1 The Institute for Mind and Biology, The University of Chicago, Chicago, IL 60637 and 2 Monell Chemical Senses Center, Philadelphia, PA 19104, USA
3 To whom correspondence should be addressed at: Department of Psychology, The University of Chicago, 5730 S. Woodlawn Avenue, Chicago, IL 60637, USA. e-mail: mkm1{at}uchicago.edu
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Abstract |
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Key words: breastfeeding/chemosignals/lactation/menstrual cycle/pheromone
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Introduction |
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To date, a few studies have shown that natural compounds produced in the axillary region of women and men can trigger neuroendocrine responses in recipient women and thus are considered to be pheromones. For example, axillary compounds collected from women during the ovulatory phase of their menstrual cycle lengthened the recipient womans ovarian cycle, delayed the pre-ovulatory surge of LH and decreased LH pulsing, whereas those collected during the follicular phase shortened cycle length by accelerating the pre-ovulatory LH surge and increasing LH pulse frequency (Stern and McClintock, 1998; McClintock, 2000
; Shinohara et al., 2001
). Shortening of the cycle (Cutler et al., 1986
) and alterations in the pulsatile release of LH (Preti et al., 2003
) were also observed when women were exposed to axillary compounds collected from men.
In spite of the fact that females of most mammalian species spend a greater portion of their reproductive life spans in birth cycles of conception, pregnancy, and lactation than in spontaneous unfertilized ovarian cycles (Altmann et al., 1978; Gudermuth et al., 1984
; Hedricks and McClintock, 1985
; Ellison, 2001
), there has been little investigation on whether lactating women and their infants influence the ovarian function and behaviour of other women with whom they interact. Animal model studies have revealed that pheromones from lactating rats and their pups induce maternal behaviours in adult conspecifics (Mennella and Moltz, 1988a
,b, 1989
) and increase the variability of ovarian cycles in recipient females by lengthening the cycle (McClintock, 1984
; Mennella and Moltz, 1989
)
Because prior studies have demonstrated effects of ovarian pheromones in both humans and rats (McClintock, 1984; Cutler, 1987
; Cutler and Stine, 1988
; Mennella and Moltz, 1989
; Stern and McClintock, 1998
; Shinohara et al., 2001
), the present study tested the hypothesis that exposure to chemosignals produced by lactating women and their infants would disrupt ovarian cyclicity, changing the follicular and luteal phases. Specifically, this novel study hypothesized that pheromones from breastfeeding (non-ovulating) women would increase the variability of ovarian cycles, particularly by lengthening them, and also by shortening them, as the effects of pheromones depend on the state of the ovary at the time of pheromone exposure (Schank and McClintock, 1992
). Indeed, phase response curves are an integral part of dynamically complex oscillating systems. Thus, we chose regression analyses that would reveal how breastfeeding compounds might perturb cycle length, based on the ovarian cycles initial state just prior to exposure. We also assessed whether sustained exposure to breastfeeding compounds continued to have similar effects in subsequent cycles.
To this aim, we collected natural compounds produced by both members of the breastfeeding dyadthe lactating mother and her infantand determined the effects of initial and sustained exposure to such compounds on the length of ovarian cycle and its variance in recipient, nulliparous women.
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Materials and methods |
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Collection procedures
Donors
Axillary and breast secretions were collected from 26 lactating women (31% African American, 69% Caucasian) living in the Philadelphia area (aged 32.2 ± 1.4 years), who were feeding their infants exclusively by nursing (13 girls, 13 boys; mean age = 3.5 ± 0.3 months) and had not yet resumed menstruation. Each donor participated in the study for 5 or 10 days. All procedures were approved by the Office of Regulatory Affairs at the University of Pennsylvania and informed consent was obtained from each subject before study participation.
Because previous research has shown that dietary flavors can be transmitted to human milk (Mennella, 1995), the mothers were instructed to eat a bland diet low in sulphur-containing foods. To encourage compliance, they were given a list of foods and spices to avoid (e.g. garlic, onion, curry) and were asked to record all foods and beverages consumed during this period. None of the mothers reported consuming such foods or spices during the collection period.
Procedures
Each day of the collection period, the donors bathed without perfumed products and wore 4x6 inch cotton WebrilTM pads (The Kendall Company, USA) in their nursing brassiere for 8 h, after which the pads were placed in glass vials [following modified methods used by Russell et al. (1980
) and Stern and McClintock (1998
)]. Dress shields (J.C.Penny, USA) were provided to secure the axillary pads in place. Nylon gloves (Scientific Instrument Services, USA) were worn by the women and experimenters when handling the pads.
Control pads with carrier solution were treated to match the axillary and breast pads both in moisture and appearance. Potassium phosphate (K2HPO4) buffer solution was used as the control carrier solution since the components of this fluid are similar in kind, concentration and pH to that of female sweat and breast milk (ICRP, 1975; Lentner, 1981
). Each breastfeeding and control pad was cut into four sections for future distribution and then frozen immediately at 80°C in glass vials.
Procedures of exposing women to breastfeeding compounds and determining cycle length
Recipients
At least 40 women (20 in each group) were required to have an 80% chance of detecting an effect on menstrual cycle length; this is based on the reported SD of 2.5 days for women aged 1835 years (an alpha of 0.05 and three independent variables). Hence, from January 1998 to March 1999, women were recruited for a 3 month study through posters, newspapers and fliers in a university community in Chicago. Each woman was screened and then included into the study if she was non-smoking, nulliparous, aged 1835 years, had a history of regular menstrual cycles, and was not using birth control pills or an intrauterine device. She was included if she was within 30% of ideal body mass index (BMI; 21.5 kg/m2), did not have a history of sinus problems, frequent colds, allergy symptoms, or nasal congestion, did not report psychiatric symptoms, was within normal range of olfaction as assessed by the University of Pennsylvania Smell Identification Test (UPSIT; Sensonics, Inc., USA) (Doty et al., 1984), and did not report high levels of pre-menstrual tension (Steiner et al., 1980
). Of the 114 recruited women who met these inclusion criteria, 84 agreed to comply with study procedures and enrolled in the study.
Because preconceived ideas or knowledge about pheromones could potentially influence their responses, study participants were blind to the hypotheses and the source of the compounds. The study was presented to subjects as an examination of odour perception during the menstrual cycle; the word pheromone was avoided in all communications. Participants were given a list of possible odorants that they might receive which included infant or sweat odours or no odour at all. They were told that the odorant might be different for each cycle. They were also asked to avoid wearing all perfumes or scented products for the duration of the study. All procedures were approved by the Institutional Review Board at The University of Chicago, and informed consent was obtained before participation.
Procedures
All recipient women were studied for one baseline cycle during which they were given two vials daily, both of which contained a control pad (Stern and McClintock, 1998). During the two subsequent experimental cycles, half of the women continued to be exposed to the control pads (control group; n = 30), whereas the remaining women were exposed to pads worn next to the axillae and breasts of lactating women, each of which was contained in a separate vial (experimental group; n = 27). Each woman in the experimental group received pads from at least three lactating women donors during each experimental cycle. Investigators who were blind to the identity of the donors and treatment condition of the subjects coded the vials containing the pads and generated the studys block sequence for allocating women to study groups. At the end of a womans baseline cycle, when risk of study discontinuation had decreased (see Figure 1), these investigators also randomly assigned recipient women to the study groups using an algorithm based on the date of a womans next menses. A different set of investigators enrolled participants, distributed the pads to the subjects, and assessed the study outcomes. The latter investigators did not know the identity of the donor, the type of pad (i.e. breastfeeding, carrier control) offered, the cycle status of the recipient, or the method of group assignment.
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Menstrual cycle assessment
Participants, who were trained on the procedures prior to the start of the study, recorded morning basal body temperature, evening cervical mucus characteristics and sexual activity, motivation and desire (the results of which will be reported elsewhere) throughout the 3 months of study participation. During the week prior to their expected day of ovulation, they tested their urine every evening (17:0019:00) for LH (Ovukit; Quidel Corporation, USA). This method has >95% accuracy (Stern and McClintock, 1996) in detecting the pre-ovulatory LH surge, a singular hormonal event that triggers ovulation and demarcates the follicular from the ovulatory phase of the cycle. In addition, subjects collected first morning urine on the 5th, 7th and 9th days following the LH surge, from which we assayed for progesterone glucuronide, an indicator of ovulation and functional corpus luteum. These data were used together with data on vaginal secretions, menses, and basal body temperature to define the phases of the menstrual cycle (Baviera et al., 1988
). Hereafter, menses is defined as the first to the last day of blood in vaginal secretions, including brown spotting. The follicular phase comprises the days between the last day of menses and the LH surge onset day. The ovulatory phase is the day of the LH surge onset plus the two subsequent days (ovulation occurs 30 h after the onset of the LH surge in urine). The luteal phase is comprised of the days between the end of the ovulatory phase and the first day of the subsequent menses. Menses onset demarcates the end of one menstrual cycle and initiates the next.
To assess the effect of breastfeeding chemosignals on normal menstrual cycles, we excluded women from analyses with abnormally long or short cycles that were self-reported during the screening phase (n = 2 women), experienced prospectively during the study (1 woman excluded for a long baseline cycle), or identified during preliminary analyses of initial cycle length (baseline, n = 7 women; cycle 1, n = 12 women). A normal cycle length was defined as 2434 days, inclusive, which was within 1 SD of the study samples mean baseline cycle length. This is a standard inclusion criteria because cycles outside 1 SD of the study samples mean cycle length are known to be atypical and not likely to be followed by a normal cycle (14% of cycles at 1835 years of age; Treloar et al., 1967; Harlow et al., 2000
). More specifically, atypical cycles may reflect luteal phase defects or anovulation, and menses is more likely to result from an alternate mechanism such as the endometrial breakthrough bleeding (Yen et al., 1999
).
Statistical analyses
The primary outcome variables were lengths of the three menstrual cycles and follicular and luteal phases of each cycle. To determine whether the baseline cycle length significantly predicted response to breastfeeding compounds when compared with control pads, cycle length data from each woman was plotted with respect to time, prior to any summary statistics. Next, to quantify the effect of initial conditions, we conducted simple linear regressions between the lengths of the initial cycle and subsequent cycles (i.e. between baseline length and cycle 1 length as well as between cycle 1 and cycle 2). Multiple regression was used to assess the effects of breastfeeding compounds on cycle length. Treatment condition (breastfeeding compound versus carrier control), length of the initial cycle, and their interaction were independent variables, and length of the subsequent cycle was the dependent variable. Similar models were used to assess effects of breastfeeding compounds on lengths of the follicular and luteal phases. For all of these analyses, the initial cycle (baseline or cycle 1) was normal in length (see above methods and definitions). A subset of women had normal cycles during both baseline and cycle 1 (n = 42 women); an analysis of this subset revealed that breastfeeding compounds had the same significant effect.
From the data collected during the twice-weekly visits, we determined how often each woman reported that she detected an odour (percentage of yes responses obtained during the eight observation visits during baseline and 16 observation visits during the two treatment cycles). Group differences were tested using repeated measures of analysis on frequency of odour detection with treatment condition (breastfeeding, control) as the between-subjects factor and cycle (baseline, experimental cycles) as the within-subjects factor. Individual differences in reporting the pads odours were established with repeated measures analysis of variance (16 observations per participant). Within the breastfeeding group, we used multiple regression to determine whether womens frequency of odour detection throughout the experimental months (16 observations per participant) mediated the effects of breastfeeding compounds on the ovarian cycle, with initial cycle length and odour detection frequency as independent variables and subsequent cycle length as the dependent variable. Power constraints precluded inclusion of other independent variables (e.g. treatment condition and its interaction with other variables) into a larger multiple regression model that encompassed the control as well as the experimental groups.
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Results |
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Regulation of menstrual cycle length
When cycle length data from each woman were plotted with respect to time (Figure 2), the striking difference between the experimental and control groups was the anticipated increase in cycle length variance that the treatment condition initiated. Moreover, in both conditions, the initial cycle length predicted the direction of change in subsequent cycle length.
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The effect of breastfeeding compounds was even more pronounced during the second month of exposure (Figure 3C and D). Cycle 1 lengths predicted cycle 2 lengths (r = 0.82, P 0.001). Again, change in cycle length from cycle 1 to cycle 2 in the experimental group was significantly different from than that of the control group (groupxcycle length interaction in a multiple regression [B = 1.02 (standardized regression coefficient = 3.94), P
0.01]; Figure 3C and D).
Follicular and luteal phase length
During the follicular phase, the experimental group showed the same response in phase length as seen for the overall cycle length. Baseline follicular phase lengths predicted the length of the subsequent follicular phase (r = 0.70, P 0.001), and the follicular phase length in cycle 1 predicted its lengths in cycle 2 (r = 0.86, P
0.001). Again, the pattern was significantly different from that of the control group during the baseline and first month of chemosignal exposure (groupxcycle length interaction in a multiple regression [B = 0.73 (standardized regression coefficient = 0.82), P
0.04]; Figure 4A and B), an effect that became even more striking during a subsequent month of exposure (groupxcycle length interaction in a multiple regression [B = 0.94 (standardized regression coefficient = 1.0), P
0.003; Figure 4C and D]. Therefore, the breastfeeding compounds also maintained follicular phase lengths according to an individuals set-point at the time of exposure and disrupted the normal pattern of regression to the modal length.
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Discussion |
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This effect became even more striking during a second cycle of exposure. In contrast, women in the control group experienced a variation in cycle length that was regulated towards the population modal cycle length, a finding that is consistent with previous studies (Harlow and Zeger, 1991; Spencer, 2001
). This dependence on initial conditions is one of the defining characteristics of a formally chaotic system (Glass and Mackey, 1988
) and further supports the contention that individual or subpopulation differences cannot be ignored when examining treatments that alter oscillating cycles such as the human menstrual cycle.
The observation that normal biological cycles have set points for their periodicity and that these set points can be altered in normal biological cycles is not new in the literature. The concept of homeostasis of periodicity describes non-random, oscillating systems (Winfree, 1980) such as the human menstrual cycle. These systems run according to an endocrine clock that remains in a particular state or returns to that state after having been in other accessible states resulting from perturbations (Winfree, 1980
). Inflicting a stimulus, such as a dose of a given hormone, or a chemosignal that triggers a hormonal response, should theoretically be able to reset the clock to a new set-point, or disrupt the homeostatic regulation of periodicity, as we demonstrate here.
Because both the follicular and luteal phases of the cycle mediated the response to breastfeeding compounds, the neuroendocrine response to breastfeeding compounds could be mediated by LH pulsatility, estrogen threshold for the LH surge, as well as prolactin, progesterone and corticosterone secretion. Since the follicular phase responses and not luteal phase responses were significantly maintained during the second month of exposure, the present data suggest that more prepotent neuroendocrine mechanisms may be those predominant in the follicular phase. Animal model studies demonstrate that pheromones mediate ovarian cycle length by regulating the incidence of partial surges of LH as well as progesterone and prolactin levels after ovulation during the luteal phase (McClintock, 1983a,b; Gans, 1993
). Nevertheless, this remains to be investigated further in humans, since inherent species differences in ovarian function preclude specific predictions about the human menstrual cycle based on the animal literature.
Although we found no evidence that odours emanating from the mother, infant, or both contributed to the observed effects on cycle length, research has shown that compounds emanating from a breastfeeding environment can be recognized by and affect the behaviours of both the mother and child (Macfarlane, 1975; Cernoch and Porter, 1985
; Schaal, 1986
; Sullivan and Toubas, 1998
). The newborns preference for their mothers breasts during conditions when they are unwashed and thereby more odorous (Varendi et al., 1994
) suggest that, like other mammalian young, the recognition of and preference for maternal odours may play a role in guiding the infant to the nipple area and facilitating early nipple attachment and breastfeeding.
The present findings suggest that breastfeeding compounds have the potential for being social chemosignals and may or may not contain chemicals that ultimately fulfil the criteria for a human pheromone (Beauchamp et al., 1976, 2000
; McClintock, 2000
, 2002
). The traditional definition of pheromones states that they are chemical signals produced by one member of a species and received by another, triggering neuroendocrine responses underlying behaviour and physiology (Karlson and Butenandt, 1959
; Karlson and Luscher, 1959
). The active component(s) of the breastfeeding compounds modulated the neuroendocrine mechanisms controlling the timing of the pre-ovulatory LH surge as well as the length of luteal phases of other women. These breastfeeding compounds are naturally produced, and contain axillary sweat and breast milk from the mothers, and most likely saliva from infants, and skin cells from either mother or infant.
That social interactions within groups of women and with men change the timing of the menstrual cycle and the pre-ovulatory LH surge has also been demonstrated in a variety of settings. Other studies have also demonstrated that human axillary compounds from men and women regulate LH, its pulsatility, the timing of the pre-ovulatory LH surge and menstrual cycle length (Stern and McClintock, 1998; McClintock, 2000
; Shinohara et al., 2001
; Preti et al., 2003
).
This direct application of compounds parallels the effect of spontaneous social interactions on the menstrual cycle. For example, women who spend time with men are more likely to have ovulatory menstrual cycles (McClintock, 1971; Veith et al., 1983
; Stanislaw and Rice, 1987
). In addition, women who live together have menstrual cycles that are either synchronized or non-randomly distributed (McClintock, 1971
; A.Weller and L.Weller, 1993
, 1997
; McClintock, 1998
). It is important to acknowledge that not all investigations have found social interactions to affect ovarian cycles, although these latter studies focus on social settings where women live primarily with men, have infrequent interaction with each other, or have variable living conditions (Graham, 1992
; L.Weller and A.Weller, 1993
).
These human effects parallel those seen in a wide variety of mammals. In other mammalian species, social chemosignals and pheromones also regulate ovulation (McClintock, 2002). Among females with scarce resources, these systems can function to suppress ovulation in a form of competition or to signal the availability of resources. In humans, these compounds may have served to regulate fecundity in women in the context of traditional societies where limitations of food resources make fertility highly seasonal (Ellison et al., 2001
). Women with variable menstrual cycle lengths (i.e. cycles that change by >10 days from cycle to cycle) have reduced fecundity (defined as the probability within a given cycle that a woman will become pregnant; Kolstad et al., 1999
). Prior to further speculation on function, more research needs to be done on the nature of the response when women are in a variety of natural reproductive states.
This is the first study to demonstrate that continuous exposure to breastfeeding compounds affects the neuroendocrine mechanisms regulating menstrual cycle length. Future studies should identify the specific neuroendocrine responses that mediate their marked effects as well as demonstrate these effects occurring in a normal social contextthat is, with nulliparous women directly interacting with breastfeeding women as opposed to interacting artificially through collected, bottled secretions wiped underneath the nose. Future studies should also examine the effect of breastfeeding compounds on non-normal cycles in which menstrual bleeding might be regulated by alternate mechanisms. Definitively labeling breastfeeding chemosignals as human pheromones will require demonstrating that they do indeed operate in the context of normal daily interactions with breastfeeding women and their infants.
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Acknowledgements |
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Submitted on January 9, 2003; resubmitted on July 8, 2003; accepted on September 29, 2003.