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Biology of Reproduction 59, 1317-1320 (1998)
©Copyright 1998 Society for the Study of Reproduction, Inc.

Role of the Adrenal Gland and Adrenal-Mediated Chemosignals in Suppression of Estrus in the House Mouse: The Lee-Boot Effect Revisited1

Weidong Maa, Zhongshan Miaoa, and Milos V. Novotny2,a

a Department of Chemistry, Indiana University, Bloomington, Indiana 47405


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mature female mice, grouped in the absence of a male stimulus, exhibit a suppressed estrous cycle (the so-called Lee-Boot effect). We have designed a series of experiments to elucidate the involvement of the adrenal gland in this phenomenon. Our initial results indicate that adrenalectomized mice exhibit a regular estrous cycle in either isolated or grouped conditions. A single, intact mouse caged with five adrenalectomized females showed repeated normal cycles. When the urine samples from group-caged intact mice or group-caged adrenalectomized mice were applied to the external nares of singly caged females, estrous cycles were inhibited in the animals receiving urine from the intact mice but not from the adrenalectomized mice. In addition, corticosterone therapy restored the function of estrus suppression in grouped, adrenalectomized mice.

We had previously shown that the urinary excretion of several volatile compounds (2-heptanone, trans-5-hepten-2-one, trans-4-hepten-2-one, pentyl acetate, cis-2-penten-1-yl acetate, and 2,5-dimethylpyrazine) was adrenal mediated (Science 1986; 231:722–725). A further testing of these compounds in relation to estrus suppression has now revealed that a mixture of these compounds is effective, but removing 2,5-dimethylpyrazine from the mixture abolished the biological response. The overall results of this study show conclusively an important role of the adrenal gland and adrenal-mediated urinary metabolites in estrus suppression.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The ovarian activity of rodents is primarily controlled by hormones from the pituitary gland and other tissues. The external factors, such as chemosignaling, play an additional, important role in the regulation of estrous cycles. In the house mouse, for example, isolated females tend to display short estrous cycles of 4–6 days in duration, while females housed under crowded conditions exhibit irregular or prolonged cycles [1, 2]. This phenomenon of estrus suppression has been termed the Lee-Boot effect after the scientists who first quantified it [3]. The estrus inhibition appears to be olfactorily mediated [4, 5] and independent of the other aspects of overcrowding, such as tactile and visual stimuli [6]. It has been presumed that the inhibitory chemosignals are excreted in the urine [7]. The signals appear mediated, at least partly, through the vomeronasal organ, since excision of the organs reduces the number of females experiencing a delayed estrus [8]. Additionally, ablation of the olfactory bulbs prevents spontaneous pseudopregnancy in grouped females [4]. The degree of estrus suppression in a group is partially determined by its size. While the cycles of mice living in pairs are lengthened only slightly (compared to those of isolated animals), a significant effect is observed with 4–6 group members [5]. A complete suppression occurs when all-female groups become even larger [6].

Although estrus suppression in grouped females has been demonstrated fairly well in different laboratories, there are numerous controversies over the physiological mechanism of this pheromonal communication. Several research groups reported that a mutual suppression of the estrous cycle was dependent on ovarian hormones, since ovariectomy attenuated the ability to suppress the cycles of other females [9–11]. However, surgical removal did not abolish the suppressive effect [9, 12], indicating that there were other effective signals that were independent of the ovary. Moreover, additional investigators argued that the ovarian hormones were not at all responsible for this pheromonal cue [13–15]. It was even postulated that the inhibition of estrous cycle was due to a factor released from the clitoral gland [9]. Yet another study pointed out that this gland did not seem to have a role in the production of estrus suppression pheromones [16].

Crowding is usually considered to be a stressful factor for animals [17, 18], pointing to a role of adrenal glands. Studies supporting this concept have been largely based on the changes of adrenal weight and corticosterone concentration [19–21]. Using a functional approach in the present work, we explored a possible relationship between the mouse adrenal gland and estrus suppression. The estrous cycles of intact and adrenalectomized females were monitored under isolated and grouped conditions. Urine samples and bedding materials from grouped females were examined for their activity in estrus disruption. The effect of adrenalectomy, followed by a hormone therapy, on the production of chemosignals that delay estrus was also assessed. In addition, several adrenal-controlled volatile compounds were tested for their effectiveness in estrus delay.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experimental Animals

Adult ICR/Albino female mice (3–4 mo old) were purchased from Harlan Sprague-Dawley, Inc. (Indianapolis, IN). The animals were housed in cages with dimensions of 12 x 27 x 17 cm. The experimental rooms were maintained at 22°C and 70% humidity. The light schedule was set according to a 12-h regime, with lights-on at 0700 h. Bedding material was changed weekly for all experiments. Food and water were supplied ad libitum. Adrenalectomy was performed by the supplier. Sodium chloride (1%) was added to the drinking water of the adrenalectomized mice. The estrous status was monitored by the conventional vaginal smearing method [22]. Estrous cycles were recorded daily for all individual animals. All observations were carried out in rooms free of any male mice. In some cases, when the animals were used more than once for different experiments, there was at least a 2-wk interval between experiments to allow the animals to recover, minimizing any carryover effects. The average length of the estrous cycle in each experiment was expressed as a mean ± SE. The data were analyzed using nonpaired and paired Student's t-test [23]. The probability level for a significant difference was set at p < 0.05.

Experiment 1

The first experiment was a pilot study to determine whether adrenalectomy had any influence on the estrous cycle of isolated females; 12 intact and 17 adrenalectomized, singly caged mice were housed in separate rooms, while their estrous cycles were monitored daily for 12 days.

Experiment 2

The objective of this experiment was to examine difference in the estrous cycle between the adrenalectomized (n = 34) and intact (n = 24) mice kept under grouped conditions. The two groups were housed in separate rooms, 5–6 per cage. After a 4-day adaptation period, the estrous status of the mice was examined daily for 17 days. For statistical analysis, each cage was used as a sampling unit and was represented by its arithmetic mean.

Experiment 3

This experiment was designed to test whether the adrenalectomized mice were able to produce chemosignals affecting the estrous cycle of the intact mice. Two treatments were used. In treatment A, 1 intact mouse was kept with 5 adrenalectomized mice in each cage. After a 4-day adaptation period, the estrous cycle of the intact mouse was monitored daily for 22 days. Six cages were used for this group. In treatment B, 1 intact mouse was housed with 5 other intact mice (3 cages were used). Their estrous status was examined daily for 22 days after a 4-day adaptation period.

Experiment 4

The purpose of this experiment was to study whether the urine from grouped mice was responsible for estrus inhibition. Adrenalectomized mice and intact mice were grouped separately, 6 mice per cage, for 1 wk before urine collection. Urine samples were obtained by holding the animals over a glass plate and gently pressing the abdomen areas. The samples were pooled and stored frozen (-20°C) until use (within 1 mo). Subsequently, the singly caged mice were treated with the urine of either adrenalectomized (treatment A, n = 15) or intact mice (treatment B, n = 15). Approximately 50-µl urine aliquots were applied to the external nasal nares using a small tube adapted to a syringe. This treatment was performed twice daily for the whole experimental period (once in the morning; second time in the afternoon). After 4-day pretreatment (vaginal smear was not determined at this period), estrous cycles of the singly caged mice were monitored daily for 16 days.

Experiment 5

The objective of this experiment was to examine whether the bedding materials soiled by intact grouped mice (or adrenalectomized and grouped mice) could cause estrus suppression in singly caged mice. About 500 g of the bedding material soiled by grouped females (with 7 mice per cage, soiled for 1 wk) was applied to each cage of isolated females. The bedding for the isolated animals was replaced with "new" bedding used by grouped females once a week for the entire experimental period. After 1-wk adaptation, the estrous status of the singly caged mice was checked daily for 15 days. Two treatments were designed: in treatment A, 16 singly caged females received bedding from the grouped adrenalectomized females, and in treatment B, 16 singly caged females received bedding from the grouped intact mice.

Experiment 6

In a previous study, we had demonstrated that the urinary levels of several compounds (2-heptanone, trans-5-hepten-2-one, trans-4-hepten-2-one, pentyl acetate, cis-2-penten-1-yl acetate, and 2,5-dimethylpyrazine) were adrenal dependent [24]. The objective of the experiment reported here was to investigate whether these adrenal-mediated chemicals were effective in induction of the estrus suppression in singly caged mice. The adult females were singly caged and assigned to two treatments: in treatment A, 17 singly caged females were treated with a mixture of the six urinary compounds, and in treatment B, 16 singly caged animals were treated with water as a control. A drop of test solutions (about 50 µl) was applied to the external nasal nares through a syringe, twice per day, for the entire experimental period. After a 4-day pretreatment, the estrous cycle of each animal was examined daily for 19 days. 2-Heptanone, trans-5-hepten-2-one, trans-4-hepten-2-one, n-pentyl acetate, cis-2-penten-1-yl acetate, and 2,5 dimethylpyrazine were dissolved in distilled water at concentrations of 2.5, 0.28, 0.39, 0.50, 1.10, and 0.25 ppm, respectively, to mimic their natural urinary concentrations [24].

Experiment 7

This experiment was similar to experiment 6, except that 2,5-dimethylpyrazine was excluded from the mixture. In treatment A, 17 singly caged mice were treated with the test mixture; in treatment B, 15 singly caged mice were treated with water. Two applications were performed daily for the whole experimental period. Drops of 50 µl of test solutions were delivered to the external nares each time. After a 4-day pretreatment, the estrous status of each animal was examined daily for 12 days.

Experiment 8

This experiment was designed to test whether replacement with corticosterone (an adrenal hormone) could restore the adrenal function of adrenalectomized mice in estrus suppression. Adult, adrenalectomized female mice were grouped (5–6 mice per cage, with 3 cages used). After a 4-day adaptation period, the estrous status of each animal was examined daily for 10 days (treatment A). Then, on the 11th day, each animal (still in a grouped condition) was injected with 400 µg corticosterone daily for 14 days (treatment B). The estrous status was examined daily. For statistical analysis, each cage was represented by its arithmetic mean and considered as a sampling unit.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiment 1

No difference was detected in the length of the cycle between the intact mice and the adrenalectomized mice under isolated conditions (4.33 ± 0.23 vs. 4.50 ± 0.22 days, p > 0.05). The animals from both groups exhibited normal estrous cycles (typically, 4–5 days in duration), suggesting that adrenalectomy has no effect on the estrous cyclicity.

Experiment 2

While the grouped intact mice showed prolonged cycles (8.50 ± 1.74 days), the grouped and adrenalectomized mice exhibited nearly regular cycles (5.87 ± 0.41 days). The difference between these two treatments was highly significant (p < 0.004).

Experiment 3

When an intact test mouse was caged with a group of adrenalectomized mice, its cycle remained unchanged (4.95 ± 0.25 days). However, when an intact test mouse was caged with other intact females, its cycle was lengthened significantly due to the increased population density (7.69 ± 1.62 days, p < 0.002). This suggests that, after adrenalectomy, the mice were not able to produce the chemosignals inducing estrus delay even though they were in a grouped environment.

Experiment 4

Experiment 4 demonstrated that singly caged mice treated with urine from grouped intact females had longer cycles than the singly caged mice treated with urine from grouped adrenalectomized females (6.09 ± 0.23 vs. 5.25 ± 0.23 days, p < 0.042). This result implies that urine was at least one of the pheromone sources, with the adrenal gland playing a key role in producing this pheromone.

Experiment 5

Cycles of isolated females exposed to bedding from grouped intact females were not different from those of isolated females exposed to bedding from grouped adrenalectomized females (4.85 ± 0.44 vs. 5.00 ± 0.56 days, p > 0.05).

Experiment 6

When compared with the control, i.e., treatment with water, the mixture of the six adrenal-mediated compounds was highly effective in inhibiting estrus in the individually caged mice (5.54 ± 0.32 vs. 7.70 ± 0.53 days, p < 0.02). This result further demonstrates the role of the adrenal gland in estrus disruption.

Experiment 7

After 2,5-dimethylpyrazine was excluded from the mixture, the remaining five compounds were no longer effective in estrus suppression (treatment vs. water: 4.94 ± 0.52 vs. 4.80 ± 0.26 days, p > 0.05). This suggests that pyrazine is a necessary ingredient in the mixture. In a previous study [25] using a different experimental procedure, we found that 2,5-dimethylpyrazine alone was also active in inducing the estrus delay.

Experiment 8

The normal cyclicity of grouped adrenalectomized mice, as demonstrated in experiment 2, was confirmed in this experiment (4.31 ± 0.21 days). However, after corticosterone treatment, the cycles of these grouped, adrenalectomized mice increased significantly (6.73 ± 0.53 days, p < 0.022), indicating that corticosterone may control the metabolism of the estrus delay pheromone.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study has established an apparent relationship between estrus suppression and the adrenal function. Estrous cycles were significantly delayed in grouped intact females but not in grouped adrenalectomized animals. A corticosterone supplement to the adrenalectomized mice could restore the ability to inhibit estrous cycles. It has also been verified that urine is a major source of the estrus-suppressive chemosignal. The mixture of the six previously identified adrenal-mediated volatile compounds [24] is effective in estrus suppression. 2,5-Dimethylpyrazine was found here to be a necessary mixture component for its biological activity.

It has long been established that a high population density inhibits reproduction in young female mice. Caging immature females in groups, or exposing singly caged young females to the urine of grouped females, is known to delay the onset of their puberty. The studies of Drickamer [26] early on gave a strong indication that the puberty inhibition effect was associated with the adrenal function. Subsequent investigations proved conclusively that adrenalectomy [27], but not ovariectomy [28], abolished the biological effect of excreted urine on puberty delay in juvenile mice, while adrenal hormone therapy could restore the effect of urine on maturation delay [29]. In light of these results, estrus suppression (in adult females) and puberty delay (in juvenile females) could be seen as having a common endocrinological denominator. After all, puberty can be viewed as the first estrus in young females.

In an earlier study [5], with single females housed in a cage previously soiled by a group of other females, estrus was not frequently observed. The results shown here and elsewhere [30] are at variance with this observation. We assume that variations due to degree of exposure (amount of bedding used, time of animals' contact with bedding, and evaporation of a volatile pheromone at different temperatures, air humidity, cage ventilation, etc.) may account for these discrepancies.

Bronson and Chapman [19] discussed the effect of grouping on estrous cycles and adrenal function. Since they could not detect any changes in the weight of adrenal glands and corticosterone levels after the grouping, it was concluded that the group-housed female mice were not stressed by this procedure. In several of the present experiments, the adrenal gland has been shown clearly to be involved in estrus suppression. In fact, there is much conflicting evidence on the effect of isolation (as opposed to grouping) on the adrenal function. However, a number of investigators have demonstrated an increase of adrenal weight after grouping [31–36]. An increase in adrenal weight is associated with elevated adrenal activity [20, 21, 34, 36]. However, a number of investigators have been unable to demonstrate differences in adrenal weight and activity as a result of isolation/grouping [37–42]. Additionally, there are even a few cases in which an increase in adrenal weight of isolated animals (compared with grouped animals) was observed, leading to formulation of the concept of "isolation stress" [19, 43–47]. Thus, finding the appropriate endocrine correlates of these phenomena remains the subject of future experiments.

It is likely that there is a dose-dependent response in the Lee-Boot effect. The estrus inhibition pheromone may exist in the urine of singly caged females and appears to be controlled by the adrenal, but its low concentration may not be sufficient to cause a biological response. However, when the animals become grouped and stressed, an increasing amount of pheromone from most or all animals could reach a threshold level for estrus inhibition. This explanation is tentatively supported by the fact that the cycle length was slightly affected when just 2 females were grouped but was lengthened appreciably when group size was increased to 4–6.

As a possible counterbalance to the female estrus-suppressive chemosignal, male pheromones have been known to renew the cycles of grouped females and synchronize their estrus (the Whitten effect). It is not clear, at present, whether the presence of a male or his pheromone(s) reduces production of the adrenal-mediated chemosignal in females or, alternatively, overrides the female's inhibitory signal.


   FOOTNOTES
 
1 This work was supported by PHS grant no. DC 02418 from the National Institute of Deafness and Communicative Disorders, U.S. Department of Health and Human Services. Back

2 Correspondence. FAX: 812 855 8300; novotny{at}indiana.edu Back

Accepted: July 13, 1998.

Received: January 12, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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