Am J Physiol Endocrinol Metab 296: E1319E1325, 2009.

First published March 24, 2009; doi:10.1152/ajpendo.90940.2008.

High serum testosterone levels are associated with excessive erythrocytosis

of chronic mountain sickness in men
Gustavo F. Gonzales,1,2 Manuel Gasco,1 Vilma Tapia,2 and Cynthia Gonzales-Castaneda1
1

Laboratory of Endocrinology and Reproduction, Faculty of Sciences and Philosophy, Alberto Cazorla Talleri; 2Instituto
de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima, Peru
Submitted 23 November 2008; accepted in final form 14 March 2009

Gonzales GF, Gasco M, Tapia V, Gonzales-Castaneda C.

High serum testosterone levels are associated with excessive erythrocytosis of chronic mountain sickness in men. Am J Physiol
Endocrinol Metab 296: E1319 E1325, 2009. First published
March 24, 2009; doi:10.1152/ajpendo.90940.2008.Chronic mountain
sickness (CMS) is characterized by excessive erythrocytosis (EE)
secondary to hypoventilation. Erythropoietin (Epo) and testosterone
regulate erythrocyte production. Low thyroid hormone levels are also
associated to hypoventilation. Hence, these hormones can play a role
in etiopathogeny of EE. The purpose of this study was to elucidate the
effect of sexual and thyroid hormones and Epo in residents from Lima
(150 m) and Cerro de Pasco (4,340 m), Peru, and the response to
human chorionic gonadotrophin stimulation (hCG). Three groups, one
at low altitude and two at high altitude [1 with hemoglobin values
16 21 g/dl and the second with Hb 21 g/dl (EE)], were studied.
hCG was administered intramuscularly in a single dose (1,000 IU),
and blood samples were obtained at 0, 6, 12, 24, 48, and 72 h after
injection. High-altitude natives present similar levels of gonadotropins
and thyroid hormones but lower dehydroepiandrosterone sulphate
(DHEAS) levels (P 0.01) and greater Epo (P 0.01), 17hydroxyprogesterone (P 0.01), and testosterone levels (P 0.01)
than those at 150 m. Serum testosterone levels (524.13 55.91 g/dl
vs. 328.14 53.23 ng/dl, means SE; P 0.05) and testosterone/
DHEAS ratios are higher (7.98 1.1 vs. 3.65 1.1; P 0.01) and
DHEAS levels lower in the EE group (83.85 14.60 g/dl vs.
148.95 19.11 ug/dl; P 0.05), whereas Epo was not further
affected. Testosterone levels were highest and DHEAS levels lowest
in the EE group at all times after hCG stimulation. In conclusion, high
androgen activity could be involved in the etiopathogeny of CMS.
This evidence provides an opportunity to develop new therapeutic
strategies.
sex hormones; altitude; estradiol; dehydroepiandrosterone sulfate

live permanently at high altitude

(2,500 m) in North America, Central America, South America, East Africa, and Asia (31). Approximately 30% of the
Peruvian population (about 9 million people) lives at high
altitude (13). One of the health problems associated with the
life at high altitude has been chronic mountain sickness (CMS),
also called Monges disease, since first described by Carlos
Monge Medrano in Peru in 1925 (30). This disease can eventually be fatal. Symptoms are headache, dizziness, shortness of
breath, fatigue, loss of memory, and insomnia (24).
CMS, a lack of adaptation to altitude (53), is characterized
by excessive erythrocytosis (EE) secondary to hypoventilation
(36, 38). Hypoventilation is accentuated mainly during sleep at
high altitude (48). The prevalence of CMS is increased with
altitude and age, and it is more frequent in men (36). Therefore,

MORE THAN 140 MILLION PEOPLE

Address for reprint requests and other correspondence: G. F. Gonzales,

Universidad Peruana Cayetano Heredia, Ave. Honorio Delgado 430, Lima 31,
Peru (e-mail: ggr@upch.edu.pe).
http://www.ajpendo.org

it is important to determine mechanisms of regulation of EE at

high altitude to develop strategies for treatment or prevention.
Erythropoiesis is a process hormonally regulated. At least
two hormones have been described with properties to induce
erythrocyte productions, namely erythropoietin (Epo) (42) and
testosterone (55).
Epo is a 30.4-kDa glycoprotein hormone produced mainly
by the kidney and is a key regulator of red blood cell production (42). Epo stimulates the proliferation and differentiation of
bone marrow erythroid precursors (9, 28). In Andean natives,
there is a high variability in Epo and erythrocytic response to
high altitude; however, there is no correlation between serum
Epo levels in high-altitude natives with EE and those living at
high altitudes without this pathological condition (25).
Testosterone also plays an erythropoietic role (21, 27, 34).
Testosterone probably acts directly on bone marrow at the level
of polychromatophylic erythroblasts and enhances the synthesis of ribosomal RNA or its precursors and stimulates a nuclear
ribonuclease (55). Moreover, testosterone stimulates red cell
production in males in a dose-dependent manner, especially in
older men (7).
Testosterone decreases ventilation (10) and increases erythropoiesis, whereas estradiol has opposed actions (8, 19, 50).
For instance, higher estrogen levels have been related to higher
arterial oxygen saturation (46). This may explain the differences in ventilatory responses between sexes (11, 44). In
addition, a reduction in total sleep time, longer hypoxic episodes, and increases in the respiratory disturbances index (the
number of apneas and hypopneas per hour) have been observed
in older men exposed to high doses of testosterone (26).
Therefore, the hypothesis is that testosterone could be related
to EE and in turn to CMS etiopathogeny.
Other hormones as thyroid hormones could also play a role
in CMS etiopathogeny since hypothyroidism is associated with
hypoventilation (29, 44). Although hypothyroidism is unlikely
to cause sleep apnea (44), it would be important to determine
whether thyroid hormones are different in subjects with EE in
relation to those without EE at high altitude.
Pulmonary hypertension is another condition associated
with CMS as a result of hypoxemia (36). Dehydroepiandrosterone sulfate (DHEAS) has been shown to activate the calciumgated potassium channels and reduce pulmonary vascular wall
remodeling and right ventricle hypertrophy as well as pulmonary hypertension induced by hypoxia (17). Consequently, it is
possible that low-serum DHEAS levels may be implicated in
CMS etiopathogeny associated with pulmonary hypertension
at high altitudes.
For these reasons, the present study aimed to determine
serum levels of testosterone under basal and human chorionic
gonadotropin (hCG)-stimulated conditions and basal serum

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levels of thyroid hormones, DHEAS, and Epo in natives of

Cerro de Pasco, Peru (4,340 m), with or without erythrocytosis
(Hb 21 g/dl). Additionally, measurements of the gonadotropins (LH and FSH), the serum levels of 17-hydroxyprogesterone, a testosterone precursor, and the serum estradiol level, a
testosterone metabolite, were taken. Estradiol is a major female
hormone; however, recent studies have suggested a physiological role in men (2, 23, 32, 35).
Currently, therapeutic strategies for CMS are scarce and
include displacement of residence to lower altitudes, repetitive
blood letting, and administration of drugs such as medroxyprogesterone, enalapril, almitrine, or acetozolamide (43). However, no pharmacological or medical treatment is completely
effective (41). Therefore, it is important to study other factors
that could play a role in CMS etiopathogeny.
MATERIALS AND METHODS

Subjects. Seventy adult men aged 35 65 yr volunteered to participate in this study. Forty-two men were born at high altitude (2,000
m) and had spent 30 yr living in Cerro de Pasco (4,340 m), and 28
were born in and live in Lima, Peru, at 150 m.
The study was approved by the Institutional Review Board at the
Universidad Peruana Cayetano Heredia. Informed consent was obtained from each participant in the study. Men were not receiving any
medication for 3 mo before the study, nor had they had phlebotomy
during the year prior to the study. They represent a prospective cohort.
Subjects were excluded from the study if they had pathologies that
could aggravate the erythrocytosis, such as smoking habit, chronic
obstructive pulmonary disease, cardiovascular and renal diseases, or
BMI 25, or if they had received medication in the last 3 mo.
Sample size. Sample size was calculated with an -error of 0.05
and a power of 80%.
Experimental protocol. A basal venous blood sample was drawn
from an antecubital vein of each subject between 0800 and 1000 by a
trained professional. Immediately thereafter, 1,000 IU of hCG (Pregnyl; Organon) was intramuscularly injected into each participant.
Then, venous blood samples were drawn at 6, 12, 24, 48, and 72 h
after a single hCG injection.
Survey. The sociodemographic variables were recorded through a
questionnaire that included alcohol, coffee and/or tobacco consumption, and time of residence at high altitude.
BMI. Height and weight were obtained from each subject, and BMI
was calculated as kg/m2.
Serum hormone measurements. Venous blood samples were allowed to clot and then centrifuged at 1,000 g for 10 min at room
temperature to obtain serum that was immediately stored at 20C
until assayed for hormonal analysis. Basal serum values of FSH, LH,
thyroid hormones, DHEAS, Epo, 17-hydroxyprogesterone, total testosterone, and estradiol in Lima and Cerro de Pasco were evaluated.
Testosterone, estradiol, and DHEAS were also measured after a
stimulus with an intramuscular injection of 1,000 IU hCG (Pregnyl) at
0, 6, 12, 24, 48, and 72 h. DHEAS and DHEA are readily interconvertible in the human body. Moreover, serum dehydroepiandrosterone
(DHEA) and DHEAS levels were significantly elevated after the
DHEA administration in men (54).
Triiodothyronine (T3), thyroxine (T4), total testosterone, estradiol,
17-hydroxyprogesterone, and DHEAS were measured by radioimmunoassay using commercial kits (Diagnostic Products, Los Angeles,
CA). LH and FSH were measured by immunoradiometric assay using
commercial kits from Diagnostic Products. The hormone labeled with
125
iodine was used as radioactive marker. Erythropoietin was measured by chemiluminescence using Immunolite kits. The results are
expressed as mIU/ml.
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Characteristics of the assays as within-assay variation, betweenassay variation, and sensitivity for each hormone measured are shown
in Table 1.
Hb measurement. Hb concentration was measured on site with a
HemoCue (Anglholm, Sweden) system. The hematocrit was measured
in each sample with the microhematocrit method. The coefficient of
determination between Hb measurement and hematocrit was 0.99.
Data presented in this paper were based only on Hb measurements.
Subjects from Cerro de Pasco were grouped according to their Hb
levels: Hb 16 21 g/dl (n 20) or Hb 21 g/dl (EE; n 22).
Pulse oxygen saturation. The arterial oxygen saturation was measured in the second left finger by pulse oximetry using a Nellcor N-20
oximeter (Pleasanton, CA). This equipment also provides heart rate
value.
Blood lead levels. The blood sample was obtained by vein puncture
(vacutainer) and collected in tubes containing EDTA. Disposable
materials were used for each participant, and they were lead free. The
anodic voltimetry technique (Lead Care, Chelmstord, MA) was used
to determine blood lead levels. Values were expressed as g/dl.
Statistical analysis. Results were recorded in a database in Excel
and analyzed using the statistical package Stata (version 8.0; Stata,
College Station, TX). Data are expressed as means SE. The
homogeneity of variances has been determined with the Bartlett test.
If homogenous, analysis of variance (ANOVA) test was used to
determine differences among groups. If there were differences, the
mean comparisons between each one of the groups were determined
using the Scheffe test. The variables with no homogenous distribution
were analyzed using the Kruskal-Wallis nonparametric test. The
comparisons between pairs of medians were determined using the
Mann-Whitney U-test.
Multiple regression analyses have also been performed. Response
to hCG stimulation was assessed by two-way ANOVA. Then, differences between pairs of groups or pairs of periods after injections were
assessed. A P value of 0.05 is considered to be statistically significant.
RESULTS

Basal studies. Comparisons of basal characteristics between

men at low altitude and at high altitude are in Table 2.
Statistical analysis showed that men at high altitude were
characterized by higher age (P 0.01), lower BMI (P 0.01),
high Hb levels (P 0.01), high blood lead levels (P 0.05),
low pulse oxygen saturation (SpO2; P 0.01), high serum
levels of 17-hydroxyprogesterone (P 0.01), testosterone
(P 0.01), estradiol (P 0.05), and Epo (P 0.01), and low
serum levels of DHEAS (P 0.01). Serum LH, FSH, T3, and
T4 were similar at low and at high altitudes (P 0.05).
Table 1. Characteristics of the assays to serum
hormone measurements
Serum Hormone

Within-Assay
Variation, %

Between-Assay
Variation, %

Sensitivity

17-OHP
Erythropoietin
Estradiol
Total T4
Total T3
DHEAS
Total testosterone
FSH
LH

6.7
5.8
7.0
2.8
5.9
4.4
5.0
2.2
1.6

11
6.3
8.1
4.2
6.6
6.3
6.7
5.7
3.3

0.07 ng/ml
1.0 mIU/ml
8 pg/ml
0.25 g/dl
7 ng/dl
1.1 g/dl
4 ng/dl
0.06 mIU/ml
0.15 mIU/ml

17-OHP, 17-hydroxyprogesterone; T4, thyroxine; T3, triiodothyronine;

DHEAS, dehydroepiandrosterone sulfate.

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E1321

Table 2. Age and some physiological and hormone

characteristics of adult men evaluated in Lima (150 m)
and Cerro de Pasco, Peru (4,340 m)
Variables

Low Altitude (n 28)

High Altitude (n 41)

Age, yr
42.431.24
47.341.17*
Body mass index, kg/m2
28.190.73
24.330.44*
Hemoglobin, g/dl
14.240.16
21.140.39*
%Pulse oxygen saturation
98.50.2
86.40.6*
Heart rate, beats/min
73.51.6
71.31.5
Blood lead level, g/dl
4.10.3
6.10.4**
LH, mIU/ml
5.050.67 (4.02)
4.050.39 (3.91)
FSH, mIU/ml
4.630.46 (3.91)
5.320.34 (4.99)
Total testosterone, ng/dl 224.1042.99 (103.00) 428.5241.2* (369.5)**
Estradiol, pg/ml
27.903.64 (25.58)
52.166.60* (34.34)**
17-OHP, ng/ml
0.270.07 (0.12)
0.880.08* (0.75)**
DHEAS, g/dl
213.9518.18 (201.65) 113.9229.6* (80.08)**
109.032.65 (112.10) 100.713.25 (102.10)
T3, ng/dl
T4, g/dl
10.120.33 (10.44)
9.560.37 (9.96)
Erythropoietin, mIU/ml
12.61.0 (11.8)
31.63.6* (25.9)

Fig. 1. Serum testosterone/dehydroepiandrosterone sulfate (T/DHEAS) ratio

in men from Lima and Cerro de Pasco, Peru, with Hb values 16 21 g/dl
(CP-1) and 21 g/dl (CP-2). Data are means SE. *P 0.01 with respect to
Lima; **P 0.05 with respect to values in CP-2 (men from Cerro de Pasco
with Hb values 16 21 g/dl).

Data are means SE. DHEAS, DHEA sulphate. Low altitude: men from
Lima (150 m). High altitude: men from Cerro de Pasco (4,340 m); n no. of
subjects. Medians are in parentheses. *Students t-test, P 0.01; **rank-sum,
P 0.05 with respect to men at low altitude.

In Table 3 are presented data of men at high altitude grouped

according to Hb levels. Blood lead levels (P 0.01) and serum
testosterone levels (P 0.05) showed a significant increase for
the high-Hb group.
At HA, DHEAS levels showed a significant decrease for the
high Hb group (P 0.05). Age, BMI, SpO2, heart rate, serum
estradiol, and serum 17-hydroxyprogesterone levels were
similar between the groups with EE and without EE (Table 3).
The median Epo levels were similar in the groups with different Hb levels at high altitude (Table 3).
Serum testosterone/DHEAS ratio was significantly higher in
Cerro de Pasco than in Lima. The ratio showed a significant
increase according to Hb grouping in Cerro de Pasco (Fig. 1).
Sexual hormones and Epo association:. At HA, Epo levels
were not associated with serum testosterone (r2 0.04),
estradiol (r2 0.002, P 0.05), 17-hydroxyprogesterone
(r2 0.09, P 0.05), or DHEAS (r2 0.07, P 0.05) levels
(Table 4).
Table 5 summarizes the regression models adjusted for age,
BMI, SpO2, heart rate, and blood lead levels. Serum testoster-

one (P 0.032) was directly related to increasing Hb levels at

HAs, whereas DHEAS levels (P 0.04) were inversely
associated with increasing Hb levels at HAs. Epo levels in
serum were not related to Hb values in men at high altitude
(P 0.57).
hCG stimulation. For the assessment of hormone response to
hCG stimulation, serum estradiol and serum DHEAS were
submitted to logarithmic transformation before analysis.
Figure 2 shows the response of men at low altitude and high
altitude to 1,000 IU hCG.
Data have been assessed by two-way ANOVA to determining differences between groups and differences between times
of hCG stimulus. All hormones showed differences between
groups and time.
Post hoc analysis showed that serum 17-hydroxyprogesterone values were similar at all times after hCG in both groups
at high altitude. However, values were higher than at sea level
at all times after hCG (P 0.05). The three curves for DHEAS
were different (P 0.01 between men at low altitude and men
with Hb 21 g/dl; P 0.05 between men at low altitude and
men with Hb 16 21 g/dl; P 0.05 between men with Hb
16 21 g/dl and men with Hb 21 g/dl).
Testosterone response to hCG at low altitude was similar to
the curve in the group at high altitude with Hb 16 21 g/dl
except at 48 h (P 0.01). Values at low altitudes were lowest
at all times with respect to values in men with Hb 21 g/dl

Table 3. Characteristics of the variables studied in men at high altitude grouped according hemoglobin levels
Variables

CP-1 (n 20)

CP-2 (n 21)

Age, yr
Body mass index, kg/m2
%Pulse oxygen saturation
Heart rate, beats/min
Blood lead level, g/dl
LH, mIU/ml
FSH, mIU/ml
Total testosterone, ng/dl
Estradiol, pg/ml
17-OHP, ng/ml
DHEAS, g/dl
T3, ng/dl
T4, g/dl
Erythropoietin, mIU/ml

45.101.68
24.780.64
87.80.7
69.42.0
5.10.3
3.850.38 (3.91)
5.530.53 (5.62)
328.1453.23 (242.68)
50.229.19 (32.95)
0.770.10 (0.58)
148.9519.11 (140.80)
98.093.29 (100.64)
10.220.45 (9.99)
27.83.1 (25.9)

49.481.52
23.910.61
85.20.9
73.22.4
7.10.5*
4.340.74 (3.89)
5.110.43 (4.91)
524.1355.91b (467.62)**
53.929.71 (35.88)
0.960.12 (0.77)
83.8514.60b (80.08)**
103.065.50 (104.70)
8.830.56 (8.90)
35.05.1 (26.9)

Data are means SE. CP-1, men from Cerro de Pasco with hemoglobin values 16 21 g/dl (without excessive erythrocytosis); CP-2, men from Cerro de
Pasco with hemoglobin 21 g/dl (excessive erythrocytosis). Medians are between parentheses. *P 0.01; **P 0.05 with respect to high altitude.
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Table 4. Linear regression analysis between serum

erythropoietin levels and sex hormones in adult men at high
altitude
Serum Erythropoietin Levels Vs.

Linear Regression Equation

r2

17-OHP
DHEAS
Testosterone
Estradiol

20.24X16.83
0.14X50.95
0.02X24.21
0.03X33.09

0.09
0.07
0.04
0.002

0.05
0.05
0.05
0.05

r2 Coefficient of determination.

(P 0.01). Testosterone values were higher in the group with

Hb 21 g/dl than in the group with Hb 16 21 g/dl at all
times except at 48 h (P 0.05). Serum estradiol values were
similar at all times after hCG in both groups at high altitude.
However, values were higher than at sea level at all times after
hCG (P 0.05).
DISCUSSION

In the present study, the SpO2 value was lower at high

altitude, but, as previously reported (48), it is not further
decreased in the group with EE. This may indicate the existence of an additional factor to the oxygen desaturation to
continue with erythropoietic stimuli to produce EE at high
altitude. However, it is also possible that no significant decrease in SpO2 might be caused by too-large scattering or
too-small sample.
Men with EE at high altitude have higher blood lead levels
and higher testosterone levels than men at high altitude without
EE. On the contrary, DHEAS levels are lower, whereas the
Epo, LH, FSH, and thyroid hormones levels do not differ
between groups with different hemoglobin levels at high altitude. Although hypothyroidism was associated with hypoventilation (29), the present data do not support a role for thyroid
hormones in men with EE. In fact, serum thyroid hormones
were similar in men with and without EE at high altitude.
The population studied at high altitude was residing in Cerro
de Pasco, Peru, located at 4,340 m altitude. Cerro de Pasco is
a mining city, and for that reason it is not rare to find higher
blood lead levels in its population. Surprisingly, the group with
highest hemoglobin levels has a higher lead blood level.
However, mean blood lead levels were within normal concentrations (25 g/dl). Studies in lead-contaminated regions
have not observed an association between blood lead and
hemoglobin levels in adult women (37). The -aminolevulinic
acid dehydratase (ALAD) seems to regulate the lead action in
the organism. The carriers of the ALAD2 allele have higher
blood lead levels and higher hemoglobin levels than the carriers of the ALAD1 allele (22, 47). It is possible that ALAD2
allele is more frequent in the group with EE, which would
explain the presence of the highest lead and hemoglobin levels
in this group compared with those without EE; however, this
must be experimentally demonstrated.
Epo is known to be increased after acute exposure to high
altitude (16), and it is reduced when native men at high altitude
descend to sea level (40). Although the Epo is known as a
hormone that regulates erythropoiesis, the studies oriented to
demonstrate their participation in EE in natives at high altitude
are not conclusive (25, 49, 52). According to our results, adult
male residents at high altitudes greater than 4,000 m have
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higher Epo levels than men at low altitudes. This confirms the
role of Epo in stimulating erythropoiesis in hypoxia conditions.
However, when Epo is studied in subjects with different
hemoglobin levels at high altitude, there is no further increase
in Epo levels. This may indicate that Epo is not responsible of
the EE observed at high altitude. In addition, neither systemic
studies nor molecular studies of Epo and Epo receptor expression find an association between the polymorphisms related to
these genes and EE (28).
Instead, our results demonstrate that basal serum testosterone, estradiol, and 17-hydroxyprogesterone levels are higher
in Cerro de Pasco than in Lima. Furthermore, in natives at high
altitudes, testosterone levels are higher in men with EE than in
those without EE. These results were also associated with
lower DHEAS levels. In women at higher altitudes, an increase
in hemoglobin levels was associated with an increase in serum
testosterone (14). This may indicate that a higher bioandrogenic activity at high altitude could explain the EE observed in
the Peruvian Andean population. An inverse relationship between serum testosterone levels and oxygen saturation has also
been observed in obese men with obstructive sleep apnea at sea
level (12). Sleep apnea is a condition associated with EE and
CMS at high altitudes (36). Therefore, it is possible to expect
an association between elevated serum testosterone levels with
high erythropoiesis.
Previously, it has been suggested that high testosterone
concentrations such as those in the upper ranges of sea level
values could compromise adaptation to high altitude, particularly among older men (3). Our study demonstrates for the first
time that serum testosterone levels have higher values (basal
and hCG stimulated) in EE compared with men without EE at
high altitudes.
Testosterone, after acting, is converted to estradiol by the
aromatase enzyme. Estradiol and progesterone have been used
as respiratory stimulators to reduce hypoventilation and improve erythropoiesis (44). However, testosterone may reduce
their effect by downregulating estradiol and progesterone receptors (45). In that circumstance, high testosterone levels at
high altitudes may blunt the estradiol and progesterone actions
on ventilation favoring hypoventilation and high stimulus for
erythropoiesis. Serum estradiol levels in older men are almost
similar to those observed in postmenopausal women of the
same age (32, 51). However, values in premenopausal women
are four to five times higher than in men and postmenopausal
women (32, 51).
Table 5. Models of multiple regression analysis for each
serum hormone to assess the hemoglobin values in adult
men at high altitude (4,340 m)
Hemoglobin

Coefficient of
Regression

SE

Confidence
Interval (at 95%)

Serum testosterone
Serum estradiol
Serum 17-OHP
DHEAS
Eryhtropoietin
T/DHEAS ratio

0.003
0.67
1.14
0.28
0.39
1.26

0.001
0.51
0.69
0.13
0.68
0.36

0.03
0.20
0.11
0.04
0.57
0.001

0.0002 0.005
1.72 0.37
0.26 2.54
0.55 0.01
1.79 1.00
0.54 2.00

T/DHEAS, testosterone/dehydroepiandrosterone sulfate. Each line represents a model in which age, pulse oxygen saturation, body mass index, heart
rate, and blood lead levels were adjusted.

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E1323

Fig. 2. Response of men at low altitude (150 m) and at high altitude (4,340 m) to 1,000 IU of a single intramuscular injection of human chronic gonadotropin.
Men from high altitudes have been grouped according to Hb levels. Men from low altitudes have been considered as control, and men from high altitudes have
been grouped according to Hb levels in Hb 16 21 g/dl and Hb 21 g/dl. A: serum response of 17-hydroxyprogesterone (17-OHP) levels. B: response of serum
DHEAS. C: response of serum testosterone. D: response of serum estradiol levels. For analysis, estradiol levels and DHEAS levels were logarithmically
transformed. Data are means SE.

Testosterone is produced in the Leydig cells from one of its

precursors, the 17-hydroxyprogesterone (1). The process of
androgenesis indicates that 17-hydroxyprogesterone is converted in several steps to dehydropeiandrosterone sulfate, and
then after one step more it is converted to testosterone. Because
17-hydroxyprogesterone is increased at high altitude with
respect to sea level, this elevation indicates that the process of
producing testosterone at high altitude is elevated since the
precursor, 17-hydroxyprogesterone, was elevated. Because
serum LH level was not different between groups with increasing hemoglobin levels at high altitudes, it suggests a higher
response to gonadotropin stimulus in men with EE at high
altitude, as confirmed after the stimulus with 1,000 IU of hCG.
In vitro studies showed that proliferation of Leydig cells and
testosterone release was enhanced significantly by hypoxia.
During hypoxia, administration of hCG also enhanced proliferation of Leydig cells and testosterone release (20).
DHEAS is readily convertible to DHEA (39). DHEA by
action of the 3-hydroxysteroid dehydrogenase (15) is converted to androstenedione, and this by the 17-hydroxysteroid
dehydrogenase (4) is metabolized to testosterone. Differences
in testosterone/DHEAS ratio between EE and the non-EE
group suggest a higher conversion rate from DHEAS to androstenedione and then to testosterone. A higher conversion
from androstenedione to testosterone has been observed in
women at high altitudes compared with women at low
altitudes (14). It is probable that natives not adapted to live
at high altitude (CMS) have higher activity of 17-hydroxysteroid and probably 3-hydroxysteroid, promoting a
AJP-Endocrinol Metab VOL

higher conversion to testosterone under basal and hCGstimulated conditions.

At sea level, it is known that gonadotropin stimulation
increases serum levels of both DHEAS and testosterone (39).
Then, at high altitudes, a situation in which serum levels of
DHEAS are low and serum testosterone values are high suggests a higher conversion rate from DHEAS to testosterone in
this particular group.
CMS has also been associated with pulmonary hypertension
(36). DHEA and DHEAS are pulmonary vasodilators, and they
inhibit hypoxic-induced pulmonary hypertension (6, 17). Low
serum DHEAS levels could be associated with the pulmonary
hypertension observed in patients with CMS at high altitudes (36).
High DHEAS levels have been associated with coronary
disease (18). The low DHEAS levels at high altitude compared
with sea level could explain the low prevalence of coronary
diseases at high altitude (33) and in part be protective for this
pathology at high altitude.
This evidence suggests the possibility for new therapeutic
strategies, including administration of DHEAS/DHEA or reducing the activity of the 17-hydroxysteroid enzymes.
In summary, EE is associated with high serum testosterone
and testosterone/DHEAS ratio. It is confirmed that Epo is
responsible for increasing hemoglobin production at high altitude, but an effect on excessive erythrocytosis is discarded.
ACKNOWLEDGMENTS
The technical support from Julio Rubio is acknowledged. We also thank the
volunteers who participated in the studies for their time and effort.

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TESTOSTERONE ON ETIOPATHOGENY OF EXCESSIVE ERYTHROCYTOSIS

GRANTS
This study was supported by a grant from the Fogarty Program of The
National Institutes of Health (NIH Research Grant No. 5-D43-TW-005746-04,
funded by the Fogarty International Center, the National Institutes on Environmental Health Services, the National Institute for Occupational Safety and
Health, and the Agency for Toxic Substances and Disease Registry).
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