Evolutionary Endocrinology and Immunology

Infectious diseases have been important selection pressures instrumental in the evolution of human and non-human primates, and mammalian immunity has evolved into a complex system of components whose proper performance is influenced by many physiological systems, including reproductive hormones of the endocrine system. Interestingly, an evolutionary perspective can contribute valuably to medical research and practices, including basic aspects of immunology and endocrinology.

As predicted by evolutionary and life history theories, testosterone variation within an individual should function as an adaptive mechanism to augment reproductive effort or bolster immunity according to available energy and disease risk in the environment. Because testosterone modulates immune, reproductive, and somatic metabolic functions, assessing interactions between testosterone, measures of metabolism, and immune factors during infection are insightful for understanding male physiological ecology and the optimization of hormone levels under various environmental conditions.

Testosterone levels may vary according to energy balance, but only under the most taxing circumstances. More taxing aspects of male reproductive effort that may be sensitive to environmental stressors include the physiological and behavioral mechanisms involved in attracting a mate, competing with conspecifics for access to mates, and protection and provisioning of offspring and mates. In such cases, androgenic sensitive tissue (i.e., skeletal muscle mass) is a much better proxy of male reproductive effort than is spermatogenesis, and maintaining high testosterone levels can augment male reproductive success (via work capacity and sexual selection) by allocating energy towards muscle anabolism and other musculoskeletal functions (i.e., red blood cell quantity and cortical bone density). However, this is balanced against the costs of maintaining high testosterone levels, mainly increased energetic costs and the risk of negative energy balance, increased risk of prostate cancer, production of oxygen radicals, increased risk of injury due to hormonally-augmented behaviors such as aggression, violence and risk taking, reduced tissue (especially adipose) and organ maintenance, and suppression of immune functions. These costs likely account for the functional significance of high variability in testosterone levels within and between individuals. Variation of testosterone level will act as a physiological mechanism regulating the differential investment in either reproductive effort (i.e., musculoskeletal performance, courtship and copulatory behaviors, etc.) or survivorship (i.e., immunocompetence, adipose tissue, etc.) according to availability of energy, availability of mates, and disease risk in the environment.

Much of Dr. Muehlenbein’s current work is focused on quantifying the endocrine and metabolic responses to infection in human males and clarifying these trade-offs between the reproductive and immune functions. This work includes the quantification of the energetic demands of immunocompetence in humans. Other related projects that Dr. Muehlenbein is involved include: phylogenetic analyses of endocrine-immune correlates in the Primate order (collaboration with Dr. Charles Nunn at the Max Planck Institute for Evolutionary Anthropology); analyses of the effects of androgen intervention on the immune response in clinically obese and HIV-infected men (collaboration with Dr. Shalander Bhasin at the Boston Medical Center); analyses of gonadotropin changes in response to Plasmodium vivax infection in Honduran men (collaboration with with Dr. Richard Bribiescas at Yale University); and assessment of metabolic changes and immune-endocrine interactions in male college students either receiving vaccinations or treatment for influenza, cold, and other upper respiratory tract infection (collaboration with Dr. Julie Bonner at University of Wisconsin-Milwaukee).

Emerging Infectious Diseases

Monitoring ecosystem health is of vital importance to the global community. This is especially the case in Sabah, Borneo where close interaction between people and wildlife is a privilege of both Malaysians and tourists. Over 1.8 million registered international tourists visited Sabah in 2005. Approximately 85,000 visited Sepilok Rehabilitation Centre to witness the daily feedings of habituated semi-free-ranging orang-utans, and approximately 40,000 people visited the village of Sukau, the epicenter of wild orang-utans, elephants, proboscis monkeys and macaques in Sabah. Human-wildlife contact will continue to increase in Sabah due to increased demand from tourists to experience direct encounters with these animals in addition to increased local population size and oil-palm plantation encroachment.

Such increased contact could facilitate zoonotic (animal to human) disease transmission. In fact, over half of all human diseases are zoonotic in origin, and the situation seems to be worsening from the impact of global environmental change. Human contact with wildlife can also facilitate the emergence of novel infectious diseases (those that have recently evolved, expanded in geographic range, changed in pathogenesis, and/or moved from one host species to another). This is of direct relevance to Malaysia not only because of high levels of contact between humans and wildlife, but also because of demonstrated presence of these diseases. For example, Nipah virus, a paramyxovirus which originated from fruit bats, killed over 100 people in Malaysia in early 1999.

It is important to describe the diseases found in humans, livestock and wildlife inhabiting the same areas so that we may monitor any disease transmission between these groups. Humans and primates can readily exchange infectious organisms when cohabitating in the same area, even in the absence of bushmeat. It is also important to monitor diseases found in tourists so that we may ensure the long-term survival of Sabah’s wildlife. These ecotourists can pose some risk to Sabah’s wildlife because they are often sick (and likely infectious) during visitations. These tourists can transmit infections to wildlife, and vice versa. Such disease transmission has resulted in animal fatalities in the past, and such a situation must be avoided in Sabah at all costs. To do so requires a project composed of scientists from a diverse array of disciplines, including veterinary medicine, conservation biology, and public health.

To meet the demand for active wildlife disease surveillance, Dr. Muehlenbein is organizing the “Sabah Ecosystem Health Project” which will monitor human and animal health in and around the Lower Kinabatangan Wildlife Sanctuary, Kabili-Sepilok Virgin Jungle Reserve and Tabin Wildlife Reserve of Sabah, Malaysia. This includes detailed descriptions of the interactions between people and wildlife as well as people’s perceptions of wildlife, conservation, bushmeat usage and sanitation. An epidemiological survey of disease prevalence will include people (locals and tourists), wildlife (primates [macaques, proboscis, and orangutans], small mammals, birds and bats), livestock (cattle, bison, goat and chicken), domestic pets (dogs and cats) and arthropods in and around these areas. Specific infectious organisms of interest include: avian and human influenzas, upper respiratory tract infections, tuberculosis, filariasis, Legionella, leptospirosis, intestinal parasites, and meliodiosis.

Human Female Behavioral Endocrinology

Females are often seen as relatively identical in reproductive potential and in the realization of that potential, with resources for survival and the survival of offspring as the only limiting factors. This has sometimes led to a misunderstanding of how and what females compete for. Females require resources that can be used for future offspring and/or resources to support current offspring. These are important assets, more so than outright physical dominance or access to copulatory opportunities. In effect, females should compete not over access to copulatory events, but access to quality males for copulatory events.

Males and females display markedly different strategies concerning aggressive behavior. Human males engage in direct aggression more frequently than females; with differences appearing in childhood. Females tend to prefer indirect forms of aggression. In humans, girls and women are more likely to compete through indirect forms of aggression such as shunning, stigmatizing, gossiping, and derogation. A possible form of intrasexual competition is for females to elevate the attractiveness of their own appearance when compared to that of their peers. This can be accomplished by making rivals appear to be less attractive to potential mates by derogating the rival’s physical attributes and stressing their own.

Ovarian hormones mediate reproductive behaviors in females including mating, ovulation, pregnancy, birth, and lactation. Like testosterone, release of estrogen and progesterone is regulated by the hypothalamus via the secretion of gonadotrophic-releasing hormone. The hypothalamus-pituitary-ovarian axis constitutes a complex system that works to maintain the allostatic load of the reproductive system. Levels of estrogen, testosterone and progesterone fluctuate across the menstrual cycle in humans, as well as numerous other species. Studies have suggested that that human female sexual desires change across the menstrual cycle, with peaks in sexual desire occurring most commonly during the peri-ovulatory period. A few studies have shown significant relations between salivary estradiol levels and elevated jealousy responses during the time of rising and high fertility. These cyclical changes in female sexual behavior across the menstrual cycle suggest that females’ responses to a potential rival may also vary across the menstrual cycle and with estradiol levels. Therefore, it is possible that any evolved psychological or behavioral dispositions regarding reproduction-related relationships are potentially moderated by estradiol levels. 

Orangutan Behavioral Endocrinology

Human disturbance of wildlife is obviously very complicated, and anthropogenic disturbances in general may affect animal physiology adversely. The impact that humans have on primate health has typically focused on disease transmission potential, a vital consideration given the increasing demand from tourists to experience direct encounters with these animals. Ecotourism is a potential tool to assist conservationist efforts in preserving populations of these wild animals, particularly great apes. It is therefore important to produce definitive guidelines that will protect visitors from possible risks as well as ensure long-term well-being of the animals, and this begins with monitoring the effects of habituation on animal physiology.

Habituation consists of a waning response following repeated stimulation without reinforcement. The effects of habituation and tourism on animal physiology have only rarely been investigated even though such stressors can theoretically cause immunosuppression, increasing susceptibility to infectious diseases, and decreasing reproductive success. Unfortunately, endocrine and infection measures have never been combined in any study on habituation or ecotourism. A logical hypothesis for any species under investigation would be that habituation and altered frequency of human presence/contact is associated with changes in glucocorticoid and infection levels. Dr. Muehlenbein, Dr. Marc Ancrenaz and colleagues are undertaking one such study in the Kinabatangan Wildlife Sanctuary, Sabah, Malaysia. Fecal samples are collected from orangutans involved with the Kinabatangan Orangutan Conservation Project and Red Ape Encounters ecotourism program and analyzed for both intestinal parasites and cortisol before, during and after controlled visits from tourist groups of varying sizes. Results of this study are pending, but it is hopeful that such studies can help produce guidelines that will ensure the long-term well-being of these animals.

Endocrine Functions in Endurance Athletes