Mechanisms of fetal programming of adult hypertension: role of sex hormones.

Epidemiological and experimental studies suggest that the in utero environment plays a critical role in the development of adult disease, including cardiovascular disease and hypertension. Intrauterine growth retardation produced by maternal undernutrition or exposure to maternal glucocorticoids during critical periods of organogenesis impairs fetal growth and produces offspring that develop hypertension early in life.1 This concept of “fetal programming” was first proposed by Barker et al2 to describe the relationship between low birth weight and subsequent risk for the development of cardiovascular disease and hypertension, insulin resistance, and type 2 diabetes mellitus in adult life. Several studies have confirmed and extended the Barker et al2 hypothesis to fetal programming of Parkinson’s disease, dementia, osteoporosis, and polycystic ovary syndrome.3 Although most clinical and experimental studies support the role for fetal programming of adult hypertension, there is still controversy regarding the cause and mechanisms underlying this phenomenon. Studies to date implicate reduced nephron endowment, factors that affect endothelial and arterial compliance, alterations in the function of renin-angiotensin system (RAS), and programming of the major organs and endocrine/neural systems involved in long-term blood pressure regulation.1 Despite intense investigation into the mechanisms underlying fetal programming of adult hypertension, there is still no unifying hypothesis on how these different mechanisms and pathways are programmed in utero and how they ultimately result in dysregulation of blood pressure later in life. It is well documented that premenopausal women exhibit a lower incidence of cardiovascular disease and hypertension compared with age-matched men.4 After menopause, the risk for development and the rate of progression of hypertension in women become comparable to those seen in age-matched men.4 These observations indicate that female sex hormones may protect against the development of hypertension premenopausally and that their absence after menopause may create a stage for the development of hypertension. Alternatively, the fact that the male sex is a risk for the development of hypertension suggests that male sex hormones may adversely regulate blood pressure. Indeed, absence of testosterone in experimental models abolishes hypertension,5 most likely through interaction with the RAS. These observations suggest that both male and female sex hormones, via interaction with other regulatory pathways, including the RAS, contribute to the development and progression of hypertension. However, few studies to date have examined the contribution of sex hormones in fetal programming of adult hypertension. In the present issue of Hypertension, Ojeda et al6 describe the contribution of estradiol in the regulation of postpubertal blood pressure in the intrauterine growth-restricted (IUGR) offspring. Previous studies from this laboratory showed that placental insufficiency in the rat results in development of hypertension in both prepubertal male and female offspring.7 This study also showed that, after puberty, only male offspring remain hypertensive, whereas females become normotensive by 10 weeks of age, coinciding with increased levels of estradiol associated with puberty.7 Based on these findings, Ojeda et al6 hypothesized in the current study that estradiol may stabilize blood pressure. To test this hypothesis, Ojeda et al6 ovariectomized female control and IUGR offspring at 10 weeks of age and implanted them with radiotelemeters for monitoring systemic blood pressure. A subgroup of ovariectomized animals received 17 -estradiol replacement and/or an angiotensin-converting enzyme inhibitor, enalapril, for 14 days. The major findings of this study are as follows: (1) ovariectomized IUGR females have increased blood pressure compared with intact IUGR females; (2) 17 -estradiol replacement attenuates this ovariectomy-induced increase in blood pressure; and (3) angiotensin-converting enzyme inhibition also attenuates the ovariectomy-induced increase in blood pressure. Ojeda et al6 conclude that hypertension in the female IUGR offspring is RAS mediated and that estradiol contributes to the normalization of blood pressure in these animals. Previous studies by Ojeda et al7 showed that testosterone plays a role in modulating hypertension in adult male IUGR offspring by regulating the RAS. These observations, in addition to the finding of the current study that estradiol is protective against the development of hypertension in adult female IUGR offspring, suggest an important role for sex hormones in regulating blood pressure in adulthood. Studies by Ojeda et al7 and others have shown that, in addition to modulating the RAS, other regulatory pathways, including NO, are targets for sex hormones in regulating blood pressure in IUGR offspring.8 These findings suggest that sex hormones are unlikely to regulate blood pressure directly but rather modulate the activity of other blood pressure regulaThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine and the Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, Washington, DC. Correspondence to Christine Maric, Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, 394 Building D, 4000 Reservoir Rd, NW, Washington, DC 20057. E-mail [email protected] (Hypertension. 2007;50:000-000.) © 2007 American Heart Association, Inc.