Prenatal Development and Regression in Humans: “Classical” Vomeronasal Organ Structure Suggests Possibility of Prenatal Function

Development

Initial vomeronasal structures in staged human embryos are observed between weeks 4 and 5 (Carnegie stages 13 to 1510; Fig. 4.1 ). The medial epithelium of the olfactory placode gives rise to the vomeronasal neurons, nervus terminalis, cells expressing gonadotrophin releasing hormone (GnRH), and some further neurons.11,12 Vomero-nasal and terminalis ganglia appear around stages 18 and 19 as clusters of protein gene product 9.5 (PGP 9.5)–immunoreactive cells migrating out of the epithelium ( Fig. 4.2a, c ). Vomeronasal and olfactory axons start to grow into the primitive olfactory bulb, and GnRH cells begin to migrate to the hypothalamus, following vomeronasal or nervus terminalis substructures. They normally begin reaching the median eminence by week 8, but some cells may remain along the migration pathway.13 An intriguing connection between olfaction and sex becomes apparent if GnRH cells fail to reach the hypothalamus, resulting in hypogonadotrophic hypogonadism, often associated with anosmia (Kallmann syndrome).14,15 Around week 8, a VND similar to that seen in rodents becomes visible ( Fig. 4.1a ). This duct is lined by neuroepithelial cells reactive for neurotubulin, neural cell adhesion molecule, and PGP 9.5, but not for OMP, a reliable marker for functional olfactory and rodent vomeronasal neurons. In contrast to rodents, humans do not form a clearly separate AOB.16,17

Most Vomeronasal Organ–related Structures have Disappeared in Adult Humans

Most constituents of the VNO are no longer detectable at birth in humans. The only remaining structure is the VND, which exhibits considerable variability in shape, size, and even presence or detectability. The VND is situated superior to the paraseptal cartilage and runs smoothly craniodorsally. The opening of the VND is less than 2 mm in diameter, sometimes pigmented a brownishyellow ( Fig. 4.2 ). Generally described as a blind-ending duct or a mucosal pouch located in the anterior nasal septum, its length varies between 3 and 22 mm.17 The frequency of detection depends strongly on the technique of investigation: histological studies reveal a higher percentage of VNDs than rhinoscopic or endoscopic investigations ( Table 4.1 ).29 Unlike in rodents, there is no difference between the two sides of the duct with regard to a possible “sensory” and “nonsensory” epithelium. Histologically, the epithelium of the VND contains portions of sensory-like formations, but neuronal markers are no longer expressed, and nor are there any nerve terminals left in the vicinity of the epithelium.30 Taken together, the vomeronasal epithelium of the adult human VND expresses highly specialized histochemical features; however, it does not provide the essential requirements for classical neuroepithelial information transfer into the brain. Owing to its exposed location in the anterior septum, the VND can easily be damaged during nasoseptal or orthognatic surgery. Despite occasional anecdotal reports and speculation (e.g., Foltán and Sedý 200931), there are no studies that provide measurable functional evidence that VND damage leads to behavioral changes after nasoseptal surgery.

Are There Human Pheromones?

Chemical compounds that convey information from one individual to another of the same species are commonly called pheromones. By original definition (notably in insects which lack a morphological VNO), these are, “substances which are secreted to the outside by an individual and received by a second individual of the same species, in which they release a specific reaction, e.g., a definite behaviour or a developmental process.”32 The mediation of chemosensory signals in social and sexual behavior has been widely documented in animals.33 A similar function seems likely in humans but has been less widely documented (reviewed by Grammer et al 200534):

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  Meredith35 proposes restricting the definition for pheromone by including a requirement for mutual benefit to sender and receiver, putting pheromone communication in an evolutionary context. The communication function, if any, for example of human odor response, is obscure, so these would not necessarily meet the more restrictive definition for pheromone communication. However, this scientific definition is not universally accepted and the term pheromone is used loosely in both scientific and popular publications.

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Frequency of vomeronasal duct in adult humans varies according to the investigation technique

  Reference	N	Frequency
  Potiquet 189121	200	25%
  Johnson et al 198522	100	Patients 39% (endoscopy) Postmortem specimens 70% (histology)
  Stensaas et al 199123	410	93%
  Moran et al 199124	200	100% bilateral
  Garcia-Velasco and Mondragon 199125	1,000	90%
  Trotier et al 200026	1,842	Patients 26% (endoscopy)
  Gaafar et al 199827	200	Patients 76% (endoscopy)
  Won et al 200028	78	36%
  Knecht et al 200129	173	65% (41% bilateral, 24% unilateral; endoscopy)
  Witt et al 200230	25	65% (histology)

  
  
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  The chemical nature of proposed pheromone compounds is heterogeneous, but some pheromone candidates in humans and animals may be chemically related.36 Possible production sites for human pheromone candidates include urine, smegma-producing urogenital glands, lachrymal glands,37 axillary apocrine glands, and mammary glands,38 mirroring known pheromone sources in animals.

  
  
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  There may also be similarities in the relationship between complex “odor prints” and components of the immune system that confer individual identity (e.g., human lymphocyte antigens [HLA], or the rodent major histocompatibility complex).39 People have been shown to be capable of identifying odors of closely related persons (from samples of axillary volatiles collected from T-shirts) better than would be expected by chance alone.40 Thus, there could be “signaler pheromones” that help individuals recognize relatives. There is also some evidence for a physiological response that varies with the reproductive cycle of female odor donors, including modulation of the menstrual cycle in other women and an increase in testosterone in men.41,42 The unidentified compounds involved may be classified as “primer pheromones,” producing an endocrine response and (maybe) a delayed change in behavior. Less convincingly, pheromones representing paternally inherited HLA alleles may influence mate choice.43,44

  
  
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  In humans, activation of the hypothalamus by some odors is sexually dimorphic (and sexual orientation–specific) in brain imaging studies,45 but evidence suggests that the detection of such odors is via the main olfactory system, not the vomeronasal organ or VND.