School for Physiology, Nutrition and Consumer Sciences, Potchefstroom University, Potchefstroom, South Africa

Correspondence to: Dr HW Huisman, School for Physiology, Nutrition and Consumer Sciences, Potchefstroom University, Potchefstroom, South Africa. E-mail: flghwh@puknet.puk.ac.za

People living in large informal settlements in South Africa showed a significant increase in cardio/cerebrovascular disease. This study was undertaken to compare the cardiovascular and endocrine parameters of urbanized and rural black female and males. The hormone levels such as prolactin, cortisol and testosterone may also change with urbanization and could make a contribution to the high rate of hypertension. For this study, 1202 black subjects were selected from 37 randomly selected rural and urbanized settlements. Resting blood pressure was recorded with a Finapres apparatus. Cardiac output, stroke volume, heart rate, total peripheral vascular resistance and compliance had been obtained with the Fast Modelflow software program. An acute laboratory stressor (hand dynamometer exercise) was applied to challenge the cardiovascular system and the measurements were repeated. Blood sampling was done and hormone levels were determined by biochemical analyses. For females, significant lower levels of cortisol were found in the urban strata in comparison with the rural strata. The testosterone levels were significantly lower and the prolactin levels significantly higher for females in the informal settlements compared with the rural strata. It is noticeable that most cardiovascular parameters showed the highest changes with the application of the stressor in the informal settlement strata and the lowest in people living on farms for both male and female. The prolactin levels in males are significantly higher in the informal settlement stratum. Subjects living in informal settlements showed a noticeable endocrine pattern of ongoing stress that can be associated with changes in the cardiovascular parameters with urbanization. This can partly explain the reported high rate of cardio/cerbrovascular disease in black South Africans living in informal settlements.

Journal of Human Hypertension (2002) 16, 829-835. doi:10.1038/sj.jhh.1001493

hypertension; cardiovascular reactivity; urbanization; prolactin; testosterone; cortisol

Introduction

Living in large informal settlements in the North West province of South Africa means to live in a potentially hostile environment, where poverty has led to a process of social and cultural disruption, increased levels of stress and a significant increase in chronic diseases of lifestyle like hypertension, coronary heart disease and cerebrovascular disease.^1,2,3,4 The way of life in the urbanized areas differs drastically from those in the rural areas. Tswana's living in informal settlements (townships) seems to be more vulnerable to stress and excessive increases in blood pressure during daily-life events than Tswana's living in the urban areas. This greater cardiovascular reactivity during acute stress situations may lead to the development of hypertension in their later lives.^5,6,7,8 With urbanization, some of the hormone levels such as cortisol, prolactin and testosterone may also change and contribute to the development of hypertension.⁹

The environment can influence the functioning of the cardiovascular system.¹⁰ The changes in the cardiovascular function can be measured, and from the literature it is clear that the response is not always the same.^{6,8,10,11,12,13,14} Henry et al¹⁵ proposed a model that divided the stress reaction in a defence or active coping mode and a defeat or passive coping mode, with specific changes in the cardiovascular and endocrine parameters. The defence-arousal pattern is characterized by blood pressure reactivity mainly caused by an increase in cardiac output (CO) and a decline in total peripheral resistance (TPR), while the defeat-arousal pattern shows blood pressure reactivity caused by an increase in TPR and a decrease in CO.^{10,15,16,17,18}

According to the model of Henry et al,¹⁵ the endocrine response of the defence reaction is associated with an increase in testosterone levels with small changes in cortisol, and the defeat reaction is associated with an increase in cortisol levels and the testosterone level may decrease. Stress that evokes uncertainty and anxiety, or where the environmental stimulus exceeds available coping resources and induces negative emotions, will lead to increased levels of cortisol as a result of the activation of hypothalamic-pitutary-adrenal axis (HPA-axis).^19,20,21 There is however evidence for decreased cortisol levels in situations of ongoing stress.^22,23 In anxious subjects a reduced reactivity of the HPA-axis was found.²⁴ Hellhammer and Wade²⁵ as well as McEwen²⁶ associated hypocortisolism as malfunctioning of the HPA-axis in conditions of prolonged stress. The finding of relatively decreased, rather than increased, levels of cortisol in individuals who have been exposed to severe levels of stress or suffer from stress-related disorders is paradoxical to the model of Henry et al¹⁵ and to the view of many other researchers in the past century. There is therefore no clearcut and generally accepted model for cortisol responses to stress. Both hypercortisolism and hypocortisolism have been described as a stress response and can be modified by environmental social factors and gender.^22,25,26 According to Heim et al²² and Hellhammer and Wade,²⁵ hypercortisolism is associated with the initial phase of stress, dominance in society and male gender and hypocortisolism is associated with chronic stress, lower social position and female gender. Although these associations must be handled with caution, the ongoing stress of the harsh living conditions in an informal settlement may lead to a decrease of cortisol levels. It is however difficult to define hyper- or hypocortisolism in terms of basal hormone levels, and therefore comparison between groups may be a better approach in a study of this nature.²²

An increased level of cortisol is normally associated with hypertension. Whitworth et al²⁷ discuss in their review several mechanisms for cortisol-induced hypertension: sodium retention, haemo-dynamic changes, vascular responsiveness, increased sympathetic nervous activity and hyperinsulinemia, but whether these changes are sufficient to account for the hypertension remains unclear. The nitric oxide system may also play a role in cortisol-induced hypertension.^28,29 It is also reported that cortisol is not a direct determinant of blood pressure, but cortisol may regulate other key components of vascular risk such as low high-density lipoprotein (HDL) cholesterol and fat distribution.³⁰

Heightened prolactin levels are also associated with powerless situation stress.^23,31,32 Increased levels of prolactin may also decrease nitric oxide and testosterone levels with a consequent influence on blood pressure.^33,34

It is reported that the levels of testosterone are higher in individuals who are in control of their situation or show a more aggressive behaviour.^15,20 A negative correlation was found between testosterone and epinephrine levels and it is suggested that adrenomedullary hormonal system activation causes a decrease in testosterone levels. This contradiction of findings is difficult to explain.³⁵ Lower levels of testosterone occurred with increasing age but also with the defeat reaction mode, and during the experience of a hopeless situation.^15,32 The effects of testosterone on the cardiovascular system are not totally clear, but it seems that higher levels of testosterone will lower the total and low-density lipoprotein (LDL) cholesterol and will impair vascular reactivity. A low level of testosterone was associated with enhanced cardiovascular reactivity, atherosclerotic disease and cardiovascular events. Testosterone may act as a direct vasorelaxant through influence on the vascular wall endocrine/paracrine factors.^32,36,37,38 It is also reported that the vasorelaxing effect of testosterone is endothelium independent, with the possible involvement of potassium channel modulation.^39,40

There is a pressing need for epidemiological studies in Africa, to determine the risk factors for the development of hypertension in specific living circumstances.⁴¹ This part of the transition and health during urbanization in South Africans (THUSA) study was designed to determine the changes in the cardiovascular and endocrine parameters that may be associated with the high incidence of cardio/cerebrovascular disease in subjects living in informal settlements, compared with the rural community. The aim of this study was to determine whether there is a physiological stress response associated with chronic, unavoidable stressful conditions. Especially, females living in informal settlements may experience the harsh living conditions in a more extreme and unavoidable way than males, which could lead to lower cortisol and testosterone levels and heightened prolactin levels.

Methods

Study design

In order to plan the drawing of a sample from a study population, levels of urbanization had to be defined. The definitions of 'urban' and 'rural' used in epidemiological research should not be a universally prescribed definition, but rather a definition determined by the aim of the study.⁴² In South African communities, the population of a city also includes people living in informal settlements in the peri-urban fringe area or the greater metropolitan area. In the THUSA study, besides two rural strata (people living in tribal areas, stratum 1 and people living on farms, stratum 2), three different strata of urbanization were distinguished for urban subjects, namely stratum 3 for the subjects living in informal settlements, stratum 4 for subjects living in established townships with full access to water and electricity and stratum 5 for fully Westernized subjects living in Western-type houses in upper-class suburbs. Given the aim of the THUSA study, subjects who stayed only temporarily in the city or a rural area were not included in the study sample.

With the assistance of a bio-statistician, 37 study sites were randomly selected from the four geographical quarters of the North West Province of South Africa. Visits were made to these sites during the weeks preceding the collection of data, in order to get permission from government officials and tribal chiefs to work in the area and to notify the local community of the visit of the research team. Since research is strange to many of the black people, especially in strata 1-3, randomization of a sample is sometimes unacceptable to the study population. Although subjects were recruited from randomly selected sites throughout the North West Province, a total random sample of subjects was not possible because of logistic reasons and the fact that volunteers had to be used for blood sampling. This convenience sample was acceptable because the objectives of the study were to examine the influence of urbanization on cardiovascular and endocrine parameters and not primarily the prevalence nor the incidence of hypertension. During a period of 5 days at each site all volunteers were recruited according to inclusion criteria, which were apparently healthy men and women 20-60 years of age. Exclusion criteria were pregnancy, lactation, casual visitors, drunkenness and treatment for chronic diseases, for example, hypertension and diabetes mellitus, mental diseases or other serious diseases. Volunteers who did not meet the inclusion criteria were screened for hypertension and diabetes mellitus and referred for treatment where necessary. Subjects were grouped into five age deciles, and age did not statistically differ between the five strata. A convenience sample of all volunteers who compiled with the inclusion criteria was recruited from each of 37 sites over a period of 2 years (1996 and 1997). Included in the study were a total of 1202 subjects subdivided as follows: stratum 1: 151 males and 205 females, stratum2: 57 males and 103 females, stratum 3: 91 males and 124 females, stratum 4: 175 males and 174 females and stratum 5: 62 males and 60 females. All endocrine determinations were not necessarily done on all subjects because of difficulties with the sampling of blood. The number of subjects used for blood sampling was as follows: stratum 1: 144 males and 198 females, stratum 2: 56 males and 97 females, stratum 3: 68 males and 92 females, stratum 4: 144 males and 152 females and stratum 5: 52 males and 55 females.

Local organizers assisted in recruiting of subjects. A field laboratory was established in each centre for the processing of blood samples.

The Ethics committee of the University approved the study and all the subjects gave informed consent.

Data collection

The data collection was performed between 9:00 and 13:00. The subjects were all introduced to the experimental set-up, after which each one was separately subjected to the following procedures: blood sampling was performed during the first part of the data collection period, and the number of subjects were adequate to limit the effect of circadian hormonal rhythms. The spreading of subjects during the blood sampling time was identical throughout the entire study. Blood samples were drawn from the vena cephalica or medial cubital vein of the subjects, and plasma and serum were prepared according to standard methods. All the biochemical analyses were done in the same laboratory by using standardized methods as follows: cortisol and testosterone with ¹²⁵L RIA kit, Dia Sorin, Minnesota, USA and prolactin with RIA kit, Nichols Institute Diagnostics.

Subsequently, the subject was connected to a Finapres (finger-arterial pressure) apparatus^43,44 and blood pressure recorded continuously. After at least a 10 min period of rest, resting blood pressure values were obtained. Blood pressure was regarded as resting, when the systolic blood pressure did not change with more than 10 mmHg during the last minute of this period; otherwise the resting period was extended with a maximum of 2 min. This procedure was followed because it is important to obtain reliable resting values that or not too much aroused by external influences. The resting blood pressure was then recorded continuously for 1 min.

The hand dynamometer was then used as a laboratory active stressor to challenge the cardiovascular system for 1 min.⁶ Each subject pulled the hand dynamometer at 50% of his or her maximum. The data were stored on magnetic tape by means of a Kyowa RTP-50A four-channel data recorder and digitized for further analysis by means of the Fast Modelflow software program.^44,45 In this way, the cardiac output (CO), stroke volume (SV), heart rate (HR), total peripheral resistance (TPR), the systolic blood pressure (SBP), diastolic blood pressure (DBP), 'Windkessel' compliance of the arterial system (Cw) and mean arterial pressure (MAP) were obtained. Cardiovascular reactivity was calculated as the percentage change from resting to plateau values obtained during application of the laboratory stressor.

Statistical analysis

All processed data were transferred to Microsoft Excel 2000 and further statistically analyzed by means of the software computer package STATISTICA (Statsoft,2000). MANOVA (Tukey HSD test) and correlations were done as indicated in the results. Results were regarded as significant when P<0.05.

Results

The mean values of the cardiovascular and endocrine parameters of the subjects according to stratum are shown in Table 1 (males) and Table 2 (females). The SBP and DBP are the lowest in stratum 1 (most rural stratum) for both males and females and the SBP is significantly (P<0.05) lower in comparison with stratum 4 (established townships). The DBP was significantly (P<0.05) lower for males in stratum 1 in comparison with all the other strata and for females the DBP in stratum 1 is significantly (P<0.05) lower than in stratum 2 (farm workers) as well as stratum 4.

The SBP and DBP pressure changes during the application of the stressor or systolic/diastolic blood pressure reactivity (SBP reactivity/DBP reactivity) are the highest in stratum 3 for both males and females, and is also significantly higher than in stratum 2 where the lowest SBP reactivity and DBP reactivity for both males and females were found.

Further, the SV for both males and females showed the highest values in the most rural stratum (stratum 1) and for the males there is a significant difference when compared with the subjects in stratum 3. The TPR is the lowest in stratum 1 for both males and females, where males showed a significantly higher value in all the other strata, except in stratum 5. The TPR of the females differs significantly between strata 1 and 4. The reactivity values for both SV (decrease during the application of the stressor) and TPR (increase during the application of the stressor) showed a large dispersion, but SV reactivity for females is the highest in stratum 3 and differs significantly from SV reactivity in stratum 2. The SV reactivity in males is highest in stratum 4 and differs significantly from stratum 1. In stratum 3, the highest TPR reactivity for females is found and differs significantly from stratum 4. The C_w does not show any significant differences between the strata. The C_w reactivity values in both males and females are the lowest in stratum 2, and in the case of the male subjects the two rural strata (strata 1 and 2) are significantly lower than the three urbanized strata (strata 3-5), and for the female subjects stratum 2 differs significantly from all the other strata.

To summarize the cardiovascular data, it is clear that for the females in stratum 3 all the cardiovascular reactivity values (SBP reactivity, DBP reactivity, SV reactivity, TPR reactivity) were the highest of all strata, except for C_w reactivity that is second highest, while in stratum 2 all the cardiovascular reactivity values were the lowest except for TPR reactivity that is the second lowest. The same is true for the males except that the highest SV reactivity is found in stratum 4 and the highest TPR reactivity in stratum 5. The lowest SV reactivity and TPR reactivity for male subjects are found in stratum 1.

The mean cortisol level in the females of stratum 3 is 10.7 g/dl, which represents a decrease of more than 10% in comparison with stratum 1 or 2 and is the lowest in stratum 5 with a value of 10.0 g/dl. Although there are no significant differences between stratum 3 in comparison with the rural strata 1 or 2, there is a significant (P<0.05) difference between a combination of the two rural strata (stratum 1 and 2) compared to a combination of the three urbanized strata (stratum 3-5). In the males, the value of cortisol is the lowest in stratum 5 with a value of 12.22 g/dl, and differs significantly with all the other strata.

The prolactin level in stratum 3 is the highest of all strata for both males and females with values of 10.0 and 11.5 ng/ml, respectively. For males, it differs significantly with stratum 2 and for females with strata 1, 2 and 5.

The testosterone levels in females are the lowest in stratum 3 with a value of 0.18 ng/ml and differ significantly with strata 1, 2 and 5. For the males, the value of testosterone is 4.8 ng/ml in strata 1, 2 and 3, 5.2 ng/ml in stratum 4 and 6.3 ng/ml in stratum 5. The two rural strata (strata 1 and 2) differ significantly from strata 4 and 5 for the male subjects.

As expected, there is a highly significant (P<0.001) difference between the testosterone levels for males and females with a mean value of 5.17 ng/ml for males and 0.26 ng/ml for females. There is also a highly significant (P<0.001) difference between C_w for males and females with values 1.62 and 1.21 ml/mmHg, respectively.

A positive correlation was found between the testosterone levels and compliance (r=0.439, P<0.001).

Discussion

In this study, the cardiovascular and endocrine parameters of the urban subjects are compared to rural subjects, since the incidence of hypertension is low in rural communities.^4,5,9 According to van Rooyen et al,⁴ the highest rate of hypertension occurs in stratum 3 (subjects living in informal settlements) with 34.8 and 31.4% for SBP and 22.7 and 26.9% for DBP in males and females, respectively, and they argued that these subjects experience difficult life situations that lead to adjustments in the cardiovascular system. This is also in accordance with the literature.^{3,46,47,48,49}, In subjects living on the farms (stratum 2), the rate of hypertension is the lowest for all strata in male (13.2% for both SBP and DBP), but relatively high for female subjects (SBP 28.2%, DBP 21.5%). In stratum 1 (most rural subjects), the rate of hypertension is 19.2 and 22.2% for SBP and 14.6 and 21.4% for DBP in males and females, respectively.

Females

The results show that the prolactin levels of the females living in the informal settlements (stratum 3) are significantly higher and the testosterone and cortisol levels are significantly lower than the values found in the rural communities (strata 1 and 2). The DBP reactivity is higher than the SBP reactivity in stratum 3, and the negative SV reactivity and the positive TPR reactivity were the greatest in this stratum while the C_w reactivity showed also a decline, which all indicate a defeat reactivity pattern and stimulation of the HPA axis. Increased levels of cortisol are expected in the traditional view when the HPA axis is stimulated, but recently hypocortisolism is reported under conditions of chronic stress probably as a result of increased feedback inhibition of the pituitary-adrenal level of the HPA axis.²² It seems that this lower level of cortisol does not inhibit the increase in cardiovascular reactivity and the rate of hypertension. Low levels of testosterone are reported to enhance vascular responsiveness. Heightened prolactin levels as well as low levels of testosterone may disturb the delicate balance between vasoconstriction and vasodilatation in favour of constriction. In this study, it is found that there is a correlation between testosterone and C_w, which can help explain the high vascular responsiveness found in stratum 3 subjects. The physiological data give support to the idea that the females in the informal settlements live in chronic and unavoidable stressful conditions, which may lead to increased levels of prolactin and lowered testosterone and cortisol levels^22,32, with concomitant development of hypertension.

Males

The prolactin levels are high in males living in the informal settlements (stratum 3), but the cortisol and testosterone levels do not differ from that in the rural males. The cortisol levels are however significantly higher than that of subjects living in the high-class suburbs (stratum 5). This gives rise to the idea that the subjects in stratum 3 also experience stress, but not to such an extent that their testoste-rone secretion is diminished and their cortisol secretion is suppressed by negative feedback control mechanisms.^22,26, A possibility is that the activation of the adrenomedullary hormonal system may be involved in the testosterone levels, which is lower than what can be expected, in the defence (or in control of the situation) mode.³⁵ It is more likely however that this is an indication of a defeat or submissive reactivity pattern because of the high levels of prolactin and the absence of a rise in testosterone as well as the high level of cortisol in comparison with stratum 5. Subjects in stratum 3 showed mixed results in respect of the cardiovascular parameters, however, the C_w reactivity as well as SV showed a significant decline in comparison with the rural groups, which support the idea of a dominant defeat pattern.

In stratum 5, subjects living in the upper class suburbs showed significantly lower levels of cortisol and significantly higher levels of testosterone, but a relatively low level of prolactin (Table 2). This is an indication of the sympathetic adrenal medullary defence pattern of people more in control of their situation.

In conclusion it is clear that, when people living in the informal settlements are compared to people living in the rural areas, there is a difference between males and females in respect of the endocrine and cardiovascular parameters. The lower cortisol levels in females are in accordance with the perception of an ongoing and unavoidable stress situation, but is however not associated with an increase in blood pressure levels or increased vascular responsiveness.^22,28, The lower testosterone and higher prolactin levels in females are in accordance with vasoconstriction and therefore with increased DBP reactivity and TPR reactivity.⁴⁰ This may interfere with blood pressure, and these parameters are therefore associated with the high rate of hypertension in stratum 3 subjects.

The males showed a more mixed pattern with high prolactin levels and decreased C_w reactivity in subjects living in informal settlements. Prolactin may suppress testosterone levels and increase the vascular responsiveness³³ and could therefore be associated with hypertension.

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Table 1 Cardiovascular and endocrine data for males (s.e.m.=standard error of mean)

Table 2 Cardiovascular and endocrine data for females (s.e.m.=standard error of mean)