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Cortisol: A Growth Hormone for the Fetal Heart?

Physiology Department, Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: E. Marelyn Wintour, Physiology Department, Monash University, Clayton, Victoria 3800, Australia.

	Introduction

Top Introduction Heart Development Issues Arising References

 
In most mammalian species, with the exception of some rodents, the major adrenal glucocorticoid is cortisol. This is commonly known as a stress hormone and has significant actions to inhibit inflammation, as a gluconeogenic agent, and in supporting the cardiovascular system. In excess, in the adult, cortisol causes bones and muscle to weaken, due to its protein catabolic activity. In the fetus, many of the adult functions occur, and excess will cause intrauterine growth retardation. In addition, in the fetus, cortisol has a major role in the maturation of many organs and systems, including the respiratory, renal, and cardiovascular. It is therefore a somewhat unexpected and exciting finding from the Thornburg laboratory (1), which reports substantial and convincing evidence that in the ovine fetal heart cortisol acts as a growth hormone, stimulating cardiac myocyte hyperplasia and not maturation.

	Heart Development

Top Introduction Heart Development Issues Arising References

 
During development the cardiac myocyte is uninucleated and thus can enter the normal cell cycle and divide. At some stage, the uninucleated cardiac myocyte begins to mature, by becoming binucleated, after which cell division ceases. Any further growth can only occur by hypertrophy. In the fetal sheep, at midgestation (75 d; term, 145–150 d) all cardiac myocytes are uninucleated, but by 135 d, more than 50% are binucleate and terminally differentiated (2). During this period, the fetal cortisol concentrations are significantly lower than those of the mother, but these rise to exceed maternal values from 130 d until term (3). In the present study (1), the local intracardiac concentrations of cortisol were increased approximately 3-fold, by hormone infusion into the circumflex coronary artery, and in 7 d the heart to body weight ratio was increased by 34%, without any significant change in myocyte size or percent of binucleation. Thus, hyperplastic growth had occurred, confirmed by an increased proportion of cells in the active cell cycle.

	Issues Arising

Top Introduction Heart Development Issues Arising References

 
This leads to two major questions: 1) by which receptor does this occur; and 2) what are the implications for premature human neonates treated with exogenous glucocorticoid before birth? Both classical glucocorticoid receptors and the mineralocorticoid receptor (MR) are present in the ovine fetus by 30 d of gestation (4). In the adult heart, it has been postulated that some adverse effects (cardiac hypertrophy and fibrosis) in low-renin/low-aldosterone situations are due to the occupancy and activation of MR by the endogenous glucocorticoid (5, 6). It would be interesting to know whether the effects described in the current study could be attenuated by simultaneous use of an MR antagonist.

In terms of implications for the human situation, the human fetal adrenal differs from the ovine in having a fetal zone but is similar with respect to the triphasic secretion pattern of cortisol (7) in that cortisol biosynthesis is on early (during second half of first trimester), then off in the middle trimester, and on again in the last third of pregnancy. The period of early cortisol biosynthetic capacity is necessary to safeguard normal sexual development in the female. In both species, it has been proposed that the off period of cortisol biosynthesis is necessary to allow normal growth to occur before final maturation and preparation for parturition (3, 8), which is the major function of the late period of cortisol biosynthesis. It is precisely in view of this maturation function that women who threaten to deliver prematurely are routinely treated with the synthetic glucocorticoid, betamethasone (9). The salient question is whether this will affect the development of the fetal heart.

There is one very recent paper in which sophisticated methodology was applied to assess the cardiac structure and function of two groups of premature babies that did or did not receive a single course of antenatal betamethasone (10). The good news is that this study showed that there were no significant effects of this treatment. Whether this was due to species difference, the shorter time of exposure (2 d), or the fact that not all natural and synthetic glucocorticoids have identical actions (11) is unknown. There have, however, been numerous deleterious effects attributed to multiple courses of prenatal betamethasone treatment (8).

In conclusion, cortisol has been shown to have a direct effect as a cardiac growth hormone in the ovine fetus. It remains to be seen whether this can be used as therapy in premature babies with cardiac growth abnormalities.

	Footnotes

 
Abbreviation: MR, Mineralocorticoid receptor.

Received April 21, 2006.

Accepted for publication May 4, 2006.

	References

Top Introduction Heart Development Issues Arising References

 

1. Giraud GD, Louey S, Jonker S, Schultz J, Thornburg KL 2006 Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology 147:3643–3649[Abstract/Free Full Text]
2. Burrell JH, Boyn AM, Kumarasamy V, Hsieh A, Head SI, Lumbers ER 2003 Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec 274A:952–961
3. Wintour EM, Crawford R, McFalane A, Moritz K, Tangalakis K 1995 Regulation and function of the fetal adrenal in sheep. Endocr Res 21:81–89[Medline]
4. Peers A, Hantzis V, Dodic M, Koukoulas I, Gibson A, Baird R, Salemi R, Wintour EM 2001 Functional glucocorticoid receptors in the mesonephros of the ovine fetus. Kidney Int 59:425–433[CrossRef][Medline]
5. Nagata K, Obata K, Xu J, Ichibara S, Noda A, Kimata H, Izawa H, Murohara T, Yokota M 2006 Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension 47:656–664[Abstract/Free Full Text]
6. Funder JW 2006 Mineralocorticoid receptors and cardiovascular damage: it’s not just aldosterone. Hypertension 47:634–635[Free Full Text]
7. Goto M, Hanley KP, Marcos J, Wood PJ, Wright S, Postle AD, Cameron IT, Mason JI, Wilson DI, Hanley NA 2006 In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Investig 116:953–960[CrossRef][Medline]
8. Gibb W, Challis JR 2002 Mechanisms of term and preterm birth. J Obstet Gynaecol Can 24:874–883[Medline]
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10. Vural M, Yilmaz I, Ozfunc F, Ilikkan B, Erginoz E, Perk Y 2006 Cardiac effects of a single course of antenatal betamethasone in preterm infants. Arch Dis Child Fetal Neonatal Ed 91:118–122
11. Moritz KM, Boon WM, Wintour EM 2005 Glucocorticoid programming of adult disease. Cell Tissue Res 322:81–88[CrossRef][Medline]

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