pISSN: 2287-4208 / eISSN: 2287-4690

Review Article
World J Mens Health 2017 August 35(2): 59-64
https://doi.org/10.5534/wjmh.2017.35.2.59

Hypertension and Male Fertility

David Guo1, Shufeng Li1, Barry Behr2, Michael L Eisenberg1,2
Departments of 1Urology, 2Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA

As the age of paternity rises in the developed world, issues of chronic disease may affect prospective fathers. Given the high
prevalence of hypertension, researchers have begun to explore the relationship between hypertensive disease and male fertility.
The current literature suggests an association between hypertension and semen quality. The use of various antihypertensive
medications has also been linked to impaired semen parameters, making it difficult to discern whether the association exists with
hypertension or its treatment. Further investigation is warranted to determine whether the observed associations are causal.

Key Words: Adrenergic beta-antagonists; Hypertension; Infertility; Semen analysis

INTRODUCTION scriptions, with 705 million prescriptions dispensed in

2014 [4]. Despite this, the relationship between hyper-
The average age of paternity is rising in America. Data tension and male fertility has received limited attention.
from the Centers for Disease Control have shown that the The prior literature has posited a link between the in-
birth rate for fathers from ages 25 to 29 years decreased fertility and the metabolic syndrome, a cluster of con-
15%, while the birthrate for fathers from ages 35 to 39 ditions including insulin insensitivity, obesity, hyper-
years increased by 18% from 2000 to 2013 [1]. Importantly, lipidemia, and hypertension. For example, several groups
as men age, they are more prone to develop chronic have highlighted a collection of studies that suggested an
illnesses. Considering the link between several medical association between infertility and obesity/high body
diseases and impaired semen quality [2], it is important to mass index, diabetes, and dyslipidemia [5-8]. Ventimiglia
investigate the potential impact of chronic illness on male et al [9] explored the association between medical co-
fertility. morbidity and semen quality, reporting an inverse rela-
Hypertension is the most common chronic illness re- tionship and implying that metabolic syndrome had a neg-
ported among men in the USA, affecting 30% of adult ative impact on reproductive health. Nevertheless, the lit-
males [3]. Not surprisingly, the use of prescription anti- erature regarding hypertension in isolation, or its treat-
hypertensive medications is also common. Antihypertensive ment, is limited.
medications lead all other categories in annual pre-

Received: Apr 23, 2017; Revised: Jun 19, 2017; Accepted: Jun 20, 2017
Correspondence to: Michael L Eisenberg
Departments of Urology, Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, A259B,
Stanford, CA 94305, USA.
Tel: +1-650-723-3391, Fax: +1-650-724-9609, E-mail: [email protected]
Copyright © 2017 Korean Society for Sexual Medicine and Andrology
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
60 World J Mens Health Vol. 35, No. 2, August 2017

HYPERTENSION AND CURRENT capture prevalent disease, only men who were diagnosed
SEMEN QUALITY with hypertension prior to or within one year after semen
analysis were included. Abnormal semen parameters
Rare studies have linked hypertension to some aspects were defined based on the World Health Organization
of sperm physiology. A Brazilian group employed a rat (WHO) 5th edition of the Manual on Semen Analyses (i.e.,
model for renovascular hypertension to demonstrate de- subfertile values: semen volume ＜1.5 mL, sperm concen-
creased sexual behavior and impaired spermatogenesis, tration ＜15 mol/mL, sperm motility ＜40%, sperm mor-
which they attributed to imbalances in prolactin, testoster- phology ＜14% normal forms) [14]. Antihypertensive
one and follicle stimulating hormone [10]. In addition, an medications were only included if taken in the year prior
Italian group found higher levels of clusterin, a glyco- to the semen analysis.
protein associated with abnormal sperm morphology, in a To compare men with hypertension and those without,
small cohort hypertensive men compared to normo- we used the Wilcoxon rank-sum test for age, and
tensive men [11]. These studies were small in scale and ex- chi-square for age group and year of evaluation. Semen
ploratory in nature. tests were analyzed in a mixed effect linear model with re-
We utilized the Stanford Infertility data to investigate peated measures. All semen tests were square-root-trans-
the association between hypertension and semen quality. formed per convention for the analyses given their non-
The study cohort consists of men who were evaluated for Gaussian distribution. The percentage of men with Subop-
infertility as part of an infertile couple between 1994 and timal Semen Parameters according to WHO 5th edition
2011 at the Stanford Reproductive Endocrinology and criteria were analyzed using a generalized linear mixed
Infertility Center. This center evaluates and treats infertile model with repeated measures. The tests were adjusted
couples with both male and female infertility. The labo- for patient age and the year of fertility evaluation. For the
ratory performs a high volume of semen analyses for fertil- comparisons between men who took diuretics and those
ity evaluation and sperm preparations for use with assisted who did not, the Wilcoxon rank-sum test was also applied
reproductive techniques. Men evaluated for infertility due to their limited number. All p-values were two-sided,
were self-referred, or were referred by an internist, gyne- with p＜0.05 considered statistically significant. Analyses
cologist, urologist, or reproductive endocrinologist. The were performed using SAS ver. 9.3 (SAS Institute, Cary,
methods used for analysis of semen (sperm concentration, NC, USA).
motility, volume, morphology) have been previously de- Men with hypertension were found to be more likely to
scribed [12-14]. have one or more semen abnormalities compared to nor-
After receiving approval from the Institutional Review motensive men [2]. Moreover, compared to men without
Board, the assembled cohort was linked to insurance hypertension, men diagnosed with hypertension demon-
claims and electronic medical record data for each patient strated impaired semen parameters [15]. Hypertensive
using unique medical record numbers. We collected data men had a lower semen volume (2.1 mL vs. 3.0 mL, p＜
including medical diagnoses (International Classification 0.001), sperm motility (41.0% vs. 47.0%, p=0.008), total
of Disease, 9th edition, ICD-9), procedures (Current sperm count (103.8 vs. 147.0, p=0.005) and total motile
Procedural Terminology, CPT), and medications prescribed. sperm count (43.1 vs. 65.9, p=0.003). When stratifying
Complete medication data were available beginning in men by WHO (5th edition) semen quality criteria, a higher
2008. For antihypertensive medications, we classified prevalence of men with hypertension had subfertile se-
them into five categories: beta beta-blockers, calcium men volume (18.1% vs. 10.0%, p=0.03), sperm concen-
channel blockers, angiotensin-converting enzyme in- tration (19.4% vs. 12.2%, p=0.02), and total motile sperm
hibitors (ACEIs), angiotensin receptor blockers, and count (25.8% vs. 15.5%, p=0.01). There were also trends
diuretics. toward suboptimal motility and total motile count in men
Men with an ICD-9 code between 401.0 and 405.9 with hypertension, but these were not statistically sig-
were considered to have a diagnosis of hypertension. To nificant (Table 1).
 David Guo, et al: Hypertension and Male Fertility 61

Table 1. Comparison of men with hypertension and men without hypertension, according to absolute semen parameters and
World Health Organization (WHO) 5th criteria suboptimal semen parametersa
b
Variable Men with hypertension Men without hypertension p-value
Absolute semen parameter
Semen volume (mL) 2.1 (1.5∼3.0) 3.0 (2.0∼4.0) ＜0.001
Sperm concentration (mol/mL) 45.9 (20.9∼87.7) 53.5 (27.4∼93.0) 0.19
Motility (%) 41.0 (19.0∼59.0) 47.0 (28.0∼64.0) 0.008
Total count 103.8 (42.8∼208.7) 147.0 (67.2∼269.4) 0.005
Total motile count 43.1 (8.3∼106.9) 65.9 (19.8∼154.8) 0.003
Morphology (% normal forms) 9.0 (6.0∼14.0) 9.0 (6.0∼14.0) 0.667
WHO 5th criteria suboptimal semen parameters
Semen volume ＜1.5 mL 31 (18.1) 1,020 (10.0) 0.032
Sperm concentration ＜15 mol/mL 30 (19.4) 1,213 (12.2) 0.022
Motility ＜40% 75 (48.4) 3,924 (39.5) 0.079
Total count ＜39 mol 34 (21.9) 1,420 (14.2) 0.059
Total motile count ＜9 mol 40 (25.8) 1,533 (15.5) 0.011
Morphology ＜14 mol 90 (70.9) 5,056 (72.7) 0.951
Values are presented as median (interquartile range) or number (%).
a
Data points not available for all men (e.g., morphology); % calculated based on men for whom data is available.
b
Adjusted for age, year of analysis.

We next looked at men for whom medication data were Studies in the USA and Europe have demonstrated higher
available (n=1,167). Of those men, 88 men were taking 1 mortality rates among infertile men [16,17]. In addition,
antihypertensive medication and 45 were taking 2 or higher rates of certain types of cancers have also been re-
more antihypertensive medications. Compared to men ported among infertile men in the years following a fertil-
not taking medications, men taking 1 antihypertensive ity evaluation [18-21]. Recently, data from a large USA in-
medication had a statistically significant decrease in se- surance claims database demonstrated a higher incidence
men volume (2.0 mL vs. 2.5 mL, p=0.05) with a trend to- of heart disease and diabetes among infertile men [22].
ward a lower sperm count (p=0.07). Importantly, a higher incidence of hypertension was not
We then stratified men by individual class of anti- identified in this group, suggesting that male infertility is
hypertensive medication [15]. Several differences were not a risk factor for hypertension itself.
identified between classes of antihypertensives. Men who
were taking beta-blockers were noted to have decreased SUMMARY
volume, concentration and motility compared to men not
taking medications (p＜0.05). Men taking calcium chan- Existing data suggest an association between hyper-
nel blockers had relatively decreased sperm concen- tension and impaired semen quality. Men diagnosed with
tration. Men taking angiotensin-receptor blockers had rel- hypertension have a lower semen volume, sperm motility,
atively increased volume and decreased sperm concentra- total sperm count, and motile sperm count relative to men
tion. Men taking ACEIs had relatively decreased volume in the cohort who did not carry a diagnosis of hyper-
and decreased motility. Lastly, men taking diuretics had tension. Importantly, more men with a diagnosis of hyper-
relatively decreased volume (Table 2). tension had impaired semen volume, concentration, and
total motile count, according to WHO 5th edition criteria
INCIDENT HYPERTENSIVE DISEASE for subfertile semen parameters. Moreover, the use of be-
ta-blockers was associated with lower semen volume,
Infertility may be a harbinger of health. As such, a man's concentration, motility, total sperm count, and total mo-
reproductive fitness may also reflect his somatic fitness. tile sperm count, while men taking other antihyperten-

www.wjmh.org
62 World J Mens Health Vol. 35, No. 2, August 2017

sives had more isolated impairments in semen parameters.

(53.6∼178.3)
40.2 (27.5∼57.0)

(31.0∼67.0)

(10.7∼83.5)
(13.0∼18.0)
The direct end-organ effects of hypertension on the ar-
2.0 (1.7∼3.1)
c

teries and kidneys have been studied in depth, but the ef-
Diuretics
18

fect on the testes is not well characterized. Prior research

has addressed the relationship between hypertension and

BBs: beta-blockers, CCBs: calcium channel-blockers, ARBs: angiotensin receptor-blockers, ACE inhibitors: angiotensin converting-enzyme inhibitors.
52.0

53.4
15.0
85.7
the endocrine axis, which may affect reproductive ability.
For example, in a cross-sectional study of 1,548 men,
(44.4∼152.0)

Svartberg et al [23] demonstrated an inverse association

46.6 (29.6∼80.4)

(15.0∼55.0)
ACE inhibitors

(8.2∼89.6)
(6.0∼12.0)
1.5 (1.0∼3.0)

between total testosterone level and systolic blood

25

pressure. In a case-control study of 110 newly diagnosed

hypertensive men, Fogari et al [24] showed a 10% reduc-
24.4
10.5
36.5
62.4

tion in total testosterone levels compared to normotensive

men. However, given study design, causal pathways be-
(30.5∼203.0)
34.6 (14.5∼47.9)

(28.5∼67.5)

(22.9∼86.6)
(12.0∼16.0)

tween hypertension and testicular function cannot be

4.5 (2.8∼5.0)

inferred.
ARBs
28

While the etiology of the association between hyper-

tension and semen quality remains unknown, the relation-
48.0
150.9
58.4
16.0

ship between somatic health and semen production has

been reported [9,24,25]. Authors have suggested several
Wilcoxon rank-sum test instead of repeated mixed model due to limited number of diuretics.
(35.0∼201.0)

plausible hypotheses. For example, the fetal origins of dis-

35.5 (16.0∼56.0)

(29.0∼82.0)

(22.4∼86.1)
(8.0∼22.0)
3.0 (2.0∼4.5)b

ease theory posits a common in utero exposure could lead

CCBs

to both infertility and hypertension [26-28]. In addition,

42

the coexistence with other components of the metabolic

53.5

49.6
81.4

16.0

syndrome (e.g., obesity, hyperlipidemia) have been dem-

onstrated to associate with impaired semen quality [7,8].
The etiology may also relate to treatment rather than the
b

(11.0∼57.0)b
b

Values are presented as number only or median (interquartile range).

18.0 (10.0∼41.4)

(13.7∼64.3)

Analysis confined to men for whom medication data was available.

b

(4.0∼19.0)
(2.1∼27.5)
b
1.7 (1.0∼2.8)

disease alone. The current report identified multiple ab-

Table 2. Semen parameters and individual classes of medications

normalities associated with beta-blockers but not other in-

BBs
73

dividual classes of antihypertensives. This is particularly

9.0
8.1
27.0
27.5

relevant given that beta-blockers represent one of the most

commonly medications prescribed, with over 85.3 mil-
lion prescriptions dispensed in the USA in 2014 [4].
(37.5∼200.0)
(10.4∼110.4)
40.7 (20.0∼72.8)

(24.0∼73.0)

(6.0∼15.0)
a
Entire cohort

Importantly, several medications have been investi-

2.5 (1.5∼3.5)
1,167

gated previously for their impact on fertility. For example,

retrograde ejaculation is known to be a common side ef-
10.0
49.0
96.6
42.2

fect of alpha-blockers and consequently would decrease

semen volume [29]. Thus, the non-selective alpha-blocker
phenoxybenzamine was investigated as a male oral con-
Total motile count (mol)
Morphology (%) normal

traceptive in the 1980s [30]. In addition, a case report

Sperm concentration
Semen volume (mL)

documented a pregnancy for an infertile couple following

Total count (mol)
Variable

the discontinuation of the calcium channel-blocker nifidi-

Motility (%)

pine [31]. An in vitro study suggested that certain receptors

(mol/mL)

p＜0.05.

for normal acrosomal reaction were reversibly impaired

form
Total

by calcium-channel blockers [32].

b
a

c
 David Guo, et al: Hypertension and Male Fertility 63

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hypertension and antihypertensives on semen quality. J Urol
No potential conflict of interest relevant to this article 2015;193:e1117.
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DJ, et al. Semen quality, infertility and mortality in the USA.
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