Secular changes in cardiovascular risk factors in Swedish 50-year-old men over a 50-year period: The study of men born in 1913,1923,1933,1943,1953 and 1963

Abstract

Background

During the past decades, declining trends in mean cholesterol levels and smoking have been observed in Western Europe, whereas obesity and a sedentary lifestyle have increased. Simultaneously, there has been a marked decrease in mortality from cardiovascular (CV) diseases.

Methods

The aim of the study was to determine whether these trends in CV risk factors continued over a period of 50 years. Six systematic or random population samples of 50-year-old men (n = 3563) living in Gothenburg, Sweden, were investigated between 1963 and 2013.

Results

During the 50 years, mean body mass index (BMI) at 50 years of age increased by 2 kg/m², from 24.8 kg/m² in 1963 to 26.8 kg/m² in 2013 (p < 0.001). A decrease in systolic blood pressure of nearly 10 mmHg was observed from 1963 to 1993, but was not sustained through the past two decades. Mean serum cholesterol fell from 6.42 (SD 1.12) mmol/L to 5.34 (SD 0.97) mmol/L. The prevalence of smoking at 50 years of age decreased markedly from 56.1% in 1963 to 11.9% in 2013. The number of participants with a sedentary lifestyle during leisure time decreased until 1993, but has remained unchanged since. In 2013, 50-year-old men had a 6.9–times higher likelihood of lacking CV risk factors than 50-year-old men in 1963 (95% confidence interval (CI): 3.5–13.3, p < 0.001). The odds ratio for having four or more risk factors was only 0.13 (95% CI: 0.062–0.29, p < 0.001).

Conclusion

Despite increasing body weight, the total CV risk factor burden has decreased in 50-year-old men over the past 50 years.

Keywords

Secular trends cardiovascular risk factors obesity lifestyle

Introduction

A declining trend in cardiovascular (CV) disease and mortality has been observed in Western high-income countries.^1,2 Since the 1970s, CV incidence and mortality have decreased by approximately 2% per year.³ The reduction in CV mortality is largely explained by improvements in CV risk factors such as smoking, hypertension and hyperlipidaemia, as well as improved treatment of coronary heart disease (CHD).^4–6

In order to follow changes in risk factors over a long time (secular trends), random population samples from the same geographical area may be investigated repeatedly. Few studies have provided information on secular trends in CV risk factors over an extended period.^7–11 ‘The study of men born in 1913’ began in 1963, with the aim of investigating the impact of CV risk factors on CHD in a sample of 50-year-old men from the general population.^12,13 With 10-year intervals, new samples of 50-year-old men living in the same urban area were investigated with the same methodology. We have previously reported a decrease in smoking habits and cholesterol levels in these cohorts, as well as an increase in body weight over a period of 40 years.^11,14 Similar results have been reported globally.^15,16

Lifestyle and risk factor patterns tend to change continuously. Concurrent with rising rates of obesity over the past few decades, different diets have been proposed as treatments. In Sweden, one of the more popular diets during the past decade has combined a low intake of carbohydrates while simultaneously increasing dietary fat, resulting in an increased consumption of saturated fat.¹⁷ In the Västerbotten Intervention Programme, which was an epidemiological study in northern Sweden, a reversal of the decreasing trends of population cholesterol levels was observed, with increasing levels of serum cholesterol appearing after 2008.¹⁰ A similar increase, however, was not found in the northern Sweden ‘MONICA study’, which reported a continuing improvement in CV risk factors until 2009, including serum cholesterol.⁸ Given the discrepancies of these findings, and in order to provide updated secular trends of CV risk factors in 50-year-old men living in the south of Sweden, we now add data from a sixth cohort of 50-year-old men born in 1963.

Method

Study population

In 1963, all men born in 1913 on a day divisible by three of each month (i.e. days 3, 6, 9 and so on) and living in the city of Gothenburg, Sweden, were invited to a health examination. In all, 973 men met these criteria and 855 (88%) participated.¹² New samples of men living in the city of Gothenburg and born in 1923, 1933, 1943, 1953 and 1963 were selected and investigated, all at the age of 50 years (Table 1).

Table 1.

Participation rates in six cohorts of men aged 50 years living in Gothenburg, Sweden.

Birth year	Year of examination	Number invited	Number examined	Participation rate (%)
1913	1963	973^a	855	87.9
1923	1973	292^b	226	77.4
1933	1983	1016^c	776	76.4
1943	1993–1994	1463^d	798	54.5
1953	2003–2004	993^c	595	59.9
1963	2013–2014	649^e	313	48.2

A systematic sample of a third of the age class.

A systematic sample of a tenth of the age class.

A random sample of a third of the age class.

A random sample of half of the age class.

A random sample of a fifth of the age class.

Data collection

Data on smoking habits, leisure time physical activity, mental stress and previous diseases, including hypertension and diabetes, as well as on pharmacological treatments were collected by questionnaires. Leisure time physical activity was assessed by the Saltin–Grimby questionnaire¹⁸ and coded as 1 = sedentary (physically inactive), 2 = some light physical activity such as walking, riding a bicycle and light gardening for at least 4 hours per week, 3 = regular moderate physical activity for a minimum of 3 hours per week and 4 = regular hard physical training for competition sports. For the cohort of men born in 1913, this information was obtained at a second examination in 1967 at the age of 54 years. Groups 3 and 4 were combined because of there being few participants in the athletic training group. Men who were current smokers or had quit smoking less than 1 month before the examination were categorised as smokers. Mental stress was defined as feeling tense, irritable or filled with anxiety or having sleeping difficulties as a result of conditions at work or at home. The questionnaire contained six response options: 1 = never experienced stress, 2 = one period of stress ever, 3 = some periods of stress during the past 5 years, 4 = several periods of stress during the past 5 years, 5 = permanent stress during the past year, 6 = permanent stress during the past 5 years. Categories 5 and 6 were regarded as permanent stress.

In most cohorts, all participants were investigated in the morning after an overnight fast, but for practical reasons, 26% of the men born in 1963 were investigated in the afternoon after at least 4 hours of fasting. Body mass index (BMI; weight in kg/height in m²) was used as an indicator of relative weight and obesity. A BMI higher than 25 kg/m² was defined as overweight and a BMI ≥30 kg/m² was defined as obesity. Hypertension was diagnosed based on either medical history with current antihypertensive therapy or current blood pressure >140 mmHg (systolic) or 90 mmHg (diastolic). Blood pressures were measured in the sitting position before venepuncture to the nearest 2 mmHg after a 5–minute rest. A research nurse drew blood samples from an antecubital vein. Fasting serum cholesterol and triglyceride measurements were determined according to standard laboratory procedures. Blood glucose levels were measured, but the methods for glucose measurement were not standardised. Thus, a formal comparison of glucose between different cohorts would be difficult to interpret. Consequently, diabetes was only defined as self-reported diabetes according to the questionnaire in the present study. See Supplementary Methods for a detailed description of the screening procedure and laboratory methods.

The study complies with the Declaration of Helsinki, and the study protocol was approved by the Ethical Committee of Gothenburg (2013/649).

Statistical methods

The data were entered and analysed using SPSS software (version 20.0). Each cohort was assigned a value of between 1 and 6 according to the birth of year order. In what follows, we call this ordinal variable the cohort variable. Means and SDs of the continuous variables and percentages of the categorical variables are presented for the different cohorts. One-way analysis of variance was used to test whether the continuous variables follow a linear trend across the cohort variable. Mantel–Haenszel chi-square analysis for linear trends of proportions was performed. Spearman’s non-parametric rank correlation was used to assess relationships between the cohort variable and group variables. Binary logistic regressions were run in order to estimate the change of the odds for having one, two, three, four or more risk factors when each value of the cohort variable is compared with the value 1, which corresponds to the cohort born in 1913. A significance level of p < 0.05 was set a priori to determine statistical significance.

Results

Anthropometric measurements at 50 years of age are summarised in Table 2 for all six cohorts. From 1963 to 2003, mean height increased from 175.0 to 179.4 cm, or approximately 1 cm per decade. However, there was no further increase in men born in 1953 onwards. The mean (SD) body weight at 50 years of age increased from 75.9 (11.0) kg in 1963 to 86.4 (13.9) kg in 2013, a net increase of 10.5 kg (p < 0.001), with concomitant changes in waist circumference and BMI. The proportion of men who were obese increased from 6% to 19%. The increase in body weight and obesity continued through the last decade, with no indication of this levelling off. The ethnicity of the study participants changed over the years. In the cohort of men born in 1913, only 5% were born outside of Sweden. This proportion increased to 23% in 1953 and to 32% in 1963. Level of education increased gradually over the years. Among men born in 1913, only 29% had more than 9 years of school education. This increased for each cohort to 82% among men born in 1963.

Table 2.

Anthropometric measurements, cardiovascular risk factors, physical exercise and continuous stress in 50-year-old men in Gothenburg, Sweden, from 1963 to 2013.

Variable	Year of examination, year of birth (n)						p for trend
	1963, 1913 (855)^a	1973, 1923 (226)	1983, 1933 (776)	1993, 1943 (798)	2003, 1953 (595)	2013, 1963 (313)
Height, cm	175.0 (6.0)	175.8 (6.4)	177.4 (6.5)	178.4 (6.9)	179.4 (7.1)	179.3 (8.1)	<0.001
Weight, kg	75.9 (11.0)	78.7 (11.7)	80.7 (11.8)	82.8 (12.1)	84.8 (13.3)	86.4 (13.9)	<0.001
Waist circumference, cm	87.0 (9.6)^b	91.7 (9.8)	94.4 (9.1)	95.2 (9.5)	94.5 (9.9)	96.1 (10.8)	<0.001
BMI, kg/m²	24.8 (3.2)	25.6 (3.2)	25.6 (3.4)	26.0 (3.4)	26.3 (3.7)	26.8 (3.8)	<0.001
BMI <20, % (n)	5.3 (45)	2.7 (6)	2.6 (20)	2.4 (19)	1.8 (11)	1.3 (4)
20 ≤ BMI < 25, % (n)	51.1 (435)	43.4 (98)	43.7 (339)	39.7 (318)	38.7 (230)	31.0 (97)
25 ≤ BMI < 30, % (n)	37.6 (320)	46.5 (105)	43.3 (336)	46.7 (373)	45.7 (272)	48.6 (152)
BMI ≥30, % (n)	6.0 (51)	7.5 (17)	10.4 (81)	11.0 (88)	13.8 (82)	19.2 (60)
Systolic BP, mmHg	138.3 (20.9)	137.4 (22.1)	134.1 (16.9)	128.7 (17.1)	134.7 (17.6)	135.0 (15.4)	<0.001
Diastolic BP, mmHg	88.9 (13.2)	89.9 (14.2)	86.2 (10.6)	84.4 (10.6)	85.0 (10.4)	86.7 (9.4)	<0.001
Blood pressure treatment, % (n)	1.6 (14)	7.0 (15)	10.2 (79)	6.3 (50)	7.1 (42)	10.2 (32)	<0.001
Hypertension,^c % (n)	49.0 (419)	49.5 (108)	43.4 (336)	30.5 (242)	36.9 (219)	36.5 (114	<0.001
Serum cholesterol,^d mmol/L	6.42 (1.12)	6.46 (1.34)	6.11 (1.1)	5.88 (1.04)	5.5 (1.01)	5.34 (0.97)	<0.001
Serum triglycerides,^e mmol/L	1.26 (0.82)	1.30 (0.77)	1.46 (1.10)	1.67 (1.14)	1.71 (1.18)	1.49 (1.02)	<0.001
Lipid therapy,^f % (n)	–	–	–	3 (0.4)	23 (3.9)	16 (5.1)	<0.001
Self-reported diabetes,^g % (n)	2.5 (21)	1.8 (4)	3.5 (27)	2.5 (20)	4.0 (24)	4.2 (13)	0.29
Smoking habits, % (n)							<0.001
Never smoked	24.2 (207)	20.9 (46)	29.4 (229)	32.3 (258)	37.5 (223)	61.1 (190)
Former smokers	19.6 (168)	26.4 (58)	33.2 (258)	36.7 (293)	41.0 (244)	27.0 (84)
Current smokers, 1–14 g/day	34.6 (296)	29.1 (64)	14.9 (116)	14.8 (118)	8.9 (53)	6.1 (19)
Current smokers, >14 g/day	21.5 (184)	23.6 (52)	22.3 (173)	16.2 (129)	12.6 (75)	5.8 (18)
Physical activity at leisure time, % (n)^h							<0.001
Sedentary	35.3 (295)	22.6 (49)	21.4 (166)	15.7 (125)	17.6 (105)	17.0 (53)
Moderate activity	32.3 (270)	54.8 (119)	62.4 (484)	61.5 (491)	58.7 (349)	47.8 (149)
Regular exercise or athletic training	32.4 (271)	22.6 (49)	16.2 (126)	22.8 (182)	23.7 (141)	35.3 (110)
Permanent stress, % (n)ⁱ	–	8.7 (18)	14.9 (115)	9.4 (75)	17.3 (102)	19.2 (60)	0.003

Continuous variables are presented as mean (SD). Proportions are presented as % (n).

Anthropometric data were missing for four participants.

Data from 1967 (when the men were 54 years old) are only shown for comparison and are not included in the calculations.

Hypertension = systolic BP >140 mmHg or diastolic BP >90 mmHg or antihypertensive treatment (treatment records were missing in 15 participants, systolic BP records were missing in eight participants and diastolic BP records were missing in nine participants).

Cholesterol data were missing for 16 participants.

Triglyceride data were missing for 17 participants.

Lipid therapy data were not available in the previous three cohorts and missing in five patients in 1993.

Diabetes histories were missing for 29 participants.

Physical activity at leisure time was recorded at 54 years of age for men born in 1913.

Information on stress was not available for the men born in 1913 at 50 years of age.

BMI: body mass index; BP: blood pressure.

Table 2 also shows mean blood pressure and lipid levels, as well as percentages of previously treated hypertension and self-reported diabetes for the six cohorts. The decrease in systolic blood pressure of nearly 10 mmHg observed between 1963 and 1993 was not sustained through the last two (2003 and 2013) cohorts. The proportion of men with hypertension fell from 49.0% in 1963 to 36.9% in 2003, but tended to increase in the last two cohorts. Mean serum cholesterol fell continuously from a maximum of 6.46 (1.34) mmol/L in 1973 to 5.34 (0.97) mmol/L in 2013 (p for trend for all six cohorts < 0.001), with a slight increase in the use of lipid-lowering medications. Serum triglycerides, which tended to increase in the first four cohorts, levelled off in the last two cohorts (Table 2).

The proportion of active smokers decreased markedly over the five decades of the study. Only 11.9% of the men born in 1963 were smokers as compared with 21.5% born in 1953 and 56.1% born in 1913 (p < 0.001; Table 2). The number of participants with a sedentary lifestyle during leisure time decreased until 1993, but has remained unchanged since then. In contrast, the proportion exercising regularly seems to have increased during the past 10 years. The number of participants with permanent stress aged 50 years increased from 8.7% in 1923 to 19.2% in 1963 (p = 0.003).

An increase in BMI for each new cohort is mainly observed in the participants with a sedentary or moderate activity lifestyle in leisure time (p < 0.001) (Figure 1). For participants who reported regular exercise or athletic training, BMI did not increase significantly over time (p = 0.52).

Mean (SD) serum cholesterol levels by BMI group across all periods were 5.7 (1.3) mmol/L in men with a BMI <20 kg/m², 6.0 (1.2) mmol/L in men with a BMI from 20 to 25 kg/m², 6.1 (1.1) mmol/L in men with a BMI from 25 to 30 kg/m² and 5.9 (1.1) mmol/L in men with a BMI ≥30 kg/m². The mean serum cholesterol level decreased in a similar manner for all BMI categories over the 50 years (p < 0.001) (Figure 2).

We also calculated odds ratios (ORs) for having none, one, two, three and four or more of the CV risk factors (hypertension, diabetes, smoking, high cholesterol and BMI >25 kg/m²), with men born in 1913 as a reference (Table 3). For men born in 1963, the OR of having no risk factors was 6.9 (95% confidence interval (CI) 3.5–13.3, p < 0.001) when compared with the oldest cohort; in contrast, the OR for having four or more risk factors was 0.134 (95% CI 0.062–0.289, p < 0.001).

Table 3.

Odds ratios for having none, one, two, three or four or more cardiovascular risk factors: hypertension, diabetes, smoking, serum cholesterol >5 mmol/L and body mass index >25 (men born in 1913 served as the reference group).

	0 risk factors				1 risk factor				2 risk factors				3 risk factors				4 or more risk factors
Year of birth	n ^a	OR	95% CI	p	n	OR	95% CI	p	n	OR	95% CI	p	n	OR	95% CI	p	n	OR	95% CI	p
1913	13	1.00			128	1.00			330	1.00			255	1.00			125	1.00
1923	4	1.36	0.44–4.23	0.59	24	0.80	0.50–1.28	0.36	67	0.84	0.61–1.16	0.29	66	1.22	0.87–1.69	0.25	32	1.15	0.76–1.76	0.51
1933	25	2.18	1.11–4.29	0.02	154	1.43	1.10–1.85	0.01	277	0.90	0.73–1.10	0.30	239	1.06	0.86–1.32	0.57	69	0.58	0.42–0.79	<0.01
1943	52	4.53	2.45–8.39	<0.001	199	1.90	1.49–2.43	<0.001	284	0.88	0.72–1.08	0.22	204	0.81	0.65–1.01	0.06	53	0.42	0.30–0.58	<0.001
1953	34	3.94	2.06–7.54	<0.001	182	2.52	1.95–3.26	<0.001	208	0.86	0.69–1.07	0.17	135	0.69	0.55–0.88	<0.01	31	0.32	0.21–0.49	<0.001
1963	30	6.91	3.55–13.43	<0.001	80	1.97	1.43–2.70	<0.001	117	0.96	0.73–1.25	0.75	76	0.76	0.56–1.02	0.07	7	0.13	0.06–0.29	<0.001

In all, there were 63 participants with missing data.

CI: confidence interval; OR: odds ratio.

Discussion

We have previously described a decline in CV risk factors in the male population over a period of 40 years, mainly in terms of serum cholesterol and smoking, but with rising rates of overweight and obesity.¹¹ In this investigation, we extend our previous analyses with another cohort of 50-year-old men born in 1963, noting a continuing decline in serum cholesterol and smoking prevalence. Despite increasing levels of self-assessed physical activity during leisure time, with up to a third of 50-year-old men now exercising regularly, body weight and waist measurements continued to increase from 14% to 19% over the past decade. In parallel with these developments, attack rates of acute myocardial infarction in Gothenburg have decreased substantially, closely mirroring the decline in risk factors.¹⁴ A modelling study has shown that the major part of the substantial decline in CHD deaths in Sweden between 1986 and 2002 (39%) was explained by lower serum cholesterol levels, whereas the effect of rising obesity rates was comparatively minor (−2%). Less smoking explained 9% and more exercise 6% of the decrease in CHD deaths.⁴

The observed increase in physical activity may contribute to explaining why the rate of diabetes did not increase despite the increase in obesity. This finding is consistent with the observation in a Swedish registry study by Jansson et al.,¹⁹ who found the prevalence of pharmacologically treated diabetes to increase moderately during 2005–2013, whereas the incidence decreased modestly. Nevertheless, it should be noted that the prevalence of diabetes and obesity was much lower than that reported in in EUROSPIRE, a large European survey of patients diagnosed with CHD.²⁰ As depicted in Figure 1, the increase in obesity in the more recent cohorts was mainly present in men with a sedentary lifestyle, further stressing the importance of physical activity in the population in order to prevent obesity. The proportion of men who are active smokers decreased to an all-time low of 11.9%, and as many as 61.1% of those born in 1963 have never been smokers, as compared with 37.5% born in 1953. The same trends have been observed in other parts of the developed world, although not to the same extent. Studies from the USA and Finland have reported the prevalence of smoking in men to be approximately 20–30%.^7,9 Mean blood pressure levels decreased during the 1970s and 1980s, but have tended to increase in our latest three cohorts of Gothenburg men (i.e. those born in 1943, 1953 and 1963). This trend was not consistent with the trend seen in the populations in global health examination surveys.²¹

This increase in blood pressure may be related to the increase in obesity that we observed. The blood pressure levels observed in our study were similar to those in the northern Sweden MONICA study.⁸ Hypertension is a main risk factor for stroke, and even though the total incidence of ischaemic stroke is decreasing, an increase in stroke incidence in younger individuals was recently reported in Sweden.²²

In global population surveys, total cholesterol fell in the high-income region, and the regional declines were approximately 0.2 mmol/L per decade for both sexes.¹⁵ In a Spanish population-based study, the decrease in cholesterol levels was larger than in our study, with mean s-cholesterol falling from 5.91 to 5.47 mmol/L between 1995 and 2005 among men aged 35–74 years.²³ Mean serum cholesterol levels have continued to decrease in the Gothenburg studies, and the level at the last cohort (in 2013) was 5.34 mmol/L. However, the difference in serum cholesterol levels between the cohorts born in 1943 and 1953 was comparatively minor. The rate of lipid-lowering treatment (statins) was low, but increased from 0.4% in 1993 to 5.1% in 2013, which might have contributed slightly to the decrease in s-cholesterol.

The decrease of serum cholesterol was observed in all BMI groups, as shown in Figure 2. In the Västerbotten County study,¹⁰ serum cholesterol levels increased in 2008–2010 in men, in women and in all educational groups, potentially in response to a more lenient attitude towards the consumption of saturated fat induced by fatty diets.¹⁷ Why this did not occur in Gothenburg is unclear, but in northern Sweden those with only a basic education and who lived in the rural inlands had a more adverse development with respect to serum cholesterol. Thus, risk factor levels may differ between groups within a country. Similar trends as observed in the present study have been observed in North America. In the USA since the 1960s, the prevalence of obesity has increased from 13% to 35% in adult men and women.²⁴ In American obese persons, the prevalence of high cholesterol, high blood pressure and smoking has declined. Likewise, in the national survey of the five NHANES studies, despite increasing obesity, participants’ situation with respect to secular CV risk factors was improved at the last examination ending in 2000.⁹ Approximately 44% of the decline in CHD mortality was attributed to improved levels of risk factors, including reductions in total cholesterol, systolic blood pressure, smoking prevalence and physical inactivity, although these reductions were partially offset by the increase in BMI and the prevalence of diabetes, which accounted for an increase in the number of deaths.^5,9

The long period of observation and that the same methodology was used throughout the period of 50 years strengthen the present study, whereas the relatively small cohort sizes and a decreasing participation rate potentially constitute limitations. Our study included only men, which is another limitation. Similar trends have been described in Gothenburg women,²⁵ but as the study period and the methodology in the female cohorts were different from the present study, recent trends in women will be analysed separately. Further, we cannot exclude the possibility that the participants in our cohorts are somewhat different from non-participants. The participation rate fell from 87.9% in 1963 to 48.2% in 2013. Declining participation rates in epidemiological studies constitute a major problem when comparing trends. Morton et al. described a mean decline in participation rate of 0.67% per year in cross-sectional studies between 1970 and 2003.²⁶ It is known that participants in population studies tend to have higher socioeconomic status and to be healthier than non-participants.^27,28 In INTERGENE, a cross-sectional study with a 42% participation rate from the same geographic area as the present study, the association between socioeconomic status and CV risk factors was studied. In that study, physical activity was higher in the more educated group, while there were more smokers among those with lower education. Obesity and hypertension were also significantly associated with lower education level, while blood lipids, diabetes and perceived stress were less so.²⁹ Thus, the impact of positive changes (e.g. smoking habits and physical activity) might be overestimated, whereas adverse changes, such as increasing BMI, might be underestimated, due to the decrease in participation rates.

After the First World War, the first half of the 20th century witnessed an unparalleled increase in CHD in Western industrialised nations, followed by a sharp decline. Low- and middle-income countries are now undergoing similar transitions, and there is growing demand to understand the underlying mechanisms of these changes. A particular driver in this matter is due to a flattening of the decline in CHD trends observed among the young in the USA and the UK.^30,31 Even though we lack information from the onset of the epidemic, the current study is the only one that has investigated secular trends in random population samples over an extended period of 50 years and in which the same techniques have been used over the same period.

Conclusion

We have observed declining trends in several CV risk factors over a 50-year period in middle-aged men in a Western community in Sweden, despite continuously increasing BMI. The odds of having none of our predefined risk factors at 50 years of age were higher for men born in 1963 compared with men born in 1913. However, there is no guarantee of a continuation of the current positive trends, particularly in the face of rising obesity rates. Undoubtedly, the effects of a continuous increase in body weight, if not curtailed, will have to be monitored closely in the future.

Footnotes

Author contribution

AR, LW, CW, KC, KS and P-OH contributed to the concept and design of the work. All authors contributed to the acquisition, analysis or interpretation of the data. YZ and P-OH drafted the manuscript. All authors critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy.

Acknowledgements

The authors are grateful to the staff for their being supportive of the studies over the years and to all participating men.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils concerning economic support of research and education (ALF agreement).

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