reproduction

Physiological and Evolutionary Mechanisms of Fertility at High Altitude: Part 1

High altitudes have the potential to negatively impact normal bodily functions of individuals who are both accustomed, or not properly acclimated, to such environments. Air deficient in oxygen, colder temperatures, greater exposure to solar radiation, and higher energetic costs of subsistence compared to that of lowland environments are potentially detrimental to physiological function. Similarly, high-stress environments with riskier living conditions may lead to economic disparities and locally specific cultural practices. Despite these limitations, human populations have lived, and thrived, in high altitudes environments for thousands of years. I investigate how theses environmental stressors impact reproductive functioning and fertility of indigenous populations living at high altitude, particularly in the Andes and Himalaya Mountains. In particular, I assess whether or not altitude-related stressors and reproductive behaviors contribute to lower fertility rates among high altitude populations. Through analysis of the physiological, behavioral, and genetic properties of males and females living at high attitude, I argue that fertility rates are under strong evolutionary control that offset altitude-induced sicknesses (hypobaric hypoxia) thus limiting variation in fecundity among high altitude populations.

History of the Study of Fertility at High Altitudes

Populations and small-scale societies have a long antiquity at high altitudes, yet much of our early knowledge of whether or not males and females had normal reproductive fitness comes from chronicles written by Europeans colonizing the Andes. Archaeological investigations in the Andes are numerous and are ongoing (Rademaker et al., 2014), yet are still in a very early stage in the Himalaya Mountains (Aldenderfer, 2011). Similarly, studies of the genetic components associated with high-altitude living are novel avenues of investigation among researchers working with populations in both the Andes and Himalayas (Beall, 2006, 2007). Given this incomplete picture, fertility studies conducted among populations living in other high altitudes (e.g. ovulation among Mongolian females) will also be presented when relevant. Because both the Andes and Himalaya Mountains are both extreme high altitude environments, I will explore research on reproductive fitness from both areas while recognizing that the entire picture elucidating the nature of fertility at high altitudes remains incomplete.

It is generally assumed that the human ancestral phenotype of oxygen transport system evolved mainly in environments with normal oxygen levels, or “normoxia” at sea level (Beall, 2006; Hochachka et al., 1998). Geological, vegetational, and archaeological analyses of hominin fossil sites in rift valleys formations in Ethiopia spanning approximately 3 million years indicate that hominid habitation sites were at an altitude of 500-600 meters above sea level (masl), well below an altitude thought to induce hypoxic stress (Bonnefille et al., 2004; Redfield et al., 2003; Quade et al., 2004). Thus, it is assumed that hominid evolution occurred under normoxia, and the corollary that high-altitude hypoxia is a physiological stress seems reasonable (Beall, 2006).

Laguna Cullicocha (4635 masl)

Laguna Cullicocha (4635 masl)

Altitude stress, medically known as hypobaric hypoxia, is cased by the fall in barometric pressure with increasing altitude, resulting in fewer oxygen molecules in a breath of air compared to sea level (Beall, 2006). Barometric pressure decreases with ascending altitude, decreasing oxygen availability in ambient air. Conditions are especially prevalent in the altiplano/puna, a treeless, tundra-like landscape higher than 4000 masl, with little fuel for campsites, and is an area that requires twice the sea-level caloric intake needed to maintain normal metabolic function (Marriot, 1996). Hypobaric hypoxia becomes progressively more severe with increasing altitude and stresses biological systems because a steady, uninterrupted supply of oxygen is required for metabolism in the mitochondria (Beall, 2006). Aside from supplemental oxygen or descent, there is no such strategy to avert the effects of environmental hypoxia (Gonzales, 2007; Julian, 2011). Though hypobaric hypoxia is the most pervasive physiologic challenge associated with high-altitude exposure, lower humidity, colder temperatures, increased solar radiation, and high energetic costs of subsistence that also accompany higher elevations may also threaten physiological well-being and reproductive behavior (Baker and Little, 1976).

Despite these stressors, human populations have occupied high altitudes for thousands of years. Archaeologists have uncovered ample evidence of human residency in high altitude environments as early as 20,000 years ago (Rademaker et al., 2014). The Tibetan Plateau of the Himalaya Mountains exhibits archaeological evidence of worked stone (Aldenderfer, 2011) and handprints and footprints (Quesang site) at 4200 masl (Zhang et al., 2002). Butchered animal bones, stone artifacts, and small-scale hearths dating from 14,600 to 7500 calendar years before the present (cal yr B.P.) at Jiangxigou 1 (~3200 masl); Heimahe 1 (~3200 masl) (Brantingham and Gao, 2006); at Xidatan 2 (~4300 masl) (Brantingham et al., 2013); and at Yeniugou (3800 masl) in the northeastern part of the plateau (Tang et al., 2013).

Tibetan Plateau (approx 4500 masl)

The earliest archaeological evidence of human occupation in the South American Andes dates to as early as 10,000 to 12,000 years BCE (Rademaker et al., 2014; Bonavia, 1991). The Pucuncho Basin in the southern Peruvian Andes contains the highest-altitude Pleistocene archaeological sites yet identified in the world (4355 masl) dating to 12,800-11,500 (Rademaker et al., 2014). Additional evidence of human occupation above 4000m of altitude with an antiquity of 10,000 years also has been found at the sites of Lauricocha, Huanuco (3850m) (Cardich, 1960) and Telarmachay, San Pedro de Cajas (4400m) in the Peruvian Andes (Bonavia, 1991).

Spanish chroniclers began to note the effect high altitude environments in the Andes had on living organisms during the 16th and 17th centuries early after colonization of the New World. Conquistadors such as Cieza de Leon (1553) described much about life among the Inca during the Spanish conquest and noted that the Inca had a surprisingly high fecundity rate. It was evident that Spaniards could produce offspring up to 3400 masl, yet infertility and stillbirths were frequent among Spaniards living in settlements around and above 4000 masl (Gonzales, 2007). Early chroniclers such as de la Vega and Cobo were of the opinion that the altitude effects on organisms were mainly attributable to the cold (de la Vega, 1609; Cobo, 1653). De la Calancha (1639) remarked in his chronicle that in Potosi (4300 m), in modern-day Bolivia, the natives had normal fertility and the offspring survived, whereas Spaniards encountered problems in having descendants. In fact, it was not until 53 years after then Spaniards settled the Andes did de la Calancha (1639) describe the birth and survival of the first child from two Spaniards in Potosi (4300 masl). Overall, chroniclers found that indigenous Andean females maintained capacity to reproduce while Spanish colonists were reportedly unable to carry fetus to full term or experienced high infant mortality rates.

Drawing by Guaman Poma de Ayala (1615/1616)

Given the discrepancy of fertility rates between newcomers to the Andes and the indigenous peoples, local biologists, biological anthropologists, and geneticists began to investigate the manner in which high altitude environments impact reproduction. Yet, many studies tend to produce contradicting results. The first fertility studies investigated the effects of altitude on fertility among sheep, cattle, cats, and rabbits, and demonstrated that short-term exposure to high altitude resulted in temporary infertility (Monge, 1942, Monge and Mori- Chávez, 1942; Monge et al., 1945).Studies in the late 20th century have shown that fertility is lower in the economically underdeveloped areas of the Andes than in the more prosperous Spanish-speaking parts (Collins, 1983). Studies documenting the fecundity rate (as calculated by the number of viable offspring per female) among Peruvian highlanders has found to be from one to two births less than that of lowland Peruvians of the same ethnic background. In fact, highland natives who move to low altitudes show markedly higher rates of fertility than their counterparts who remain in the highlands (Abelson, 1976). Conversely, studies have also noted that population fertility appears to be unaffected among natives to high altitude environments (Hoff, 1984). A retrospective hospital-based study performed on women of La Paz (3600 m), Bolivia shows that high altitude does not impair fertility (Suarez-Morales, 1967). In fact, the number of viable offspring born per female in the Andes has also been documented to be higher amongst high-altitude populations compared to those at sea level, suggesting that high altitude does not reduce fecundity in human populations (Gonzales, 2007). Additionally, scholars have noted that highlanders of both the Andes and Himalayas have distinctive morphological and physiological characteristics that seemed adaptive in the sense that they might offset hypoxia stress (Baker and Little, 1976; Monge, 1978). Given the complex and sometimes conflicting nature of the fertility data, considerations of the physiological mechanisms of reproduction as well as behavioral and genetic profiles will elucidate the nature of fertility at high altitudes.

Physiological and Behavioral Impacts on Fertility and Reproduction

At high altitude, the oxygen transport system must offset ambient hypoxia in order to maintain tissue oxygen levels to support maintenance, growth and development, and reproduction. Altitude-induced stress, hypoxia in particular, may act to affect the process of reproduction at several stages: formation of gametes and gametogenesis, the ovarian cycle and menstruation, birth weights, still birth rates, infant mortality, post-partum behaviors, and age of menopause.  Assessing how hypoxic stress impacts fertility alone is problematic because fertility is also affected by many cultural, social, and behavioral factors. Populations residing at high altitudes may have less developed health, social, and communication infrastructures than those residing at sea level. These reproductive categories will be explored while considering socioeconomic disparities and cultural practices impacting fertility. Over the next few weeks, I will address each of these reproductive systems beginning with development and formation of gametes and testosterone levels.

Development and Formation of Gametes and Testosterone Levels

Delay in the development of and abnormal formation of gametes may also impact fertility. In particular, research has documented whether or not male reproductive functions are negatively affected during and after high altitude sojourns. Early studies conducted on guinea pigs taken to Morochocha, Peru (4500m), observed degenerative alterations in the seminiferous tubules, which serve a crucial role in the production of male gametes (Guerra-Garcia, 1959).

Exposure to hypoxia and physical stress of high altitudes may induce reversible spermatogenic and/or Leydig cell dysfunction, a condition that decreases testosterone production (Saxena, 1995). Analysis of gamete production conducted on three subjects who trekked for 21-24 days between 5100-6700 masl revealed an increased rate of abnormal sperm shape (Abramsson et al., 1982), which would present an important problem if the subjects wanted children (Okumura et al., 2003). Additionally, scholars have observed that sperm counts had not recovered 3 months after subjects returned from the expedition. Yet, all subjects had normal gamete production and formation after 2 years (Okumura et al., 2003). Okumura and colleagues (2003) also observed an increase in abnormally shaped sperm 1 month after the subjects returned to sea level. Sperm shape had nearly recovered to the pre-expedition state after 3 months (Okumura et al, 2003).

Mount Everest (8848 masl)

In addition to hypoxia, physical stress while trekking and carrying heavy loads may also contribute to the initial decline in testosterone levels (Okumura et al., 2003). Endocrine tests conducted on the three subjects revealed slightly lower levels of testosterone in the blood 1 month after the expedition and decreased still further after 3 months. After 2 years, testosterone levels were normal. The subjects in the study also complained of erectile dysfunction after returning from the expedition, which may have been partly due to decreased testosterone (Okumura et al., 2003).

Semen analysis and recorded reproductive hormone levels taken from seven male mountaineers trekking through the Himalayas (approximately 5900 masl) found that physical exercise at high altitudes is associated with a testicular dysfunction leading to a reduced sperm concentration probably through an altered spermiation (Pelliccione et al., 2011). Interestingly, the physical exercise improved the male’s overall body composition, which increased testosterone levels after the expedition (Pelliccione et al., 2011).

In sum, studies have demonstrated short-term exposure to high altitudes negatively impact male gamete formation and testosterone production, ultimately affecting his ability to reproduce. It should be noted, however, that male gametes production and testosterone levels return to normal once he returns to sea level for several months to 1-2 years.

These are very high altitudes where people do not reside. Historically and in the archaeological record, however, there is evidence that people would take occasional sojourns to high mountain summits in the Andes. Spanish chronicler Cobo (1653) described how the Inka embarked on ritual pilgrimages (qhapaq huachas) to mountain summits were they would leave female and male children of exemplary physical perfection as immolate tribute to the Inka Empire and mountain gods. Freeze-dried bodies of these sacrificed children have been recovered from mountain summits up to 5200 masl in Chile, Argentina, and Peru (Reinhard and Ceruti, 2000). Physiologically, even brief sojourns to extreme altitudes has a minor impact on the reproductive system.

Ovarian Cycle and Menstruation

Ovulatory disorders are a major cause of infertility (Urman et al., 2006). While follicle phase ranges vary among women, a luteal phases lasting for less than 2 weeks is considered a “luteal defect” due to low levels of the hormone progesterone and an insufficient production of uterine lining, which inhibits a female’s reproductive abilities. Fecundability may be correlated to cycle length, which determines the number of opportunities for conception in a given time span (Wood and Weinstein, 1988). Because ovarian follicle growth is characterized by cell growth and rapid cell divisions, hypothetically, hypoxia may slow this process and thereby disrupt phase lengths (Wood and Weinstein, 1988).

Recent studies have suggested that short-term exposure to high-altitude hypobaric hypoxia may negatively impact the development and function of the corpus luteum. Parraguez and colleagues (2013) examined the corpus luteum among sheep living in high altitudes and found a significant decrease the growth and function of the corpus luteum, which resulted in decreased fertility (Parraguez et al., 2013). However, it is important to note that sheep used in the study were Creole ewes, a mixed breed developed from Churra and Manchega Spanish breeds brought to the Americas by Spanish colonists and therefore do not have a long ancestry in high altitude environments (Parraguez et al., 2013).

Among indigenous Aymara women on the altiplano (3800+ masl) of the Peruvian and Bolivia Andes, Vitzthum and colleagues (2000) reported a mean cycle length of 29.1 days (n = 612 cycles, 191 women). Cycle length among nomadic herders from the Mongolian high steppe (~1,500 masl) was 27.8 days, with the mean follicular-phase length averaging 14.7 days, and mean luteal-phase length 13.2 days (Jurado et al., 2009). According to Vitzthum (2009), neither the Aymara nor Mongolian cycle ranges were particularly low or high compared to cycle length of female populations worldwide. If hypoxia does slow follicle growth, the effect is insignificant (Vitzthum, 2013).

Differential hormone profiles, specifically time between the gonadotropin peak/release of luteinizing hormone (LH) and ovulation, between high and low altitude populations may indicate an ovulatory disorder. Escudero et al. (1996) compared samples from Lima (150 m) (N=10) and Cerro de Pasco (4340) (N=10), Peru. Females in Cerro de Pasco had smaller pre-ovulatory follicle diameters and lower estrogen production during the late follicle phase. Estradiol levels only increased 80% between Cerro de Pasco females compared to 137.3% among females in Lima. Additionally, the luteinizing hormone peaked earlier among women in Cerro de Pasco compared to women in Lima. Yet, both groups of females exhibited the same duration of the luteal phase and the same endometrium measurements between high and low altitudes (Escudero et al., 1996). Escudero and colleagues (1996) conclude that the differences in hormone profiles during menstrual cycle between high altitude and sea level samples are a result of low barometric pressure.

Conversely, Vitzthum and colleagues (2001a) compared ovulation rates between indigenous “middle-class” women in La Paz (3650 masl), Bolivia, and rural women living outside La Paz in El Alto (4150 masl), and reported that the rural participants had lower ovulation rates compared to the urban middle-class women, indicating that the difference in ovulation rates is not attributed to hypoxia because the two samples reside at similar altitudes (Vitzthum et al., 2001a, 2009). It is possible that overall health and socioeconomic status may impact overall fertility, yet the differences in ovulation lengths between the middle class and rural women may reflect normal variation (Vitzthum et al., 2001). The differences in ovulation may be correlated to socioeconomic status; ultimately, however, the high altitudes and sea level samples fall within the normal ranges of phase length and do not negatively impact reproduction.

Works cited in Parts 1 and 2 

Abelson, A.E. (1976). Altitude and fertility, Anthropological Studies of Human Fertility, ed. Bemice Kaplan, Detroit, 83-92.).

Abramsson, L.; Beckman, G.; Nordenson, I. (1982). Chromosomal aberrations and male infertility. J. Urology, 128, 52–53.

Aldenderfer, M. (2011). Peopling the Tibetan plateau: Insights from archaeology. High Altitude Medical Biology, 12, 141-147.

Baker, P.T. and Little, M.A. (1976). Man in the Andes: A multidisciplinary study of high-altitude quechua: US/IBP Synthesis Series 1. Dowden, Hutchinson and Ross, Inc., Stroudsburg, PA.

Beall, C.M. (2007). Detecting natural selection in high-altitude human populations. Respiratory Physiology and Neurobiology, 158, 161-171.

Beall, C.M. (2006). Andean, Tibetan, and Ethopian Patterns of Adaptaiton to High-Altitude Hypoxia. Integrative and Comparative Biology, 46, 18-24.

Beall, C.M. (1983). Ages at menopause and menarche in a high-altitude Himalayan population. Annual Human Biology, 10, 365-370.

Beall, C.M., Kijoung, S.; Elston, R.C.; Goldstein, M.C. (2004). Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m. Proceedings for the National Academy of Science, 101, 14300-14304.

Ballew, C.; Haas, J.D. (1986) Altitude difference in body composition among Bolivian newborns. Human Biology, 58, 871-882.

Bonavia, D. (1991). Peru. Man and History. From the Origin to Century XV, first ed. Edubanco, Lima, 586.

Bonnefille, R.; Potts, R.; Chalie, D.; Jolly, D.; Peyron, O.; (2004). High-resolution vegetation and climate change associated with Pliocene Australopithecus afarensis. Proceedings for the National Academy of Science, U.S.A., 101, 12125-12129.

Brantingham, P.J.; Xing, G., Madsen, D.B.; Rhode, D.;  Perreault, C.; van der Woerd, J.; Olsen, J.W. (2013). Late occupation of the high-elevation Northern Tibetan Plateau based on cosmogenic, luminescence, and radiocarbon ages. Geoarchaeology 28, 413–431.

Brantingham, P.J. and Gao, X. (2006). Peopling of the northern Tibetan Plateau. World Archaeology, 38, 387–414.

Burch, J.C.; Vitzthum, V.J.; (2011). Project REPA: the timing of menopause in a population with high mortality risks. American Journal of Human Biology, 23, 254.

Cardich, A. (1960). Investigaciones prehistoricas en los Andes peruanos. In: Antiguo Peru: Espacio y Tiempo. Libreria Editorial Juan Mejia Baca, Lima, 89-118.

Cieza de Leon, P. (1553). Cronica del Peru. Book 2. Sevilla, Spain.

Cobo, B. (1653). Historia del Nuevo Mundo. Imprenta E. Rasco, Sevilla, Spain.

Collins, J.L. (1983). Fertility Determinants in a High Andes Community. Population and Development Review, 9, 61-75.

Crognier E.; Villena, M.; Vargas, E.; (2002). Reproduction in high altitude Aymara: physiological stress and fertility planning? Journal of Biological Science, 34, 463–473.

De La Calancha, A. (1639). Cronica Moralizadora de la Orden de San Augstin Imprenta Pedro Lacaballeria, Barcelona, Spain.

De la Vega, I.L. (1609). Comentarios Reales. Two Books. Merurio, Lima.

Escudero, F., Gonzales, G.F., Gonez, C. (1996). Hormone profile during the menstrual cycle at high altitude. International Journal of Gynecology and Obstetrics, 55, 49-58.

Giussani, D.A.; Phillips, P.S.; Anstee, S.; Barker, D.J.P.; (2001). Effects of altitude versus economic status on birth weight and body shape at birth. Pediatric Research, 49, 490–494.

Goldstein, M.C., Tsarong, P., Beall, C.M., (1983). High Altitude Hypoxia, Culture, and Human Fecundity/Fertility: A Comparative Study. American Anthropologist, 58, 28-39.

Gonez, C.; Villena, A.; Gonzales, G.F. (1993). Serum levels of adrenal androgens up to adrenarche in Peruvian children living at sea level and at high altitude. Journal of Endocrinology, 136, 517.

Gonzales, G.F. (2007). Peruvian contributions to the study on human reproduction at high altitude: From the chronicles of the Spanish conquest to the present. Respiratory Physiology and Neurobiology, 158, 172-177.

Gonzales, G.F. (1998). Demographic, reproductive, morbidity and mortality patterns at high altitude. In: Ohno, H., Kobayashi, T., Masuyama, S., Nakashima, M. (Eds.), Progress in Mountain Medicine at High Altitude, Japanese Society of Mountain Medicine, Tokorosawa, 174–179.

Gonzales, G.F. (1994). Studies on menopause in Peru. Acta Andina, 3, 55-70.

Gonzales, G.F., Tapia, V., Carrillo, C.E. (2007). Stillbirth rates in Peruvian populations at high altitude. International Journal of Gynecology and Obstetrics, 100, 221-227.

Gonzales, G.F. and Gonez, G. (2000). High serum follicle stimulating hormone (FSH) during perimenopause at high altitude, International Journal of Gynecology & Obstetrics, 68, 158-161.

Gonzales, G.F. and Villena, A. (1997). Age at menopause in central Andean Peruvian women, Menopause, 4, 32–38.

Gonzales, G.F., Villena, A., Ubilluz, M. (1996). Age at Menarche in Peruvian Girls at Sea Level and at High Altitude: Effect of Ethnic Background and Socioeconomic Status. American Journal of Human Biology, 8, 457-463.

Gonzales, G.F.; Ortiz, I. (1994) Age at menarche at sea level and high altitude in Peruvian women of different ethnic backgrounds. American Journal of Human Biology, 6, 637-640.

Gonzales, G.F., Guerra-Garcia, R., (1993). Algunas caracteristicas del embarazo y del recien nacido en la altura. In: Leon-Velarde, F., Arregui, A. (Eds.), Hipoxia: investigaciones basicas y clinicas. Homenaje a Carlos Monge Cassinelli. Instituto Frances de Estudios Andinos and Universidad Peruana Cayetano Heredia, Lima, 321–337

Greksa, L.P. (1990). Age of menarche in Bolivian girls of European and Aymara ancestry, Annual Human Biology, 17, 49–53.

Gupta, R.; Basu, A.; Pawson, I.G.; Bharati, P.; Mukhopadhyay, B.; Mukhopadhyay, S.; Roy, S.K.; Majumder, P.P.; Bhattacharya, S.K.; Bhattacharya, K.K.; Das, S.K. (1989) Altitude and human biology: a comparative study of Himalayan, Andean and Ethiopian data. In; Basu, A.; Gupta, R. ed. Human biology of Asian highland population in the global context. Calcutta: Indian Anthropological Society, 1-80.

Guerra-Garcia, R.; Velasquez, A.; Whittembury, J. (1965). Urinary testosterone in high altitude natives. Steroids, 6, 351–355.

Hartinger, S., Tapia, V., Carrillo, C., Bejarano, L., Gonzales, G.F. (2006). Birth weight at high altitudes in Peru. International Journal of Gynecology and Obstetrics, 93, 275-281.

Haas, J.D., Baker. P.T.; Hunt, E.E. (1977) The effects of high altitude on body size and composition of the newborn infant in southern Peru. Human Biology, 49, 611-628.

Hochachka, P.W.; Gunga, H.C.; Kirsch, K. (1998). Our ancestral physiological phenotype: An adaptation for hypoxia tolerance and for endurance performance? Procedures for the National Academy of Science, U.S.A., 95, 1915-1920.

INEI, (2001). Encuesta Demogra ́fica y de Salud Familiar (Peru). 2000. Instituto Nacional de Estadística e Informatíca, Lima, Perú

Jensen, G.M.; Moore, L.G. (1997) The effect of high altitude and other risk factors on birth weight: independent or interactive effects? American Journal of Public Health, 87, 1003-1007.

Julian, C.G. (2011) High Altitude During Pregnancy. Clinics in Chest Medicine, 32, 21-31.

Jurado, K.; Vitzthum, V.J.; Deimel, C.; Deschner, T. (2009). Does high animal fat and protein consumption alter the duration of ovarian cycle phases? Evidence from a study of nomadic Mongolian herders, American Journal of Human Biology, 21, 258.

Khalid, M.E., Ali, M.E.; Ali, K.Z. (1997) Full-term birth weight and placental morphology at high and low altitude. International Journal of Gynecology and Obstetrics, 57, 259-265.

Lang, S.D.R. and Lang, A. (1971). The Kunde hospital and a demographic survey of the Upper Khumbe, Nepal. New Zealand Medical Journal, 74, 1-8.

Laurenson, I.F.; Benton, M.A.; Bishop, A.J.; Mascie-Taylor, C.G.N (1985). Fertility at low and high altitude in central Nepal. Social Biology, 32, 65–70.

Marriot, B.M., and Carlson-Newberry, S.J., (1996). Nutritional Needs in Cold and High Altitude Environments: Applications for Military Personnel in Field Operations, National Academy Press, Washington, D.C.

Mazess, R.B.; (1965). Neonatal mortality and altitude in Peru. American Journal of Physical Anthropology, 23, 209–213.

McAuliffe, F.; Kametas, N.; Krampl, E.; Ernsting, J.; Nicolaides, K. (2001). Blood gases in pregnancy at sea level and at high altitude, International Journal of Obstetrics & Gynaecology, 108, 980–985.

Monge, M.C. (1978). Acclimatization in the Andes. Reissued 1948 edition. The Johns Hopkins Press, Baltimore.

Monge, M.C. (1942). Fisiologia de la reproduccion en la altura. Aplicaciones a la industria animal. An. Fac. Med. Lima, 25, 19.

Monge, M.C.; San Marin, M.; Atkins, J.; Casanon, J. (1945). Aclimatacion del Ganado ovino en las granes Alturas. An. Fac. Med. Lima, 28, 15.

Monge, M.C. and Mori-Chavez, P. (1942). Fisiologia de la reproduccion en la altura. An Fac. Med. Lima 25, 34-40.

Moore, L.G.; Young, D.A.; McCullough, R.E.; Droma, T; Zamudio, S. (2001). Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss at high altitude. American Journal of Human Biology, 13, 635–644.

Myres, J.E.; Malan, M.; Shumway, J.B.; Rowe, M.J.; Amon, E.; Woodward, S.R.; (2000). Haplogroup-associated differences in neonatal death and incidence of low birth weight at elevation: a preliminary assessment. American Journal of Obstetrics and Gynecology, 182, 1599-1605.

Okumura, A., Fuse, H., Kawauchi, Y., Mizuno, I., Akashi, T. (2003). Changes in Male Reproductive Function after High Altitude Mountaineering. High Altitude Medicine and Biology, 4, 349-353.

Parraguez, V.H.; Urquieta, B.; Pérez, L.; Castellaro, G.; De los Reyes, M.; Torres-Rovira, L.; Aguado-Martínez, A.; Astiz, S.; González-Bulnes, A. (2013). Fertility in a high-altitude environment is compromised by luteal dysfunction: the relative roles of hypoxia and oxidative stress Reproductive Biology & Endocrinology. 11 1-12.

Passano, S. (1983). Caracteristicas de las gestantes y de los recien nacidos en Puno 3812m, Doctoral Thesis, Universidad Peruana Cayetano Heredia, Lima, Peru

Pelliccione, F.; Verratti, V.; D’Angeli, A.; Micillo, A.; Doria, C.; Pezzella, A.; Iacutone, G.; FFrancavilla, F.; di Guulio, C.; Francavilla, S. (2011). American Society for Reproductive Medicine, 96, 28-33.

Quade, J.; Levin, N.; Semaw, S.; Stoug, D.; Renne, P.; Rogers, M.; and Simpson, S.; (2004). Paleoenvironments of the earliest stone toolmakers. Gona, Ethiopia. GSN Buletin, 116, 1529-1544.

Rademaker, K.; Hodgins, G.; Moore, K; Zarrillo, S.; Miller, C.; Bromley, G.R.M.; Keach, P.; Reid, D.A.; Alvarez, W.Y.; Sandweiss, D.H. (2014) Science, 346, 466-469.

Redfield, T.F.; Wheeler, R.H.; and Often, M. (2003). A kinematic model for the development of the Afar Depression and its paleogeographic implications. Earth and Planetary Science Letters, 216, 383-398.

Rimpela, A.H. and Rimpela. M.K. (1993). Towards on equal distribution of health? Socioeconomic and regional differences of the secular trend of the age of menarche in Finland from 1979 to 1989. Acta Paediatr, 82, 87-90.

Rupert, J.L.; Hochachka, P.W. (2001). Genetic approaches to understanding human adaptation to altitude in the Andes. Journal of Experimental Biology, 204, 3151–3160.

Saxena, D.K. (1995). Effect of hypoxia by intermittent altitude exposure on semen characteristics and testicular morphology of male rhesus monkeys, International Journal of Biometeorology, 38, 137–140.

Sobrevilla, L.A. (1971). Nacer en los Andes. Estudios fisiologicos sobre el embarazo y parto en la altura. Doctoral Thesis, Universidad Peruana Cayetano Heredia: Instituto de Investigaciones de la Altura, Lima, Peru 1997

Suarez-Morales, R. (1987). Fertilidad en la altura. Prensa Med. (Bolivia), 19, 79-85.

Tang, H.S.; Zhou, C.L.; Li, Q.Y.; Liang, Z. (2013) A new discovery of microlithic information at the entrance to the Northern Qingzang Plateau of the Kunlun Mountains of Qinghai. China Science Bulletin, 58, 247–253

Tronick, E.Z.; Thomas, R.B.; Daltabuit, M. (1994). The Quechua Manta Pouch: A Caretaking Practice for Buddering the Peruvian Infant against the Multiple Stressors of High Altitude, Child Development, 65, 1005-1013.

Urman, B; Yakin, K; (1988). Ovulatory disorders and infertility, Journal of Reproductive Medicine, 51, 267-283

Vitzthum, V.J. (2013). Fifty Fertile Years: Anthropologists’ Studies of Reproduction in High Altitude Natives. American Journal of Human Biology, 25, 179-189.

Vitzthum, V.J. (2009). The ecology and evolutionary endocrinology of reproduction in the human female, American Journal of Physical Anthropology, 140 (Suppl 49), 95–136.

Vitzthum, V.J.; Wiley, A.S. (2003). The proximate determinants of fertility in populations exposed to chronic hypoxia, High Altitude Medical Biology, 4, 125–139.

Vitzthum, V.J. (2001a). Why not so great is still good enough: flexible responsiveness in human reproductive functioning, In: Ellison PT, edi. Reproductive ecology and human evolution, New York: Aldine de Gryter, 179–202.

Vitzthum, V.J. (2001b). The home team advantage: reproduction in women indigenous to high altitude, Journal of Experimental Biology, 204, 3141–3150.

Vitzthum, V.J.; Spielvogel, H.; Caceres, E.; Gaines, J.. (2000). Menstrual patterns and fecundity in non-lactating and lactating cycling women in rural highland Bolivia: Implications for contraceptive choice. Contraception, 62, 181-7.

Weitz, C.A.; Pawson, I.G.; Weitz, M.V.; Lang, S.D.R.; Lang, A. (1978). Cultural factors affecting the demographic structure of a high altitude Nepalese population, Social Biology, 25, 179-195.

Wiley, A.S.; (1994). Neonatal and maternal anthropometric characteristics in a high altitude Himalayan population, American Journal of Human Biology, 6, 499–510.

Wood, J.W. (1994). Dynamics of human reproduction. New York: Aldine de Gruyter.

Wood, J.W.; Weinstein, M. (1988). A model of age-specific fecundability, Population Studies, 42, 85–113.

World Health Organization (WHO) (1986) World Health Organization Multicenter study on menstrual and ovulatory patterns in adolescent girls: I.A. multicenter cross-sectional study of menarche, Journal of Adolescent Health Care, 7, 229-235.

Yip, R. (1987) Neonatal size and infant mortality at high altitude in the western
Himalaya. American Journal of Physical Anthropology. 94, 289-305.

Zhang, D.D. and Li, S.H. (2002) Optical dating Optical dating of Tibetan human hand- and footprints: An implication for the palaeoenvironment of the last glaciation of the Tibetan Plateau. Geophysical Research Letter, 29, 16-1–16-3.