicle-stimulating hormone (FSH) from 25 to 162 µIU / ml; thyroid stimulating hormone (TSH) from 0.4 to 3.19 mUI / ml; prolactin (PRL) from 2.0 to 10 ng/ml; growth hormone (GH) from 0.0 to 3,2 ng/ml; adrenocorticotropic hormone (ACTH) from 0 to 50 UI / ml; parathyroid hormone (PTH) 0 to 1.3 ng/ml [14, 15]. The trend for endocrinological syndromes in HOA patients obtained through the comparison with the data from epidemiological frequency of hypothyroidism 15.2%; hyperprolactinemia 16.1%; hypogonadism 100%; hyper gonadotropic hormones 100% (increased FSH 100%, increased LH 100%); hypogonadism hypogonadotropic 10% [14, 15].

Statistical analysis. The rationale for the study is that healthy climacteric women present hypogonadism hypogonadotropic and HOA appears in 18% of all menopausal women, between 49 to 54 years, risk of 0.23 and a chance of 0.25 [17, 18]. Continuous variables are expressed as proportion, percentage, mean, standard deviation (sd), median, and absolute numbers using Student's t-test. Categorical variables are expressed as proportions and percentages and compared by chi-square or Fisher's exact tests and the Student test. The sample size obtained from a rheumatological population of 2162 outpatients with 25 HOA patients who filled the exclusion criteria with an expected sample size of 15 patients (CI95% 9.4–22.2) in each group. The significance level is 95%, the statistical significance p < 0.05, and the beta error is 80%. n

The study included twenty-two patients in the HOA group and eleven participants in the healthy control group.

The groups were homogeneous related to age, sex, menopause onset, and time of menopause. The HOA group without black ethnicity, and with abnormal hormonal levels in 86.4% (67.2-96.4) patients, more in controls, p<0.00000 OR 1222 (CI95%71–20830), and related to low LH titles in 40.9% (CI95%22,1-61.9), p=0.001, OR 14.5(CI95%0.8-256), and high titles of TSH in 45,4% (CI95%25.8-66.1) of patients and more than in controls, p=0.01, OR17.5 (0.9-337), and higher tiles of PRL in 31.8% (CI95%15.1-53) than the controls, p=0.04 OR 9.8 (CI95% 0.5-192).

The evaluation of the quantitative hormonal values from the patients and healthy controls demonstrated no differences related to LH, FSH, ACTH, GH, PTH, E2, PRG levels, but significant higher levels of TSH (p=0.03) and PRL (p=0.01) in the HOA group.

The HOA patients presented significantly more abnormal hormonal tests 16,6% (CI95%13.2-24.0) than the healthy control group, p<0.0000 OR 134.5 (2.08-570), with 40.09% (CI95% 22.1 -61.9) with low level of LH, p<0.000, OR 138.3 (CI95% 8.3-2209), and high levels of TSH in 45.4% (CI95% 25.8-66.1), p<0.000 OR 162 ( CI95% 9.8-2695), and high titles of PRL in 31.8% (CI95%15.1-53.05), p<0.000 OR93.5 (CI95% 5.6-1556). The evaluation of the aggregate of abnormal hormone frequency related to hypothalamic hormones demonstrated significant higher percentage in HOA group with 50% (CI95% 29.7-70.2) (p<0.000) of the sample dependent on GnRH abnormalities with low levels of LH and FSH (p<0.000), and 77.2% (CI95% 56.5-91.1) related to TRH hormones with high levels of TSH, and PRL (p<0.000).

The study demonstrated that 86.4% of the HOA sample presented more abnormal hormone levels than the controls (p = 0.03), and preponderance of white ethnicity that signals a probable genetic predisposition (Table 1). The quantitative hormonal analysis (Table 2) demonstrated more pituitary hormonal abnormalities in HOA patients related to higher titles of TSH (p = 0.03) and PRL (p = 0.01). The frequency of patients with abnormal results (Table 3) demonstrated that 16.6% (13.2–24.0) of the HOA group presented more hormonal tests than the controls (p < 0.0000), and dependent of low levels of LH (p < 0.0000), and high levels of TSH (p < 0.0000), and PRL (p < 0.0000), and trends for hypogonadism hypogonadotropic in 50% ( CI95% 29.7–70.2), hyperthyroidism in 45.4% (CI95% 25.8–66.1), and hyperprolactinemia in 31.8% (CI95%15.1-53.05). These results demonstrated significant increased frequency of hormonal syndromes in HOA patients even when compared to the expected frequency of climacteric women [12, 13, 14, 15].

The sub-clinical syndromes of hypogonadism hypogonadotropic related to LH deficiency, hypothyroidism, and hyperprolactinemia were probably dependent from the damage on hypothalamic neurons which interfere on gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) surges. These findings corroborated the previous endocrinological studies in HOA patients which demonstrated, in addition to genetic and hereditary profiles, the relationship between high estrogen levels, and hypothalamic neurons damages, and neuroendocrine misbalance on the hypothalamus-pituitary–gonads axis which modifies the dopamine, TRH, GnRH production and collaborates for cartilage inflammation and degeneration [16, 18, 17, 19, 20, 21].

The results of the hormonal profile in the HOA sample presented expected climacteric gonads hormone levels, and normal high FSH levels, but not expected abnormal low LH levels and high TSH and PRL titles.

The hormones, acting on cellular pathways in the metabolic tissular environment, are fundamental for the cartilage health, but also play an important role on the development of the degenerative syndrome. The estrogen before menopause presents an anabolic activity stimulating the chondrocytes to produce normal extracellular matrix (ECM) through the increased stimulation of the Transforming Growth Factor beta (TGFβ) activity, but after menopause changes to a catabolic profile through the TGFβ activity modification and restricts the chondrocyte proliferation in the epiphyseal plaque, increases the production of inflammatory molecules (Interleukin1/IL1, Tumor Necrosis Factor-alpha /TNF α) and enzymes, impairs the activity of platelet-derived growth factor (PDGF), inhibits the synthesis of proteoglycans (PGN), and changes the hydrophilic characteristics of the ECM [7, 22, 23]. The degenerative and inflammatory processes are depend of hormonal synergism, and demonstrated with the PRL, dependent of TRH function, which stimulates the T-lymphocyte reactivity, fibroblasts activity, synovial hyperplasia, neo-angiogenesis, production of catabolic enzymes, and chondrocyte apoptosis [20, 21, 22, 23

]. The hyperprolactinemia inhibits the anabolic activities of the TGFβ/ Smad via the PRL / JAK2 pathway, and associated with the high levels of IL1 and TGFβ found on osteoarthritic cartilage, restricts the mesenchymal-epithelial transition and deteriorates the ECM [24, 25]. Also related, the abnormal TRH activity modifies the pituitary feedback and the increased TSH level induce to a sub-clinical hypothyroidism related with tissular degeneration [11, 21].

The hormonal balance is fundamental for the tissue homeostasis which is disrupted after menopause and characterized by low levels of sexual hormones and high levels of gonadotropins. These hormones presented synergic and antagonist association demonstrated by FSH and estradiol opposite actions on the cellular differentiation of bone marrow cells: the FSH favoring the osteoclast formation and inflammatory cell activation which harm the sub-chondral bone; and the estrogen stimulates osteoblast accumulation; but after menopause the high FSH and low estrogen levels intensify the sclerostin catabolic activity, a protein made by osteocytes which intensify the bone remodeling process, the osteoarthritis phenotype, the chondrocyte differentiation and apoptosis [ 26, 27, 28, 29, 30]. The FSH participates for the bone and cartilage instability through the activation of inflammatory characteristics increasing the population of monocytoid CD14 + RANK cells which activates the receptor NGFKβ ligand and the Macrophage Colony-Stimulating Factor (M-CSF) and the secretion of IL 8 [26, 27]. The FSH also stimulates the production of the protein β-catenin, a transcriptional cellular and signaling factor, with increased levels in the osteoarthritic cartilage, which through harmful mutations and hyper-expression is associated with neoplasm (lung, breast, ovary, endometrium, liver, and bowel), and the canonical Wnt -frizzled-β-catenin pathway up-regulates the expression of follicle-stimulating hormone receptors (FSH r) interrupts the degradation of β-catenin and changes the TGFβ activity leading to an osteoarthritic like phenotype [31, 32]. The Wnt/ β-catenin signaling also reduces the action of sclerostin, a protein expressed by SOST genes in osteocytes, and harms the cartilage and sub-chondral bone integrity, and this activity had been described in the development of erosive HOA, temporomandibular OA, facet OA, diffuse idiopathic skeletal hyperostosis (DISH), and spondyloarthritis (SpA) [33].

The chondrocyte dedifferentiation characterizes the shift of the cell phenotype from the normal chondrocyte shape toward a polygonal fibroblast-like phenotype [34]. This change to a modified active fibroblast phenotype is stimulated by FSH, without estrogen participation, and inhibits the cAMP/PKA and MKK4/JNK signaling pathways inducing to an abnormal ECM production and inflammatory response [34, 35, 36, 37].

The OA presents inflammatory signs without systemic commitment which appear to be independent of CD3 activation [38]. Previous studies demonstrated the association of HOA with inflammasome, a cytosolic protein complex related to the NOD-like receptor pyrin domain containing 3 (NLRP3), and significantly present in the serum of patients with non-erosive HOA, which stimulates the production of IL1β, TNF α, IL18, TGFβ, reactive oxygen, MMP and participates for cartilage degeneration and synovial inflammation [39, 40]. This protein is activated by low levels of estrogen and progesterone, related with menopause, and modifies the Epithelial-Mesenchymal Transition (EMT), up-regulates the TGFβ catabolic action, enhances the TGFβ / Smad pathway, and participates in osteoarthritic development [41, 42, 43, 44]. These results infer the role of genetics and hereditary profile which influenced by the old age and hormonal misbalance participate on tissular derangement. The study had a limited sample size and new trials are necessary to prove the results, compare it with a male sample, relate to inflammatory activity, evaluate the hypothalamic neuroendocrine profile, and compare it with the posterior pituitary hormonal profile.

This sample of HOA climacteric patients with congenital and hereditary profiles presented normal climacteric low levels of E2 and PRG, normal climacteric high levels of FSH, and abnormal pituitary hormonal profile with low levels of LH, and high levels of TSH and PRL, and trend for subclinical hypothyroidism, hyperprolactinemia, and hypogonadism related to low levels of LH.

Ethical approval and consent to participate. Not applicable.

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Funding. Not applicable.

Availibity of data and materials. Not applicable.

Competing interests. The authors declare any competing interests.

Acknowledgement. Not applicable.

Author information.

Affiliation.

Mario Newton Leitao Azevedo. Universidade Federal do Rio de Janeiro, Rodolpho Paulo Rocco St 255, ZIP Code 21941 617, Rio de Janeiro, Brazil. https://orcid.org/0000-0002-0229-698X. [email protected]

Mario Vaisman, Universidade Federal do Rio de Janeiro, Rodolpho Paulo Rocco St 255, ZIP Code 21941 617, Rio de Janeiro, Brazil. [email protected]

Ingrid Bandeira Moss, Universidade Federal do Rio de Janeiro, Rodolpho Paulo Rocco St 255, ZIP Code 21941 617, Rio de Janeiro, Brazil. [email protected].

Breno Valdetaro Bianchi, Universidade Federal do Rio de Janeiro, Rodolpho Paulo Rocco St 255, ZIP Code 21941 617, Rio de Janeiro, Brazil. [email protected].

Blanca Elena Rios Gomes Bica, Universidade Federal do Rio de Janeiro, Rodolpho Paulo Rocco St 255, ZIP Code 21941 617, Rio de Janeiro, Brazil. [email protected].

Contribution.

M.N.L.A . made the study conception and design, wrote the main manuscript text, and is the corresponding author. [email protected], https://orcid.org/0000-0002-0229-698X, M.V. made the study conception,I.B.M. and B.V.B data collection, B.E.R.G.B. revised the final version of the manuscript. All authors reviewed the manuscript..

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Abnormal Anterior Pituitary Hormone Levels and Possible Neuroendocrine Relationships in Females With Hand Osteoarthritis: A Pilot Study.

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