Human pheromones stimulate the (human) vomeronasal organ (VNO)

Human pheromones stimulate the (human) vomeronasal organ (VNO)

Our data are the first evidence that male axillary extract causes neuroendocrine and mood alterations in women. Male extract brings on a subsequent LH pulse sooner than it would occur under endogenous rhythms, suggesting that one or more extract components influence the GnRH pulse generator. In nonhuman mammals, studies have demonstrated that conspecific chemosignals may cause a rapid increase in LH. Although the neuroendocrine response in women was not like that of female rodents, it did rival that seen in goats. Order Pheroline Pheromones here.

In ovariectomized female goats, which had been primed with estradiol to suppress the GnRH pulse generator, exposure to the chemical signals present on the hair of male goats decreased the intervals between LH pulses by about 10%, relative to control exposures, during 4 h postexposure. In contrast to these effects in female goats, under normal cycling conditions in women we observed a decrease in latency of 20%, an effect that was twofold greater than noted in animals that had been hormonally manipulated to maximize an effect.
This study presents a potential mechanism by which male axillary secretions may alter menstrual cycle length and timing. The change in LH pulsing is predominantly seen during the first two applications of extract and suggests that the male stimulus may have only a transient effect upon the GnRH pulse generator.

In addition to the noted endocrine change, which may be accurately described as a primer pheromone effect, the mood data, demonstrating a lessening of tension and increased feeling of relaxation, suggest the presence of a modulator pheromone. Whether these two effects are mediated by the same or different compounds, or sets of compounds, is unknown. No other behavioral effects were noted as a result of extract application.

All subjects perceived that alcohol or fragrance was being applied to them during their stay in the GCRC; none guessed the true nature of the stimuli or the delivery sequence. This suggests that conscious awareness of body odor is not necessary to elicit the primer and modulator pheromonal responses we observed.

LH pulse maxima (heights) during extract application were significantly greater relative to control applications in the afternoon and early evening. Further, LH pulse maxima during afternoon control applications were greater than both morning control and morning extract maxima. These results suggest a diurnal shift in LH pulse maxima. LH has been reported to increase to maximal levels during the 1100–1700 h time-frame; this time encompasses 3 h in our morning/afternoon session (0800–1400 h) and 3 h in our afternoon/early evening session (1400–2000 h). Alternatively, male extract may have a "lingering effect," which is reflected as higher levels of LH during afternoon applications of the control stimulus.

Male extract may "uncouple" the controlling effect that endogenous opiates have upon the GnRH pulse generator. In this regard, its action appears similar to a small, acute dose of an opiate antagonist such as naloxone. In the follicular phase of the human menstrual cycle, as well as in ovoids, chronic administration of opiate antagonists raises tonic LH levels. As reported above, we may have observed this in subjects receiving male extract; however, we cannot say with certainty that a diurnal effect is not responsible for the elevated LH. Future studies should attempt to resolve this question by employing the same 12-h protocol reported herein and exposing subjects to the control stimulus every 2 h for the entire 12 h.

Other studies that have examined the effects of male and female axillary secretions upon the menstrual cycle have relied upon changes in cycle length as a measure of activity. The results reported here present a potential neuroendocrine measure of extract activity and a mechanism by which axillary secretion components may change cycle length. A periodic acceleration of LH pulses might be expected to occur during intimate heterosexual encounters as part of a stable heterosexual relationship.

This pattern may ultimately result in a greater frequency of pulses and entrain the pulse generator as well as stimulate ovarian follicles with a subsequent increase in tonic estrogen levels; this increase has been demonstrated in domestic ruminants and is suggested in data from humans where plasma estrogen levels in women having regular, weekly heterosexual intercourse are higher than in women having infrequent or no heterosexual intercourse.

The recent study by Shinohara et al. describes a reduction in LH pulse interval in women exposed to the follicular phase secretions of women donors and an increase in the LH pulse interval in women exposed to ovulatory phase secretions. These results suggest that female axillary secretions affect other women; however, the effects are different from those of male axillary secretions used in our study.

Aside from the first pulse after application, we did not observe a significant increase or decrease in pulse intervals across the time we monitored LH. There are, however, significant methodological differences between the studies. The application schedule and protocol of Shinohara et al. differed from ours. These investigators applied their stimuli every 30 min; we applied every 2 h. In addition, they did not use each subject as her own control as we did.

In their study, women were randomly assigned to receive isopropanol (control), follicular phase secretions, or ovulatory phase secretions. The latter two were presented on axillary pads moistened with isopropanol swiped on the upper lip; we used an ethanol extract of axillary pads. Despite these differences, these results support and strengthen the impact of our data:
1) axillary secretions from women affect the LH pulses of other women, and
2) the changes seen in LH pulses are of the same magnitude as those seen by us. Shinohara et al. reported that follicular phase secretions decrease LH pulse interval by 28%, and ovulatory phase secretions increase pulse intervals by 16%; we noted a decrease in the latency to the next LH peak by 20%. Shinohara et al. did not examine this parameter. Based on earlier studies by the same authors, they propose androstenol (5-androst-16-en-3-ol) as the axillary constituent that is responsible for the change in LH.

One of these earlier studies reported that women who exhibited menstrual synchrony had lower olfactory thresholds to androstenol. In another study, women exposed to 2.5 mM androstenol in isopropanol (applied above the upper lip hourly for 4 h) experienced an increase in their LH interpulse interval vs. controls. The level of androstenol applied by these investigators to their subjects (300 µl of the 2.5 mM solution; personal communication to G.P.) far exceeds endogenous levels, reported to be 4–10 ng in male axillae. Furthermore, at the level used, the odor of androstenol would have been obvious to the recipients; no control odor was used to exclude the possibility that the observed results were spurious as the result of a novel odor.

Studies by Jacob and McClintock [5] utilized putative "human pheromones" reported to "stimulate the (human) vomeronasal organ" (VNO); however, see for a review of experimental evidence for and against the existence of a functional, human VNO). These compounds are steroids, but only one, 4,16-androstadienone, has been reported in the axillae in picomolar quantities, which are far lower than the levels used by Jacob and McClintock (9 nmol/recipient; the other compound, estra-1,3,5 tetraen-3-yl acetate, is a synthetic compound never reported in the axillae).

Jacob and McClintock used such high levels (1000 times greater than endogenous concentration) because they wished to increase the compound's concentration near the pits of the "vomeronasal organ." Previous studies from our laboratory have not revealed the presence of this steroid in axillary extracts produced by the extraction techniques we employed in the current study.

Consequently, although Jacob and McClintock reported modulator pheromone activity for androstadienone when used at nonphysiological concentrations, we do not speculate on it or any other compound's role in our study.