Jennifer Hubbard, 000307553, group 10, April 25,2011
Introduction
(1)Current medical therapy for ACTH-secreting pituitary tumor , a major cause of Cushing’s is limited and primarily
surgical. Recent studies have successfully decreased corticotroph secretion in rodent models with the use of Retinoic
Acid. Researchers have begun to evaluate the effectiveness of Retinoic Acid as Medical therapy for Cushing’s disease
in dogs.
(2)A major morbidity and mortality marker of Cushing’s is hypertension, causes are indecisive. Glucocortocoids
increase Na/K ATPase activity. However, they also show inhibition of mineralcortocoid action and promote
natriuresis. Renal sodium retention may be a major contributor.
Objective
(1)Since uncovering the genome sequence of the domestic dog, and canine similarities in human disease there is a
possibility that retinoic acid can be an extremely effective treatment of ACTH-secreting tumors in humans with
Cushing’s, and necessitate further human trials.
(2)This study looks at the effect of ACTH excess on renal sodium homeostasis by observing the effect of chronic
ACTH infusion on renal sodium in mice
Materials and methods
(1)42 dogs were selected, 22 treated with 9-cis retinoic acid and 20 treated with ketoconazole. Drugs were administered
for 180 d., with hepatic enzyme activity measured every 30d. The following clinical signs were evaluated: fluid
ingestion and micturition, solid ingestion, estrous cyclicity, elasticity and skin thickness, abdominal swelling, and
weight increase.
(2)Osmotic mini pumps of either ACTH or NaCl were implanted, on day 12 to 14 renal function studies were
performed. Arterial blood pressure and globular filtration (fluorescein isothiocyanate-insulin .5%) were measured, and
blood sample was used for electrolyte analysis. The antihypertensive action of alpha 1 adrenoreceptor and
V1-vasopressinergic receptor blockade were measured. Spironolactone and RU38486 were used to measure the
contribution of MR and/or GR. Canerone activity measured by mass spectrometry. Some kidney RNA was extracted.
Results
(1)There was no significant change in the ACTH or alpha-MSH in the group treated with Ktz. There was, however a
significant decrease in plasma ACTH at 90d. in the Rx group. alpha-MSH showed a similar reduction in the Rx group.
Pituitary adenoma size was reduced in Rx group with no change in size of adenoma in Ktz group. Retinoic acid brought
about improvement in all clinical signs evaluated.
(2)ACTH treated mice were hypokalemic and hypernatremic. MABP significantly elevated in ACTH treated mice, and
renal blood flow reduced. No difference in urinary Na/K ratio. Blockades caused a more significant decrease in MABP
of mice given ACTH vs. saline treated.
Summary
(1)A study was conducted evaluating the effectiveness of treating dogs with Cushing’s using Retinoic acid vs.
Ketoconazole. Treatment with Retinoic Acid showed greater reduction of over activity of pituitary-adrenal axis
and corticotrophinoma shrinkage. Retinoic acid showed an improvement in all clinical signs evaluated as well an
increased survival rate compared to Ktz. Findings highlight possibility of using Retinoic acid as treatment for humans
with Cushing’s, long-term clinical trials in humans are needed.
(2)Transient renal sodium retention contributes to presence of hypertension, promotes renal sodium reabsorption. A
study of the effect of chronic ACTH infusion on renal sodium in mice was performed . ACTH proves to promote renal
sodium reabsorption, leading to hypertension. Both GR and MR pathways are involved
Discussion
(1)Ktz works to interfere with the steroid biosynthetic pathways and has been an established treatment in dogs and
humans with Cushing’s. Retinoic acid interacts with retinoic acid receptors and RXR, blocks acitivation of POMC
transcription by Nur77 and Nurr1. It is potent in tumorous tissues, decreasing adenomatous proliferation and increasing
apoptosis. This study shows that Retinoic acid is an effective treatment of Cushings, and may be more effective then
Ktz, by its direct action on tumorous corticotrophs, supporting decreases in circulating ACTH and alpha-MSH, and
reduction is size of tumor which is not seen with Ktz treatment.
(2)This study indicates that GR-dependent contraction of plasma volume was dominate. Volume depletion stimulates
vasopressin causing continuous activation of sympathetic nervous system, both systems present elevated blood pressure
with ACTH excess. Upon measuring the receptor antagonism in maintenance phase of hypertension extensive studies
should be continued.
References
(1)Castillo V, Giacomini D, Paez-Pereda M, Stalla J, Labeur M, Theodoropoulou M, Holsboer F, Grossman A, Stalla
G, Arzt E. Retinoic Acid as a Novel Medical Therapy for Cushing’s Disease in Dogs. Endocrinology. Vol. 147, No. 9
4438-4444
(2) Bailey M, Mullins J, Kenyon c. Mineralcortocoid and Glucocortocoid Receptors Stimulate Epithelial Sodium
Channel Activity in a Mouse Model of Cushing Sndrome. Hypertension. 2009;54:890