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Table of Contents
Year : 2020  |  Volume : 6  |  Issue : 4  |  Page : 363-369

The effect of hormones of the hypothalamic-pituitary-target gland axes in a kidney-yang deficiency syndrome model

1 Teaching and Research Department of Meridians and Acupoints, School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2 Department of Acupuncture, Shanghai Pudong New District Hospital of Traditional Chinese Medicine, Shanghai, China

Date of Submission10-Apr-2020
Date of Acceptance17-May-2020
Date of Web Publication05-Oct-2020

Correspondence Address:
Prof. Ling Zhao
School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai 201203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_38_20

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Kidney-yang deficiency syndrome (KYDS) is a diagnostic pattern in the traditional Chinese medicine. Studies have shown that KYDS is related to the functional disorder of hormones of the hypothalamic-pituitary-target gland axes. The standard procedure used to mimic KYDS is the injection of a high dose of exogenous glucocorticoid (hydrocortisone and corticosterone). Such a model showed symptoms such as exhaustion, body twists, cold limbs, lying crowded together, decreased rectal temperature, sexual dysfunction, decreased reaction speed, reduced spontaneous activity, hair loss, loss of appetite, and weight loss. Moreover, the model manifested an imbalance in mutual control among the hormones of the pituitary-target gland axes, including adrenocorticotrophic hormone, CORT, CRH, thyroid-stimulating hormone, triiodothyronine, thyroxine, T, E2, follicle-stimulating hormone, luteinizing hormone, and 17-OHCS.

Keywords: Corticosterone, exogenous glucocorticoid, hydrocortisone, hypothalamic-pituitary-adrenal gland, hypothalamic-pituitary-gonad, hypothalamic-pituitary-thyroid, Kidney-Yang deficiency syndrome, steroid hormone

How to cite this article:
Ayu AD, Pan W, Huang ZQ, Zhao L. The effect of hormones of the hypothalamic-pituitary-target gland axes in a kidney-yang deficiency syndrome model. World J Tradit Chin Med 2020;6:363-9

How to cite this URL:
Ayu AD, Pan W, Huang ZQ, Zhao L. The effect of hormones of the hypothalamic-pituitary-target gland axes in a kidney-yang deficiency syndrome model. World J Tradit Chin Med [serial online] 2020 [cited 2021 Aug 2];6:363-9. Available from: https://www.wjtcm.net/text.asp?2020/6/4/363/303576

  Introduction Top

According to the traditional Chinese medicine (TCM), the kidney's function is to store the essence and govern birth, growth, and reproduction. The kidney yang is the representative of the motive force of all physiological processes and the root of transformation and movement (the physiological fire).[1],[2] Kidney-yang deficiency syndrome (KYDS) is one of the common syndrome patterns in TCM. It is the most severe of yang deficiencies with the characteristics of cold extremities (especially the lower extremities), intolerance to cold, weakness, coldness and soreness of the lower back and knees, impotency, frequent urination (especially during the night), clear polyuria, pale complexion, cough, and wheezing. The secondary symptoms may include impotency or spermatorrhea, profuse and clear leukorrhea, diarrhea (especially early in the morning), edema, and infertility.[3],[4],[5],[6],[7]

KYDS is closely related to multiple disordered metabolic pathways.[8] Modern medicine has shown that damage to and functional disorders of the hypothalamic-pituitary-target gland axes (adrenal, thyroid, and gonad) cause KYDS.[3],[5],[9],[10],[11]

A standard method to mimic kidney-yang deficiency is by injecting a high dose of exogenous glucocorticoid (e.g., hydrocortisone and corticosterone).[10] This study aimed to investigate the effect of hormones of the hypothalamic-pituitary-target gland axes using the KYDS model induced by glucocorticoid drugs (hydrocortisone or corticosterone).

  Methods Top

Ethics statement

All animal procedures were carried out in compliance with the guidelines for scientific animal procedures approved by the ethics committee of the Shanghai University of Traditional Chinese Medicine.

Previous studies have generated a KYDS model successfully using various treatments such as Chinese medicines, hormones, or surgical techniques.[6] Hydrocortisone and corticosterone injection is a common method used to create a KYDS model.[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32]

Repeated injections of various doses of hydrocortisone and corticosterone were administered to generate the model. The commonly used dosage of hydrocortisone is 10 mg and 25 mg per kg of rat body weight. Similarly, corticosterone is administered at 10 mg/kg of the body weight. The rats were injected with either drug once per day for 14–21 days. Different doses of the glucocorticoid drug might affect different target axes.[13] Previous studies have reported a mutual control relation with hormones of the pituitary-target gland axes in KYDS, assessed by various methods such as ELISA, gas-chromatography time-of-flight (TOF) mass spectrometry (MS), immunohistochemstry, liquid chromatography quadrupole-TOF-MS, ultrahigh-pressure liquid chromatography-MS, ultraperformance liquid chromatography/MS, and support vector machines.

  Results Top

According to previous studies, 14–21 days postinjection of hydrocortisone or corticosterone, the rats presented with symptoms, including exhaustion, body twists, cold limbs, lying crowded together, decreased rectal temperature, sexual dysfunction, decreased reaction speed, reduced spontaneous activity, hair loss, loss of apetite, and weight loss. The suppression resulted in a reduction of CRH, adrenocorticotrophic hormone (ACTH), CORT, 17-OHCS, cGMP, and cAMP compared to the control group. This condition led to a decrease in hormones of the HPT and HPG axes.[3],[6],[8],[11],[27],[33] The changes in hormone levels are shown in [Figure 1], [Figure 2] and [Table 1], [Table 2], [Table 3], [Table 4], [Table 5].[9],[19],[28]
Figure 1: Changes in the body weight index of rats (control group, model group, and YGP-treated group) on day 23; (b) the occurring mechanisms of KYDS-HPT axis and HPA axis disorders; and (c) H&E staining of pituitary, adrenal, thyroid and testicular tissue sections [(a–c): magnification 40x; and (d): magnification 20x]. (d) The biochemical characteristics used for the evaluation of the therapeutic effects of YGP on KYDS. Bar plots represent the mean relative hormone intensities and standard deviations, error bars represent the mean ± SD (Student's t-test: *significant difference from control group at P < 0.05; ** significant difference from control group at P < 0.01; *** significant difference from control group at P < 0.001; # significant difference from model group at P < 0.05; ## significant difference from model group at P < 0.01; ### significant difference from model group at P < 0.001. After treatment with YGP, various levels of T3,T4, T and CORT in the treatment group returned to the level of the control group) (one-way ANOVA with a Bonferroni correction).[9]

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Figure 2: The evaluation system diagrams of Kidney-Yang Deficiency Syndrome related to neuroendocrine hypofunction (day 22). (a) H&E staining for histological evaluation. The pictures of KYDS model rats showed that the number of depauperate hypothalamic neurons was reduced, the counts of basophilic cells in hypophysis was decreased, the atrophic adrenocorticals were found by observing thinning of the cortex, the thyroid follicules were atrophic, deformed, and the interstitial fibrous matter around the thyroid follicules were proliferated therein. (b) The biochemical characteristics for evaluation of neuroendocrine system. Significant changes in the concentrations of CRH, ACTH, 17-OHCS, T3, T4, T, cAMP, and cGMP were decreased in KYDS model rats (Student's t-test; *significant difference from control group 1 at P < 0.05, **significant difference from control group 1 at P < 0.01)[19]

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Table 1: The hormones changes of Hypothalamic-pituitary-target gland axes in Kidney-Yang Deficiency Syndrome induced by Hydrocortisone

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Table 2: Relative change rates of hormones of PA axis when the index values of the hormones of the PT axis were multiplied by 0.9 (%) use SVR

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Table 3: Relative change rates of hormones of PG axis when the index values of the hormones of the PA axis were multiplied by 0.9 (%) use SVR

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Table 4: Relative change rates of hormones of PA axis when the index values of the hormones of the PG axis were multiplied by 0.9 (%) use SVR

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Table 5: Relative change rates of hormones of PT axis when the index values of the hormones of the PA axis were multiplied by 0.9 (%) use SVR

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The models were verified through H and E staining; hypothalamic neurons were atrophied and cell numbers were decreased. Moreover, basophil numbers in the pituitary decreased, and nucleus pycnosis and cell gap were greater compared to the control group. In addition, the adrenal cortex in the zona fasciculata and zona reticularis was atrophied. Furthermore, there was interstitial cell hyperplasia of fibers in the thyroid gland accompanied by congestion when compared with the control group. However, in the testes, the boundaries were fuzzy with decreased caliber leading to an empty lumen and thinner layer. Moreover, there was decreased delamination and number of spermatids.[3],[9],[19],[27],[33] These results confirmed successful the establishment of the KYDS model.

Previous studies showed that certain Chinese medicine formulas can treat KYDS. Chinese medicine improved behavioral activities, physiological characteristics, and biochemical indicators in KYDS models. Besides improving these common symptoms, the active ingredient of You Gui Pill acted on the GnRH signaling pathways and played a role in the regulation of the HPT and HPA axes. Histopathology examination is depicted in [Figure 1].[7],[9] Furthermore, You Gui Pill improves oxidative damage and has a protective effect on the liver and kidney, thereby negating the ill effects of oxidative stress caused by KYDS.[34] Similarly, another Chinese medicine, Sini Decoction (SND), alleviated the effects of KYDS in a rat model through the restoration of circulating and in situ expression of HPA-axis hormones. Specifically, SND induced gene expression changes in the rat adrenal glands: upregulation of metabolic and stress response-associated genes. Upon further in vitro analysis, it was found that the protective effect of SND treatment on mitochondria and the pleiotropic effects of SND were mediated through activation of NF-κB and CRE signaling.[11] Originally described by Lu et al., Rhizoma Drinariae was shown to improve the E2 and Triiodothyronine (T3) score in a KYDS model (P < 0.01); however, improvement in thyroxine (T4) (9.27 ± 1.3 vs 8.39 ± 1.28) and T (3.76 ± 0.71 vs 2.08 ± 0.35) scores were not significant compared to the control.[10] Gui Fu Di Huang Wan increased the cAMP/cGMP ratio and had an effect on the HPA axis.[17]

  Discussion Top

The kidney-yang deficiency syndrome model induced by glucocorticoid drugs

Glucocorticoid drugs are steroid hormones produced by the adrenal gland (adrenal cortex) and play a complex role in regulating the body functions.[4],[9] The name “glucocorticoid” is derived from early observations that these hormones were involved in glucose metabolism. In a fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in the blood.[35] Exogenous glucocorticoid injection induces adrenocortical insufficiency, thereby mimicking the pathological state of hypothalamic-pituitary-target gland axes atrophy and secretion of those declined after suddenly withdrawal administration of the glucocorticoid drug.

Decline in physical activity and rectal temperature have been regarded as the characteristics of kidney-yang deficiency.[27] Exhaustion in KYDS might be related to impaired mitochondrial function since the lack of glucocorticoids selectively inhibits free fatty acids (FFAs) oxidation.[5],[36]

The effect of sarcosine dehydrogenase, creatine can be dehydrogenated to generate formaldehyde, which can glutamate deamination produced the unite two molecules of ATP and amino to generate carbamoyl phosphate in the role of amino carbamoyl phosphate synthetase. Infecting rats with hydrocortisone intereferes with the synthesis of the aforementioned molecules and energy metabolism. Increase in the expression of heat-shock proteins can protect cells from injuries. Repeated injections of exogenous hormones could disturb the stability of energy metabolism and the self-adjusting ability in vivo,[37] subsequently causing cellular damage or functional degeneration in the HPA axis. These effects were shown in the clinical manifestations of KYDS in humans.[19]

The mechanism of kidney-yang deficiency syndrome in modern medicine

The HPA axis is the main neuroendocrine system that regulates responses to stress. It is well known that high levels of ROS are produced in the glands that comprise the HPA axis. This is associated with the activation of a stress response system in several models of stress, as well as in social isolation and inflammatory and infectious diseases. Hyperactivity of the HPA axis induced by redox imbalance may occur by a reduction in negative feedback through a decrease in GR translocation to the nucleus in corticotroph cells of the pituitary. ROS are ions or small molecules containing oxygen and an free electron, it confers high reactivity to oxygen. The production of high levels of ROS into the glands that comprise the HPA axis.[38]

In working toward an understanding of the main mechanism of KYDS, research has concentrated on the neuroendocrine-immune system of modern medicine accompanied by various pathophysiologic changes in the organism with functional disorder in the hormones of the hypothalamus-pituitary-target gland axes (adrenal, thyroid, and gonad). The model induced by glucocorticoid drugs showed changes in hormones of the hypothalamus-pituitary-target gland axes such as CRH, ACTH, CORT, and 17-OHCS (hypothalamic-pituitary-adrenal); thyroid-stimulating hormone (TSH), T3, and T4 (hypothalamic-pituitary-thyroid); and T, E2, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (hypothalamic-pituitary-gonad).

Role of the hypothalamic-pituitary-adrenal gland axis

In normal physiology, three structures that modulate the response to stress are the paraventricular nucleus (PVN) of the hypothalamus, the anterior pituitary gland, and the cortex of the adrenal gland. The PVN is the source of the key neurons controlling the level of activation of the HPA axis, regulation of metabolism, growth, and immune functions, as well as pre-autonomic control of gastrointestinal, cardiovascular, and renal functions. The PVN triggers the release of hormones into circulation. CRH in the HPA axis, thyrotropin-releasing hormone (TRH) in the HPT axis, oxytocin (OT), dopamine, somatostatin, and arginine vasopressin (AVP) expressing neurons are among those that project to the median eminence. In addition, OT and AVP magnocellular neurons project to the posterior pituitary and secrete directly into circulation.[39]

The function of the pituitary gland is to secrete protein hormones while also playing a critical role in the maintenance of homeostasis during and after stress, as well as during other physiological processes (growth and metabolism). The posterior pituitary receives axonal inputs from the magnocellular OT and AVP neurons residing in the supraoptic nucleus and PVN where they release their secretory product into circulation. Corticotrophs are the cells of the anterior pituitary involved in HPA axis regulation and production of ACTH. These cells contain receptors that bind CRH to activate the synthesis of ACTH in response to humoral signals from the hypothalamus. The adrenal cortex is composed of three distinct concentric zones: the zona glomerulosa, zona fasciculata, and zona reticularis from outside to inside. In addition to the cortical zones, the adrenal medulla is also involved in the regulation of homeostasis. Activation of the autonomic nervous system leads to the secretion of epinephrine and norepinephrine. However, zona fasciculata is the main adrenal region responsible for glucocorticoid secretion. Cells in the zona fasciculata express the melanocortin receptor-2. The regulation basal and reactive hormone is from the allowed of access to the vascular system of the adrenal glands.[40]

Activation of the HPA axis and glucocorticoid secretion is tightly regulated at the level of the hypothalamus and pituitary gland by a negative feedback loop. CRH is a 41-amino acid peptide while AVP is released from the hypophysiotrophic neurons in the PVN of the hypothalamus. It is transported by hypothalamic-pituitary portal circulation and stimulates pituitary corticotroph cells to cleave proopiomelanocortin from the ACTH, which works to stimulate the pituitary to secrete ACTH into the bloodstream through the activation of CRH receptor type 1 (CRH-R1). This binds ACTH and the melanocortin type 2 receptors (MC2-R) in the zona fasciculata of the adrenal cortex, triggering the adrenal cortex to synthesize and release the glucocorticoids (cortisol in humans and corticosterone in rodents) from the adrenal gland. ACTH stimulated the production of cortisol is regulated by cAMP. Thus, exogenous glucocorticoid directly suppresses cAMP and ACTH production.[4] Therefore, hydrocortisone induces the overconsumption of energy and restricts ATP regulation and the balance between cAMP and cGMP.[4],[37]

Effect of glucocorticoids on the hypothalamus-pituitary-target gland axes

Increase in ACTH stimulates the adrenal to produce glucocorticoids. Through activation of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), glucocorticoids exert their effects. MR and GR translocate to the nucleus where they regulate gene transcription and subsequent protein synthesis after binding with steroid hormones. This happens in the pituitary and hypothalamus. Glucocorticoids are involved in the regulation of the immune system, metabolic processes, reproduction, behavior, and cognitive functions.[41] The relationship between the HPA axis and glucocorticoids is its function involving a negative feedback loop inhibiting hypothalamic and pituitary functions and ensuring the suppression of their activities at the end of physiological crisis or of a circadian cycle. The HPA axis is a neuroendocrine system regulated by the circadian cycle and stress.[38],[42]

When the liver and other body tissues break down the steroid hormone cortisol, 17-OHCS is a formed product. The HPG axis consists of interactions between the hypothalamus and the anterior pituitary gland. It promotes the growth and maturation of germ cells and the synthesis of gonadal steroids both in male and female gonads. Gonadotropin production is regulated by GnRH signaling in the pituitary. It examined how changes in plasma gonadotropins with OVX and sex steroid treatment affects brain GnRHR expression. GnRHR expression has previously been demonstrated in rodent and human brains. GnRH signaling induces neuronal LH expression. It stimulates the secretion of the anterior pituitary hormones: LH and FSH. They ultimately control the production of gonadal steroids and gametogenesis.[40],[43] On the contrary, TRH stimulates the anterior pituitary to produce the TSH. The TSH stimulates the thyroid to produce T3 and T4 until the levels in the blood return to normal. Low-circulating levels of thyroid hormones T3 and T4 causesreleasing of TRH in the hypothalamus.[44] The axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function. When the decreased level of the hormone in the HPA axis would interrupt the levels of TSH, T3, T4, T, FSH, and LH in turn. This situation is indicated when the HPT and HPG axes are in a restrained state and the typical pathological features of Kidney-yang deficiency are clear.[3],[9],[10],[19]

The support vector regression theory

The support vector regression (SVR) theory explains the aforementioned process by analyzing the regulation and feedback action among the hormones of the hypothalamic-pituitary-target gland axes in the early, middle, and advanced stage of the KYDS model (SVR model) [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]. The decrease in hormone levels in the HPA axis in the early-stage may increase the level of hormones of the HPT axis to varying degrees. The HPA axis has a feedback action on the HPT axis. While the hormones of the HPA axis decrease in the middle stage, the three hormones of the HPT axis also decrease. Hence, the cause loses efficacy of the HPA axis in the middle stage. Further effects in the advanced stages, the complete feedback regulatory circle does not form and finally unable to resist comprehensive decreases in hormones index values of the three hypothalamic-pituitary-target gland axes.[28]

  Conclusion Top

Injection of a high dose of exogenous glucocorticoid drugs interrupts and suppresses the immune system and function of many hormones of the hypothalamus-pituitary-target gland axes in a KYDS model. This leads to the imbalance in mutual control among the hormones of the pituitary-target gland axes, and particularly a decrease in the hormone levels of the HPA axis. The hormones are correlated with each other and form a complicated network to control each other's function. This review may aid in the understanding of the formation and transformation of KYDS in the future research.

Financial support and sponsorship

This work was funded by the Shanghai Three-Year development plan project for TCM ZY (2018–2020)-CCCX-2001-05 and the Clinical Characteristic Project of Acupuncture and Moxibustion of Pudong New District (PDZY-2018-0610).

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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