Endocrinology of reproductive function and pregnancy at high altitudes

Journal Pre-proof Endocrinology of reproductive function and pregnancy at high altitudes Victor H. Parraguez, Antonio Gonzalez-Bulnes PII:

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DOI:

https://doi.org/10.1016/j.coemr.2019.12.006

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To appear in:

Current Opinion in Endocrine and Metabolic Research

Received Date: 6 November 2019 Revised Date:

17 December 2019

Accepted Date: 23 December 2019

Please cite this article as: Parraguez VH, Gonzalez-Bulnes A, Endocrinology of reproductive function and pregnancy at high altitudes, Current Opinion in Endocrine and Metabolic Research, https:// doi.org/10.1016/j.coemr.2019.12.006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Ltd. All rights reserved.

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Endocrinology of reproductive function and pregnancy at high altitudes

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Victor H. Parraguez1,2, Antonio Gonzalez-Bulnes3,4*

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1

Faculty of Veterinary Sciences, University of Chile, Santiago, Chile

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2

Faculty of Agrarian Sciences, University of Chile, Santiago, Chile

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3

Comparative Physiology Lab-RA, SGIT-INIA, Madrid, Spain

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4

Faculty of Veterinary Medicine, UCM, Madrid, Spain

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* Corresponding author. E-mail address: [email protected]

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Abstract

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Reproductive function and therefore fertility, both in females and males, are affected by

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the high altitude environment. Hypobaric hypoxia affects functionality of the

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hypothalamus-hypophysis-gonads axis, sperm quality, cyclic ovulatory activity and

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quality of preovulatory follicles/oocytes/corpora lutea/embryos. Hence, chances for

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obtaining pregnancy are diminished in humans and animals living at high altitude.

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Occurrence of Intrauterine Growth Restriction (IUGR) is around 3-fold higher than at

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low altitude. Most of these deficiencies are related not only to hypoxia but also to

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increased oxidative stress. Hence, supplementation with antioxidant agents may

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constitute a useful strategy.

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Keywords: antioxidants, fertility, high-altitude, oxidative-stress, pregnancy.

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1. Introduction

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Reproduction is one of the biological functions most sensitive to changes of the

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environment. Hence, both direct (temperature and photoperiod) and indirect (food

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availability) environmental changes have strong impact on reproduction. Humans have

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succeeded to master environment and to be independent from most of these factors. The

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majority of the other animal species have developed reproductive strategies, like

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seasonal reproduction, for diminishing the effects of such environmental factors. In

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contrast, hypoxia is an unavoidable environmental factor for human and animal

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populations living at high altitude. Hypoxia has ineludible effects on reproductive

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function in both humans and domestic animals (mainly sheep introduced to high-

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plateaus), so the reproductive success of individuals is highly reduced when compared

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to low-altitude counterparts [1, 2].

38 39

The present short review article discusses the influence of hypobaric hypoxia on female

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and male fertility, considering effects on the functionality of the hypothalamus-

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hypophysis-gonads axis, sperm quality, cyclic ovulatory activity, quality of

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preovulatory follicles/oocytes and corpora lutea and/or subsequent pregnancy.

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2. Effect of high altitude on reproductive function and fertility

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Fertility is the fundamental cue in reproductive success, though the study of the effects

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of hypoxia on fertility of populations living at high altitudes has received less attention

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from scientists than pregnancy and birth outcomes. However, from a historical

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perspective, fertility was one of the first and main features found to be affected by the

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high altitude environment. Former chronicles indicate that, after arrival of the Spanish

2

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conquerors to Peru, they had problems for achieving descendants. Consistently, the

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historian Antonio de la Calancha in his chronicle entitled “Cronica Moralizadora de la

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Orden de San Agustín” (Moralizing Chronicle of Saint Agustin Order) published in

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Spain in 1639, reported that the first birth and survival of a child from a Spanish couple

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at high altitude (Potosi; 4300 meters above sea level, m.a.s.l.) occurred 53 years after

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the arrival of the Spaniards to Peru, which evidence serious reproductive difficulties in

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the newcomers. Moreover, the Spaniards moved the Peruvian capital from Jauja (3400

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m.a.s.l.) to Lima (150 m.a.s.l.) due, in part, to the reproductive difficulties experienced

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by them and their imported animals [3, 4], which constitutes the first documented

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recognition of the deleterious effect of high altitude on mammalian reproduction.

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Over the past century, a large body of observations made by the Peruvian scientist Dr.

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Carlos Monge led him to propose that low oxygen pressure reduces fertility (number of

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live births), perhaps by reducing fecundity (capacity of conceive) and/or increasing fetal

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loss (cited by [5]). More recent findings in humans show that residence at high altitude,

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both in the American Andes [6-9] and in Asian highlands [10, 11], may reduce fertility.

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Contemporary observations describe that Han, a Chinese population recently arrived

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(~50 years ago) to the Tibet region from the sea level, also experience reproductive

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difficulties nowadays [12].

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In summary, the impact of this phenomenon is huge, because approximately 140 million

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people lives at altitudes higher than 2500 m.a.s.l. and another 40 million people visit

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these regions yearly [13], and because sheep are a major economical resource for

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approximately 25 million rural people living above 2500 m.a.s.l. in developing regions

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such as the Andean and Qinghai-Tibetan high-plateaus [14]. In this sense, European

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settlers introduced sheep to the Andean highlands approximately 500 years ago and,

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currently, the reproductive efficiency in high altitude native herds still remains very

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poor, in spite of the prolonged period of adaptation. Such low reproductive efficiency is

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even more marked in ovine newcomers to high altitude [2], which limits the application

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of genetic improvement programs to introduce selected animals and increase

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productivity.

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Most of the research on the effects of hypoxia on reproductive function and pregnancy

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is based on observational studies, so data are commonly biased by concurrent factors

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(economic impoverishment, malnutrition, behavioral and socio-cultural factors [15]).

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Hence, there is a need for both comparative studies of high- and low-altitude

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populations and interventional studies under well-determined conditions isolating

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physiological causes and concurrent factors. However, such an objective cannot

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obviously performed on humans and can only be performed on animal models. In this

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scenario, sheep have a prominent role with a dual purpose. First, from a production

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perspective, for increasing fertility and productivity of the herds maintained at high-

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altitude; second, because sheep provide a widely recognized biomedical model for

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reproductive studies [16].

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Currently, as we recapitulate in the following sections, a large body of observational

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and experimental studies on the effect of hypobaric hypoxia on reproductive

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physiological and morphological characteristics of the hypophysis-gonad axis

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demonstrate that both chronic and acute exposure to hypoxia affect this axis and both in

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males and females.

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3. Effect of high altitude on male reproductive function

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High altitude has been found to have main deleterious effects on the endocrine function

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of the hypophysis-testes axis and on the exocrine function of the testes, affecting sperm

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quality and fertility.

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In this way, an early research assessing Sherpa population in Nepal [17] reported that

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high-altitude residents have higher follicle stimulating hormone (FSH) and testosterone

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and lower luteinizing hormne (LH) serum concentrations than low-altitude residents.

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Sherpa men living at low altitude showed increases in FSH and LH blood levels but

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decreased blood testosterone concentrations after being acutely exposed to high altitude.

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After around 10 days of exposure to high altitude, the FSH levels were reduced about

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50%, LH levels decrease to be undetectable and testosterone reached an intermediate

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level between low and high altitude residents. Similar results on LH and testosterone

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changes were described in a similar study but, conversely, no changes in FSH levels

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during exposure to high altitude were found [18]. Exposure of male rats to artificial

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hypobaric hypoxia equivalent to about 4600 m.a.s.l. induced a significant increase in

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plasma FSH at Day 5 of hypoxia and, although FSH levels diminished afterwards, there

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was a trend to be higher than in control at sea level along the 30 days of trial. Plasma

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LH and testosterone, in contrast, underwent a marked decrease during the whole period

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of hypoxia exposure [19].

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High altitude also affects sexual libido, semen quality and even testicular

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characteristics, as found in humans [20], sheep [21] and rats [22]. In fact, male rats

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exposed to hypobaric hypoxia have a significant decrease in the height of germinal

5

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epithelium only five days after induction of hypoxia and, by Day 30, an important

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decrease in testicular mass but a substantial increase in testicular vascularization are

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also observed.

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However, it seems that such effects in behavior and ejaculates, like in the endocrine

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axis, are at least partially overcome in males by adaptation to hypoxia [3]. The most

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current studies [23] addresses that males exposed to high altitude have impairments of

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the oxidative/antioxidant status in plasma and seminal fluid, effects which concurrently

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decrease semen quality. Administration of antioxidant agents has beneficial effects on

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blood and semen oxidative status, as well as in semen quality.

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4. Effect of high altitude on female reproductive function

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The high altitude has also been found to have a prominent effect on female fertility,

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through changes in endocrine patterns and ovarian function. Fertility is strongly

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conditioned by fecundity (capacity for conceiving), but the research on the effects of

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high altitude on fecundity and, specifically, on ovarian activity is really scarce. The

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available data on humans are only based on observational and epidemiological studies

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and some evaluation of steroids in saliva or urine studying duration and regularity of the

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menstrual cycle [5, 24]. In ewes, a seminal study at high-altitude [2] indicated that 82%

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of the native ewes but only 32% of the newcomers had regular estrus and ovulation;

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finally, 48% of the native sheep but none in the newcomers group become pregnant.

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Such stronger fertility failures after short-term exposure to hypobaric hypoxia in sheep

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newcomers to high altitude has been related to deleterious effect on both the ovarian

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function, by affecting preovulatory follicular development and corpus luteum quality,

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and the pituitary function, by diminishing plasma LH availability [25, 26]. On the other

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hand, these effects of hypoxia were not detected in sheep adapted to high altitude for

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generations (conversely, LH secretion was found to be increased), which suggests

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adaptive mechanisms.

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It is worthy to note that, in both women and sheep at high altitude, plasma progesterone

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concentrations are augmented despite a smaller size of the corpus luteum. The causes

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are still not elucidated, but such increased plasma progesterone concentrations may be a

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concomitant cause compromising female fertility by affecting the final development and

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maturation of the ovulatory follicle in the following cycle, which in turns compromises

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its ability to ovulate an oocyte competent to be fertilized and develop into a viable

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embryo [27]. In any case, hypoxia also compromises oocyte competence and therefore

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fertility. Data from in vitro fertilization procedures in women have shown that hypoxic

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oocytes, occurring during in vitro maturation, result in embryos that arrest development

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during early cleavage stages so pregnancy success is very low [28, 29].

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In addition, in a similar way to males, the effects of altitude on the preovulatory follicles

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of high-altitude naïve females may be related to oxidative stress. In sheep, experimental

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data indicate that supplementation with antioxidant vitamins for the time of

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folliculogenesis (approximately 45 days) avoids such effects [26]. Conversely, there is

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absence of significant effect of antioxidant vitamins on the anatomical and functional

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characteristics of corpus luteum exposed to high altitude [25], which suggests that the

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effects on this structure are mainly mediated by hypoxia.

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5. Effect of high altitude on pregnancy

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Occurrence of pregnancy at high altitude is strongly compromised by a decreased

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fertility, as described above. If reached, pregnancies developed at high-altitude are

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characterized by maternal and therefore fetal hypoxia. However, the adequate supply of

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nutrients and oxygen to the fetus is the critical point for an adequate development of the

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pregnancy and, in case of inadequate supply of nutrients and/or oxygen, the fetus slows

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down its growth inside the uterus, a condition named as Intrauterine Growth Restriction

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(IUGR; [30]). Appearance of IUGR results in a low birth-weight (LBW) neonate.

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Occurrence of IUGR by high-altitude, independently of other concomitant social and

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economic factors [31-33] is estimated at around 17%, whilst IUGR at low-altitude is

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estimated at 6.0% [34]. The impact of IUGR is so high that, worldwide, is the second

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cause of neonatal morbidity and mortality after prematurity [35], so IUGR is the main

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cause of the increased infant mortality found among communities living at high altitude

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[36, 37].

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Hence, conversely to fertility, the occurrence of neonatal mortality has strongly weighed

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for the development of numerous studies on the deleterious effects of altitude on

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pregnancy. The impact is very high because, as we previously said, around 140 million

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people live at high altitude. Moreover, there are another 40 million of visitors, among

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them many pregnant women, and abundant data indicates aggravated effects in

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newcomers to high altitude [37-40]. In fact, epidemiological data show that the risk of

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IUGR, premature birth, low birth-weight and infant mortality is higher in individuals

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exposed to high-altitude conditions for short periods [31, 37].

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In the case of visitors, the occurrence of IUGR is generally considered to occur during

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late pregnancy, and it is believed that visiting altitude is not detrimental to healthy

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early-pregnant women (e.g.: Consensus Statement of the UIAA Medical Commission;

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http://www.theuiaa.org/upload_area/files/1/UIAA_MedCom_Rec_No_12_Women_at_

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Altitude_2008_V1-2.pdf). However, there is evidence in sheep that both long- and

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short-term exposure to high altitude cause disturbance in maternal ovarian stereidogenic

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function and negatively affect offspring growth from conception and early embryo

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stages [41], so short-term exposure may also affects women in early stages of

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pregnancy.

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The sheep is especially interesting for pregnancy studies owing to its similarities to

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humans, including singleton pregnancies and a similar developmental trajectory [16, 42]

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and the possibility of interventional studies in controlled environments. Sheep

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pregnancies at high altitude are characterized, like in humans, by a higher incidence of

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asymmetric IUGR [43] and lower birth-weight and postnatal growth [44], especially in

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newcomers to altitude [44, 45], as is also the case in humans [12, 38, 39].

216 217

There are adaptive changes in the placenta for coping with the lack of oxygen, including

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increased placental weight and size and vascularization [45]. In addition, chronic

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hypoxia up-regulates the expression of placental angiogenic factors Vascular

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Endothelial Growth Factor (VEGF) and endothelial Nitric Oxide Synthase (eNOS) [46],

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which added to the other placental changes, constitute physiological adaptations to

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improve the maternal-fetal gas interchange. These observations are, in general,

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consistent with those described by different authors in human population at high altitude

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[30-34, 38, 39, 47-52].

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It is also necessary to have in mind that all the processes of neovascularization and

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angiogenesis are regulated by steroid hormones in mammals [53]. The placenta has an

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active role in the secretion of its own steroids [54] and, specifically in sheep, pregnancy

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is supported by placental steroidogenesis from Days 50–60 onwards [55]. In sheep

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models, placental steroid secretion has been found disturbed both during early and late

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pregnancies in females exposed to high-altitude, which negatively influences the fetal

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development [41, 56].

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Pregnancy traits, in a similar way to other pregnancy traits, may be improved by

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administration of antioxidant agents as vitamins C and E, improving placental

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steroidogenesis, placental function and increasing newborn weight and viability [41, 56,

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57].

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In conclusion, exposure to high altitudes significantly affects the function of the

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hypothalamic-pituitary-gonad axis in mammals, leading to decreased fertility. The

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factors that mostly explain the low reproductive efficiency are hypobaric hypoxia and

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oxidative stress secondary to hypoxia, where antioxidant therapy has shown to have

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beneficial, although partial, effects to prevent the effects of high altitude on

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reproductive function.

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Funding: This work was supported by Projects FONDECYT 1020706, 1070405,

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1100189 and 1130181 from CONICYT; Project DID- ENL 06/2 from Universidad de

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Chile; Projects AECID A/023494/09 and A/030536/10) from Spain Government.

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Declaration of interest: None

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** Both long- and short-term exposure to high-altitude causes disturbances in

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maternal ovarian steroidogenesis and negatively affects embryo-fetal growth

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** Sheep pregnancy in high-altitude environments frequently involves hypoxia and

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oxidative stress and causes intrauterine growth restriction. The administration of

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antioxidant vitamins in the present study enhanced placental steroidogenesis, thus

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favouring fetal development in pregnancies developing at high altitudes.

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Endocrinology of reproductive function and pregnancy at high altitudes Victor H. Parraguez and Antonio Gonzalez-Bulnes declare that there is no conflict of interest.

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