Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly

Abstract

Abstract. Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 ± 1.9 mm, mean ± sem) were accompanied by fasting hyperinsulinaemia (144 ± 21 μU/ml, mean ± sem) and drastic elevation of plasma growth hormone (GH) levels (112.6 ± 45 ng/ml, mean ± sem). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.

Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone

“…Moreover, analysis of the pulsatile plasma profile showed a trend for a higher mean basal GH concentration and a higher mean AUC 0 for GH in the five Beagle dogs. These findings are consistent with progestin-induced hypersecretion of GH [3,[27][28][29].…”

“…Blood samples for determination of the plasma concentrations of GH and IGF-I were collected before MPA treatment, at days À9, À8, À7, À5, À3, À2, À1, and 0 (=immediately before aglépristone treatment and after MPA treatment for over 1 year), at days 1, 3,5,7,8,11,13,15,18,20,22, and 25 (=during aglépristone treatment), and at days 46 and 60 (=3.5 and 5.5 weeks after the last aglépristone treatment). On days of treatment (MPA or aglépristone), blood samples were collected prior to the drug administration.…”

“…Acromegaly in humans and cats is commonly caused by a somatotroph adenoma of the pituitary gland [1], whereas in dogs the GH excess usually originates from an extra-pituitary site [2]. In dogs, endogenous progesterone secreted during the luteal phase of the estrous cycle or exogenous progestins such as medroxyprogesterone acetate (MPA) used for estrus prevention may promote www.journals.elsevierhealth.com/periodicals/the Theriogenology 66 (2006) [797][798][799][800][801][802][803] hypersecretion of GH from foci of hyperplastic ductular epithelium of the mammary gland [2][3][4]. In contrast to the pulsatile secretion pattern of GH in healthy dogs [5][6][7], the plasma GH profile in bitches with progestininduced acromegaly is not pulsatile [8].…”

Canine diabetes mellitus: can old dogs teach us new tricks?

“…The high concentration of circulating progesterone and growth hormone during dioestrus antagonises insulin function and can result in impaired glucose tolerance. This is typically subclinical in younger dogs, whereas overt dioestrous diabetes is more commonly seen in middle-aged and older animals [50]. It is likely that repeated cycles of insulin resistance and glucose intolerance during dioestrus may eventually result in permanently impaired glucose homeostasis.…”

Insulin binding characteristics in canine muscle tissue: effects of the estrous cycle phases

“…In dogs, the most common physiological cause of insulin resistance is described in the female dog during the hormonal fluctuations of the estrous cycle. During diestrus, progestogens induce the synthesis and release of growth hormone (GH) by the mammary glands in a paracrine and endocrine fashion, potentially triggering diabetes mellitus (Eingenmann et al 1983, Selman et al 1994). Moreover, Ryan & Enns (1988) demonstrated regulation of insulin binding capacity and post-binding function by estradiol and progesterone in vitro.…”