Presentation Text: Kohl, J.V. (1998). Human pheromones and the neuroendocrinology of behavior. International Society for Human Ethology, Fourteenth Biennial Conference, Simon Fraser University, Burnaby, British Columbia, Canada, Aug 19-23.

A direct route from the social environment to hormones and behavior is the five-step pathway: gene--> cell--> tissue--> organ--> organ system. Mammalian pheromones activate genes in hormone-secreting nerve cells of tissue in the brain--the most important organ involved in any organ system associated with behavior.

Simply put, to affect behavior, sensory input must first affect hormone-secreting nerve cells. The proximate link from pheromones to hormones, and ultimately to behavior, begins with the effect of pheromones on genes in nerve cells that secrete gonadotropin releasing hormone (GnRH).

Sex differences in behavior have repeatedly been linked to sexually dimorphic structures of the brain. Unlike the visual system, mammalian olfactory systems are sexually dimorphic. This makes it easier to link pheromones to sex differences in behavior, than it is to link visual input, no matter how many additional steps are required to get from the proximate to the ultimate.

Of course, there are some additional steps that confuse the link between pheromones and behavior. For example: GnRH modulates luteinizing hormone (LH) and follicle stimulating hormone (FSH), and LH/FSH ratios modulate levels of sex steroids. Ultimately it is the effect of sex steroid hormones on neurotransmission that is commonly used to explain sex differences in behavior.

Despite these additional steps, when linking sensory input to behavior, the effect of pheromones on GnRH is a great place to start. That's because hypothalamic GnRH pulsatility directs and coordinates the concurrent maturation of the central nervous, neuroendocrine, and reproductive systems.

Given the link between the concurrent maturation of these three systems, and behavior, any sensory input that affects GnRH pulsatility can reasonably be expected to influence behavior. And, mammalian pheromones are the only social-environmental sensory stimuli that have been shown to directly influence GnRH, by acting on gene expression in GnRH secreting neurons.

In studies of other animals, pheromones influence behavior. But, since there is no absolute proof that human pheromones influence behavior, my focus is on the link between human pheromones and hormones.

Mammalian pheromones from the opposite sex typically cause an increase in GnRH pulse frequency, while same sex pheromones cause a decrease in pulse frequency. And, both in animal and in human studies two things seem clear: (1) When GnRH pulse frequency increases, levels of LH and of testosterone increase. (2) When GnRH pulse frequency decreases, levels of FSH increase.

The following neuroendocrine evidence suggests that human pheromones directly alter GnRH pulse frequency:

1. an increase in levels of LH and of testosterone occurs during the first few minutes after birth in the human male neonate, but not in the female (only males are exposed to the pheromones of the opposite sex.)
2. a progesteronic vomeropherin appears to alter adult LH and FSH pulsatility
3. the pheromones of adult human females alter adult levels of LH in other human females
4. men who are exposed to the ovulatory "copulins" of women exhibit an increase in testosterone. There is also indirect evidence that suggests men and women are influenced by pheromones.

Indirect evidence:

1. the entrainment of hormone cycles in couples;
2. coitus-induced human ovulation;
3. olfactory sexual dimorphism (females detect the boar pheromone androstenone at lower thresholds than do males;
4. human odor receptors and the detection of human odors both are linked to tissue type;
5. humans can sniff out odor differences in mice differing by X or Y chromosomes and odor differences in mice varying only by tissue type;
6. a human immune response that results in fetal wastage is associated with odor and with tissue type;
7. odors determined by tissue type may be important in human mate choice.

Overall, direct and indirect evidence of human pheromones suggests that the early prenatal development of mammalian--including human--olfactory systems and of the GnRH neuronal system allows postnatal exposure to pheromones to exert organizational and activational effects on the brain and on behavior, whenever in life this exposure occurs.

These interactions form the basis of pheromonal communication in animals. That brings me back to a brief explanation of this diagram:

I use this flow chart to show the developmental staging of olfactory responsivity and its effects. In yellow is what happens prenatally to set up the sexually dimorphic olfactory systems and the GnRH neuronal system. (GnRH neurons migrate into the brain from the embryonic beginnings of the olfactory systems.)

• In green is what happens both prenatally and postnatally. For example, the hypothalamic GnRH pulse conditions the function of the hypothalamic-pituitary- gonadal and the hypothalamic-pituitary-adrenal axes. This conditioning affects levels of sex steroids and neurotransmission.
• In the white area on your right: Since LH/FSH pulsatility changes occur throughout life, we can expect that human pheromones would affect LH/FSH pulsatility and the secretion of sex steroid hormones throughout life. This means that postnatally, the effect of pheromones from the social environment continues to condition the HPG and HPA axes.
• In the white area on your left: The result of the prenatally predisposed development of the olfactory systems and the GnRH neuronal system and of the conditioning of the hypothalamic-pituitary- gonadal and adrenal axes is consistent with what we see expressed as mammalian reproductive sexual behavior, which includes human sexuality--with all its variations.

Simply put, this neuroendocrine model shows that mammalian pheromones modulate the hormonal states, which modulate the development of--and the expression of--sexuality. Since human pheromones appear to modulate the same hormonal states, it seems likely that mammalian, including human, pheromones modulate the development of and the expression of sexuality.

Human evidence that contact between the sexes results in GnRH release and followed either by changes in LH/FSH ratios or by changes in steroidogenesis suggests that GnRH might be involved very early in the initiation of a sexually organized response. It has even been suggested that pheromones are involved in the fine-tuning of the HPG and HPA axes.

Given this neuroendocrine connection with other mammals, a prediction about the human sexual response can be made: The postnatal organization of our "sexual" response may begin with the detection of pheromones and proceed to the induction of mating behavior.

Does this organization or fine-tuning equate with the olfactory conditioning of sexual responsivity to other sensory stimuli? For example, could pheromones condition the human sexual response to an ovulatory female's preference for symmetry?

To answer this and other questions about conditioning, rather than focus on the neuroendocrinology of sexuality, I prefer to use an analogy. Food preferences are based upon innate differences in the chemical senses (taste and olfaction), which are present before we are able to respond to a food's visual appeal. Subsequently, food preferences are based upon the pairing of olfactory stimuli with the sight of what appears to be an appetizing item. Nonetheless, as we development our food preferences, olfaction is more important to the conditioning of a visual response than vice versa.

When it comes to the chemical senses, food preferences and mate preferences have much in common in other animals, since mammalian neuroendocrine evidence suggests that mate preferences develop primarily on the basis of olfactory input, rather than visual or other non-olfactory sensory input.

The analogy to food preferences may help to explain why there is no conclusive proof that human pheromones influence human sexual behavior. For example, some people tend to think that a dislike for broccoli is a response to the visual presentation of this food source. But blindfold a control group, you would find that the olfactory chemistry of food is the primary factor involved in whether or not we eat it. Still, either a preference for, or an aversion to broccoli, develops over a lifetime.

Sexual preferences also develop over a lifetime that includes exposure to human pheromones, which act on sexually dimorphic olfactory systems from birth. Since there is direct evidence that human pheromones modulate hormonal states, the likely role that human pheromones play in the development of sexuality is more difficult to deny.

Is human communication dominated by non-olfactory sensory input, as many others have implied? I have seen no neuroendocrine evidence that suggests this. In contrast, this mammalian model asserts that mammalian, including human, communication is dominated by olfaction.

Human pheromones appear to activate the prenatally established mammalian pathway that modulates steroidogenesis. The link between sex steroid hormones and behavior is generally accepted. This provides reason to believe that a link between human pheromones and behavior would be generally accepted. Simply put, since there we can get from pheromones to hormones, it should be easier to accept a link between pheromones and hormonally influenced behavior.

In the absence of data to suggest that visual, tactile, auditory, or gustatory stimuli directly activate this or any other sexually dimorphic pathway, or that non- olfactory sensory stimuli may help to organize genetically-determined, physiologically-based sexually- dimorphic behaviors, the olfactory link between the social environment, genes, and sexual behavior could be considered a primary link between the social- environment and behavior.

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Jim Kohl http://www.pheromones.com -----------------------------------------------------------

"I should think that we might fairly gauge the future of biological science, centuries ahead, by estimating the time it will take to reach a complete comprehensive understanding of odor. It may not seem a profound enough problem to dominate all the life sciences, but it contains, piece by piece, all the mysteries." Thomas, L. (1980) Notes of a biology-watcher: On Smell. New England Journal of Medicine, 302,13:732.