Am J Physiol Endocrinol Metab 292: E1837–E1841, 2007.
First published February 27, 2007; doi:10.1152/ajpendo.00668.2006.
Hypertension caused by prenatal testosterone excess in female sheep
Andrew J. King,1 N. Bari Olivier,2 P. S. Mohankumar,3
James S. Lee,4 Vasantha Padmanabhan,4 and Gregory D. Fink1
Departments of 1Pharmacology and Toxicology, 2Small Animal Clinical Sciences, and 3Pathobiology
and Diagnostic Investigation, Michigan State University, East Lansing; and 4Department of Pediatrics
and the Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan
Submitted 7 December 2006; accepted in final form 21 February 2007
and insulin resistance (39) and recreates the polycystic ovary
syndrome (PCOS) phenotype in female sheep (36).
PCOS, which affects ⬃10% of women of reproductive
age (8), is a multifacetted condition comprised of infertility,
dysfunctional uterine bleeding, and components of the metabolic syndrome, including obesity. These women are at risk
for type II diabetes mellitus, dyslipidemia, hypertension,
and other cardiovascular diseases (3). Although T treatment
during fetal life recapitulates many of these features in
female sheep, the cardiovascular effects have not been
studied. The goal of this study was to determine whether
hypertension and dyslipidemia occur in this well-characterized model of PCOS.
METHODS
resulting in impaired
fetal growth, is associated with a higher incidence of cardiovascular, metabolic, and reproductive disorders in adult life
(26, 34). An abnormal intrauterine hormonal milieu can clearly
influence fetal growth and development and has been identified
as one factor known to cause intrauterine programming (25,
26). For instance, excessive prenatal exposure to glucocorticoids causes hypertension, insulin resistance, and other metabolic abnormalities in numerous animal models, including
sheep (10, 11, 27, 46). The sex steroids are well-established
intrauterine programming agents in many species, including in
sheep (36). Exposure to excess testosterone (T) during the
prenatal period causes phenotypic masculinization, intrauterine
growth retardation (7, 32, 33, 42), reproductive disruptions,
Animal preparation. All protocols were approved by the Animal
Use Committee at the University of Michigan. In total, eight agematched 2-yr old female Suffolk sheep were studied. Control (n ⫽ 4)
and prenatal T-treated (100 mg T propionate im twice weekly from
days 30 to 90 of fetal life, n ⫽ 4) sheep were ovariectomized and
replaced with early follicular phase levels of estradiol. Estradiol
replacement was by subcutaneous implantation in the axillary region
of a 10-mm Silastic implant (0.33 cm id, 0.46 cm OD; Dow Corning,
Midland, MI) containing a packed column of crystalline 17 ␤-estradiol (Sigma, St. Louis, MO) and sealed with Silastic adhesive Type A
(Dow Corning). The purpose of ovariectomy and hormone replacement was to ensure a consistent estradiol environment in all animals.
Earlier studies (14) have implicated potential blood pressure regulating effects of sex hormones. Ovary-intact prenatal T-treated females
have higher circulating levels of estradiol than controls (2) because of
their multifollicular ovarian morphology (45). This implant is expected to
produce chronic serum levels of estradiol of ⬃1 pg/ml (23, 24). Anesthesia was induced by administering 20 –30 ml of pentobarbital sodium
intravenously (50 mg/ml Nembutal Na solution; Abbott Laboratories, Chicago, IL), and the animals were intubated to maintain a
plane of anesthesia with 1–2% halothane (Halocarbon Laboratories, River Edge, NJ).
Arterial pressure measurement. During the same surgery, the catheter
of a radiotelemetry-based pressure transmitter [TA11PA-D70; Data
Sciences International (DSI)] was implanted into the femoral artery
and the body of the transmitter placed subcutaneously at the inner
thigh. Six days later, to allow a sufficient postoperative recovery
period, sheep were housed in individual small rectangular pens (3 ⫻
4 ft) with free access to food and water. A radiotelemetry receiver
(RPC-1; DSI) was mounted on the pen and connected to a data
exchange matrix and computerized data acquisition program
(Dataquest ART 3.0; DSI) to monitor arterial pressure remotely.
Starting at noon, a 24-h continuous blood pressure recording period
commenced. Mean arterial pressure (MAP), systolic blood pressure
Address for reprint requests and other correspondence: A. King, Dept. of
Pharmacology and Toxicology, B440 Life Sciences, Michigan State University, East Lansing, MI 48824 (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
intrauterine programming; polycystic ovary syndrome; dyslipidemia;
hyperglycemia; hypernatremia
A SUBOPTIMAL INTRAUTERINE ENVIRONMENT,
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0193-1849/07 $8.00 Copyright © 2007 the American Physiological Society
E1837
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King AJ, Olivier NB, Mohankumar PS, Lee JS, Padmanabhan V,
Fink GD. Hypertension caused by prenatal testosterone excess in female
sheep. Am J Physiol Endocrinol Metab 292: E1837–E1841, 2007. First
published February 27, 2007; doi:10.1152/ajpendo.00668.2006.—Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects
⬃10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multifaceted and
includes reproductive abnormalities and components of the metabolic
syndrome such as insulin resistance, obesity, dyslipidemia, and hypertension. Exposure to excess testosterone (T) during the prenatal
period may predispose individuals to PCOS phenotype. The goal of
this study was to determine whether hypertension and dyslipidemia
occur in a well-characterized model of PCOS produced by prenatal
treatment of sheep with T. Radiotelemetry was used to measure blood
pressure over a 24-h period in conscious, undisturbed animals. To
normalize circulating estradiol levels across treatment, control (n ⫽ 4)
and prenatal T-treated (100 mg T propionate im twice weekly from
days 30 to 90 of fetal life, n ⫽ 4) 2-yr-old females were ovariectomized, instrumented with a radiotelemetry transmitter, and clamped
with early follicular phase levels of estrogen using an implant. Six
days later, a 24-h recording period commenced. Prenatal T-treated
sheep were hypertensive compared with control sheep, and heart rate
tended to be higher. T-treated sheep had hyperglycemia, insulin
resistance, hypernatremia, and hyperchloremia, and both total and
LDL cholesterol tended to be higher. Plasma aldosterone and
epinephrine were significantly lower in T-treated sheep, whereas
norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild
hypertension, a risk factor reported in some women with PCOS, is
also a feature of the sheep model of PCOS produced by prenatal T
treatment.
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INTRAUTERINE-PROGRAMMED HYPERTENSION
RESULTS
Hemodynamics. The 24-h average MAP, SBP, DBP, pulse
pressure (PP), HR, body temperature, and activity level measured by radiotelemetry in control and prenatally T-treated
female sheep is shown in Table 1. Arterial pressure was ⬃10
mmHg higher in sheep treated with T during the prenatal
period. This difference was statistically significant (P ⬍ 0.05).
HR also tended to be higher in prenatal T-treated sheep by ⬃10
beats/min; however, this difference was not statistically significant (P ⫽ 0.1) in this small group of animals. Body temperature was similar in both groups. Activity level tended to be
higher in the prenatal T-treated group, but this was not statistically significant, and the counts of activity measured in this
study were relatively low in both groups. The 1-h MAP and HR
averages for the 24-h recording period in control and prenatally
T-treated female sheep are shown in Fig. 1 and demonstrate
that differences in MAP and HR between groups were evident
throughout the recording period.
Blood sample analysis. Lipid profile analysis in control and
prenatal T-treated female sheep is shown in Table 2. Total
(P ⫽ 0.17) and LDL (P ⫽ 0.08) cholesterol tended to be higher
in the prenatal T-treated group. Plasma aldosterone, norepinephrine, and epinephrine are shown in Fig. 2. Sheep treated
with T during the prenatal period had significantly lower
plasma aldosterone and epinephrine levels compared with
control sheep (P ⬍ 0.05); however, plasma norepinephrine was
not different between the groups.
Plasma electrolyte and glucose concentrations are shown in
table 3. Sheep treated with T during the prenatal period had
Fig. 1. One-hour mean arterial pressure (A) and heart rate (B) averages for the
24-h recording period in control and prenatal testosterone-treated (T-treated)
female sheep. *P ⬍ 0.05, 24-h average compared with control sheep.
statistically significant elevations in plasma Na⫹, Cl⫺, and
glucose compared with the control group (P ⬍ 0.05). There
were no statistically significant differences in body weight
(control 54 ⫾ 3 kg, T treated 56 ⫾ 5 kg), heart, kidney,
adrenal, or liver weight between the two groups.
DISCUSSION
The major new finding of this study is that prenatal exposure
to excess T causes mild hypertension in adult female sheep.
Exposure to excess T during the prenatal period in sheep
recapitulates many of the components of PCOS (36), a disease
also characterized by a clustering of cardiovascular risk factors
(8). Although the model has been exploited extensively to
understand the developmental origin of neuroendocrine and
ovarian dysfunction, as well as insulin resistance, the cardiovascular consequences have not been explored.
Interestingly, the magnitude of the hypertension resulting
from prenatal T excess was similar to what has been previously
Table 1. Twenty-four-hour averages of physiological parameters measured by radiotelemetry in
prenatal T-treated and control sheep
Group
MAP, mmHg
SBP, mmHg
DBP, mmHg
PP, mmHg
HR, beats/min
Activity, counts/min
Temp, °C
Control
T treated
90.9⫾2.8
100.5⫾2.7*
115.1⫾4.5
125.0⫾2.8
79.2⫾2.3
88.9⫾2.8*
35.9⫾3
35.9⫾0.3
73.5⫾5.9
82.5⫾7.4
1.7⫾0.4
2.8⫾0.5
38.7⫾0.2
38.9⫾0.1
Values are means ⫾ SE. T treated, prenatal testosterone treated; MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure;
PP, pulse pressure; HR, heart rate; Temp, body temperature. *P ⬍ 0.05, prenatal T-treated group compared with control group.
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(SBP), diastolic blood pressure (DBP), heart rate (HR) and body
temperature were sampled for 10 s every minute for the 24-h period.
Relative physical activity level was also measured utilizing the radiotelemetry system. An activity count is generated by the data exchange
matrix in response to a change in the strength of the telemetry signal,
as the animal moves relative to the receiver. Activity is quantified as
counts/min.
Blood sampling and analysis. After completion of the study,
unfasted blood samples were collected for lipid profile, aldosterone,
catecholamine, glucose, and electrolyte determination. A commercial
clinical pathology laboratory (Charles River Laboratories, Wilmington, MA) measured total cholesterol, triglycerides, low-density lipoproteins (LDL), and high-density lipoproteins in serum samples.
Aldosterone was measured in plasma by radioimmunoassay (Diagnostic Center for Population and Animal Health, Michigan State
University, East Lansing, MI). Plasma norepinephrine and epinephrine were measured using HPLC and electrochemical detection.
Plasma electrolytes and glucose were measured with specific ionselective electrodes (NOVA 16; Nova Biomedical, Waltham, MA).
Statistical Analysis. Statistical analysis was performed by comparing control and T-treated sheep by Student’s t-test. A P value of
⬍0.05 was considered statistically significant. All results are presented as means ⫾ SE.
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INTRAUTERINE-PROGRAMMED HYPERTENSION
Table 3. Plasma electrolytes and glucose in control and
prenatal T-treated sheep
Table 2. Lipid profiles in control and
prenatal T-treated sheep
Group
Cholesterol, mg/dl
Triglycerides, mg/dl
HDL, mg/dl
LDL, mg/dl
Group
Na⫹, mmol/l
K⫹, mmol/l
Cl⫺, mmol/l
Glucose, mg/dl
Control
T treated
54.6⫾3.5
63.2⫾4.3
14.1⫾1.4
14.6⫾2.2
39.8⫾1.6
42.0⫾2.4
12.0⫾1.2
16.3⫾1.7
Control
T treated
138.8⫾3.3
149.5⫾2.1*
4.4⫾0.1
4.4⫾0.3
108.3⫾2.2
114.5⫾1.3*
59.5⫾1.8
66.8⫾1.8*
Values are means ⫾ SE.
Values are means ⫾ SE. *P ⬍ 0.05 prenatal T-treated group compared with
control group.
be increased. Plasma cathecholamines are only a rough index
of global sympathetic activity, and more accurate assessments
of sympathetic transmitter release require utilization of radioisotope dilution measurements of total body or regional norepinephrine spillovers (15) or direct sympathetic nerve recordings (17). This is particularly important given that regionalized
sympathetic activation has been convincingly demonstrated by
direct nerve recordings in rabbits (38), and several authors (1,
16, 18 –20) have elucidated the importance of regionalized
sympathetic activation in human cardiovascular disease. Reduced plasma norepinephrine levels have been reported in
women with PCOS (28).
Surprisingly, plasma aldosterone levels were significantly
decreased in sheep treated with T during the prenatal period.
The findings of our study are consistent with a recent report (5)
documenting normal plasma aldosterone levels in sheep to be
300 –500 pmol/l. Therefore, it is unlikely that peripherally
circulating aldosterone is involved in the pathogenesis of
hypertension seen in this model, although the role of tissue
specific RAAS remains to be investigated. Women with PCOS
demonstrate an insulin resistance-related, but very modest,
increase in serum aldosterone (4). Prenatal T treatment in
sheep does cause insulin resistance (39). Therefore, the reason
Fig. 2. Plasma aldosterone (A), norepinephrine (B), and
epinephrine (C) in control and prenatal T-treated sheep.
*P ⬍ 0.05 compared with control sheep.
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reported for fetal programming with dexamethasone in sheep
(10, 11). Phenotypically, intrauterine programming by T shares
many features with prenatal glucocorticoid excess, including
intrauterine growth retardation, insulin resistance, and hypertension (26). The intrauterine programming effects of glucocorticoids on adult cardiovascular function have been well
documented in both rodent and ovine models (10 –12). Overactivity of the renin-angiotensin-aldosterone system (RAAS)
plays a key role in the pathogenesis of hypertension programmed by prenatal glucocorticoid exposure (10, 11, 13, 21,
22, 29, 35, 48). In particular, it appears that activation of the
intrinsic brain RAAS and not the peripheral RAAS is critical
(13, 37, 41). It has also been suggested (41, 43) that sympathetic nervous system overactivity may be involved. Whether
the hypertension seen in response to prenatal T excess involves
similar mechanisms remains to be elucidated.
The elevated HR seen in prenatal T-treated sheep does
support the possibility that sympathetic nervous system activation may be involved (30). A recent study using analysis of
HR variability to assess cardiac autonomic function (47)
showed increased sympathetic and decreased parasympathetic
frequency components in young women with PCOS. However,
the finding of normal plasma norepinephrine levels in these
sheep indicates that global sympathetic activity is unlikely to
E1840
INTRAUTERINE-PROGRAMMED HYPERTENSION
GRANTS
This study was supported by National Institute of Child Health and Human
Development Grant P01-HD-44232 (V. Padmanabhan). A. J. King is supported by a Pfizer safety sciences training fellowship.
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Prenatal T-treated sheep were hypernatremic and hyperchloremic compared with controls. Although the physiological
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