Understanding the effects of sustained supraphysiologic concentrations of luteinizing hormone in gonadectomized dogs: What we know and what we still need to learn

Reproductive sterilization via gonadectomy has been used for millennia in humans as a form of punishment and to facilitate subservience [1,2]. By the time of Aristotle in the fourth century BC, the physiological consequences of gonadectomy in men and boys were well-documented [3]. Because gonadectomy was performed pre-pubertally, these men grew taller than their unsterilized counterparts, due to a delay in the long bone growth plate closure that is normally initiated by the rise in gonadal steroid hormones at puberty [4]. It is important to mention that in addition to the physical differences observed, pre-pubertal gonadectomy in humans also results in grossly enlarged pituitary glands [5].

Similar to humans, pre-pubertally gonadectomized male and female dogs have significantly delayed physeal closure and grow taller than their unsterilized counterparts [6]. The effects of these skeletal changes can predispose pre-pubertally gonadectomized dogs to musculoskeletal problems later in life (e.g., slipped capital femoral epiphysiolysis) [7]. In addition to these skeletal changes, gonadectomy results in a multitude of physical, metabolic, endocrinologic, behavioral and anti-neoplastic changes in dogs that can cause in long-term health problems. The pathophysiology for these health problems can be traced back to activation of luteinizing hormone (LH) receptors in these non-reproductive tissues, resulting from sustained exposure to supraphysiologically elevated LH concentrations from lack of feedback.

In the mature intact mammal, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary gland to release LH. Luteinizing hormone stimulates the secretion of gonadal steroid hormones (testosterone in males and estradiol/progesterone in females). These gonadal steroid hormones then negatively feedback directly to the anterior pituitary as well as indirectly through to the hypothalamus to maintain circulating LH concentrations below 1 ng/mL. However, in the mature gonadectomized mammal, the absence of negative feedback results in circulating LH concentrations up 100 ng/mL [8].

Receptors for LH are widely disseminated throughout the body, including but not limited to the skin, bladder and urethra, thyroid gland, adrenal cortex, ligaments and bone, vascular endothelial cells and smooth muscle, and lymphocytes [9]. There are several ways LH receptor activation regulates cell function. For example, LH receptor activation leads to both protein kinase A (PKA) activation [10] and PKA-dependent ERK1/2 activation [11], which can increase protein synthesis and nitric oxide release. In addition, activation of LH receptors can induce cell proliferation through an ERK-dependent pathway [12]. However, less is known about how LH receptor activation in non-reproductive tissues elicits various disease states and more research in these areas is needed.

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