Behavioral discrimination between circumgenital odor from peri-ovulatory dominant and anovulatory female common marmosets (Callithrix jacchus)

Social peer groups of callitrichid monkeys [marmosets and tamarins] exhibit intrasexual dominance hierarchies in captivity. This laboratory study employed two-choice behavioral discrimination bioassys to test the hypothesis that scent from female common marmosets contains chemical cues that permit discrimination between dominant females in the periovulatory versus luteal phase of the ovarian cycle and females holding dominant versus subordinate status. When scent from only dominant females was presented, marmosets directed significantly greater amounts of investigatory behavior toward peri-ovulatory scent versus scent collected during the luteal phase of the ovarian cycle. Animals of both sexes demonstrated significant discriminatory behavior between scent deposited by dominant versus subordinate females, but only when the dominant female was in the peri-ovulatory phase of the ovarian cycle. Test animals directed equal amounts of investigative behavior toward scent from luteal-phase dominant females and subordinate females. Female test subjects deposited significantly more scent marks over presented scents than did male subjects, particularly when the scent had been donated by a peri-ovulatory female. Chemical odors specific to the periovulatory and luteal phases of the ovarian cycle may play a role in mediating behavioral interactions among marmosets.     

Social subordination stress, behavior, and central monoaminergic function in female cynomolgus monkeys

BACKGROUND: Social subordination in female cynomolgus monkeys is stressful and activates the hypothalamic-pituitary-adrenal axis. In a previous experiment behavioral depression was observed in a subset of subordinates. METHODS: In the experiment reported here behavioral and physiological indicators of stress were evaluated in dominant and subordinate female cynomolgus monkeys, and brain dopaminergic activity was assessed, as reflected in the prolactin response to haloperidol, a dopamine2 (D2) receptor antagonist. RESULTS: Subordinates were aggressed more, spent more time in fearful scanning of the social environment, spent less time as the recipients of the active affiliative behavior of being groomed, had more variable heart rates in response to a novel environment, and were hypercortisolemic compared to dominants. Prolactin responses to haloperidol challenge were lower in subordinates than dominants, an observation consistent with the hypothesis that subordinate females have decreased D2 receptor function. CONCLUSIONS: These observations suggest that social subordination is stressful and may alter brain dopaminergic function in primates. The neurophysiological characteristics of social subordinates may contribute to their susceptibility to depression.     

Cyclic changes in genital organs and vaginal cytology in cynomolgus monkeys (Macaca fascicularis)

Vaginal cytology was evaluated weekly over 12 months in 20 adult female Cynomolgus monkeys (Macaca fascicularis). After sacrifice of the animals the histology of the ovaries, uterus and vagina were studied in different phases of the menstrual cycle. The cytological examination of the vaginal smears showed that the superficial cells increased in number towards the middle of the cycle and the number of intermediate cells declined gradually. Parabasal cells were observed mainly at the beginning of the cycle; they disappeared towards the middle of the menstrual cycle. During the early follicular phase, the cells were moderately separated from each other, and during the second half of the proliferative or follicular phase, the superficial cells appeared clumped together. Leucocytes were usually absent except for at the beginning of the cycle and in the last few days of the late secretory or luteal phase. The maturation index of the vaginal smears can be considered as a tool for distinguishing the different phases of the menstrual cycle. The microscopic examination of the genital organs showed that during the proliferative or follicular phase of the cycle, which corresponds to the development of the ovarian follicles, the uterus showed growth of endometrial glands, stroma and endothelial cell proliferation with capillary sprouts. Shortly after ovulation and parallel to the formation of the corpora lutea, the endometrium enters the secretory or luteal phase, which is characterized by coiling of endometrial glands, glandular secretion and the differentiation of the spiral artery. The most striking changes in the vagina, is the marked basal cell proliferation and thickening of the stratum granulosum during the follicular phase of the menstrual cycle. The histological changes observed in the vagina demonstrated a good correlation with the observation on cytological examination of the smears. The present study demonstrated that the process of angiogenesis in the uterus during the different phases of the menstrual cycle is a multiple phenomenon involving proliferation, maturation and differentiation.     

Recombinant human inhibin-A administered early in the menstrual cycle alters concurrent pituitary and follicular, plus subsequent luteal, function in rhesus monkeys

Inhibin, a suppressor of pituitary FSH secretion in nonprimate species, may also act in the ovary to regulate follicular development. To examine whether inhibin has similar actions in primates, female rhesus monkeys (n = 3/treatment), exhibiting regular menstrual cycles, received sc injections of either vehicle or 60 micrograms/kg recombinant human inhibin-A at 0800 and 1600 h for 5 days beginning at menses. The vehicle-treated monkeys displayed menstrual cycles of normal length, with the follicular (11.3 +/- 2.5 days, mean +/- SE) and luteal (16.3 +/- 2.5 days) phases demarcated by midcycle peaks in serum estradiol (E) and bioactive LH. After the first inhibin injection, levels of immunoreactive inhibin A peaked at 10 ng/mL within 1 h and returned to baseline (< 0.1 ng/mL) before the second injection 8 h later. Although serum E and LH did not change, bioactive FSH decreased (to 66% of pretreatment levels, P < 0.05) within 8 h. Within 1 day, circulating bioactive FSH was less (P < 0.05) in inhibin-treated monkeys, compared with controls. By 2-3 days, serum E levels were also markedly (P < 0.05) reduced in inhibin-treated animals, whereas bioactive LH rose 3-fold (P < 0.05). After inhibin treatment, the midcycle rises in serum E and LH were delayed; hence, the follicular phase was prolonged (15.0 +/- 2.6 days, P < 0.05), compared with controls. Although the patterns and levels of serum LH circulating during the subsequent luteal phase seemed comparable in both groups, mean progesterone levels were suppressed to 2-3 ng/mL (P < 0.05) during the midluteal phase in inhibin-treated monkeys. However, the length of the luteal phase in inhibin-treated cycles (13.0 +/- 2.6 days) was not significantly altered. We conclude that exogenous inhibin rapidly diminishes pituitary FSH secretion in female monkeys during the early follicular phase of the menstrual cycle. This action, and/or other actions directly on the ovary, leads to subsequent effects on follicular steroidogenesis and pituitary LH secretion that culminate in an aberrant ovarian cycle characterized by an insufficient luteal phase. The study identifies, for the first time, possible activities and roles of inhibin during the ovarian cycle in primates.     

Prelordotic behavior in the hamster: A hormonally modulated transition from aggression to sexual receptivity.

Analyzed the behavioral responses of 60 female golden hamsters to sexually experienced males as a function of the stage of the female's estrous cycle. Exogenous estradiol or estradiol followed by progesterone was given to ovariectomized Ss to determine the role of these hormones in regulation of cyclic changes in the female's response to the male. Ss were paired daily with sexually active males for 10 min, and behavioral interactions were recorded. Significantly more fighting occurred during early diestrus than later in the cycle. By 8 hrs prior to the onset of sexual receptivity, 86% of Ss exhibited a behavior resembling the onset of lordosis without immobilization. Following ovariectomy, fighting was at a high level. Estradiol replacement over 28 days resulted in a significant decrease in aggression and increase in display of the prelordotic response. Initially, treatment with progesterone following 7 days of estradiol caused lordosis display. After 24 hrs a significant increase in aggression, which continued as long as progesterone was present, was observed. Thus, estradiol causes the female to become tolerant of the male's approach, the female exhibiting prelordosis in response to the male's investigation. Estradiol and progesterone are necessary for normal sexual receptivity; however, after 24 hrs, estrogen/progesterone-treated females become agonistic to the male. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral and neurobiological effects of estrogen replacement therapy and a history of triphasic oral contraceptive exposure

The effects of contraceptive steroids and estrogen replacement therapy on behavior and neuroendocrine function were evaluated in adult female cynomolgus monkeys. During the 'premenopausal' phase of the experiment, the animals were assigned to either treatment with a triphasic oral contraceptive (OC) for 24 months or the untreated control group. The monkeys were then ovariectomized and half of each of the premenopausal groups were randomly assigned to either treatment with conjugated equine estrogens (ERT) or the untreated control group for 12 months (the 'postmenopausal' phase). All evaluations were completed during the postmenopausal phase of the experiment. Both types of exogenous steroid treatments appeared to increase cardiovascular and hypothalamic-pituitary-adrenal responses to stress in socially dominant but not socially subordinate females. A history of triphasic OC administration increased contact aggression received, and reduced the prolactin response to fenfluramine, suggesting reduced serotonergic activity, for at least a year following the cessation of triphasic OC treatment.     

Consort bonding and operant behavior by female rhesus monkeys.

An operant conditioning situation was used to relate the leverpressing performance of female rhesus monkeys to different measures of social, sexual, and agonistic behavior that underlie the formation and dissolution of consort bonds. Nine females were trained to press a lever 250 times to gain access to a male partner. After access, a standard 60-min behavioral test took place (1,440 tests). Data were analyzed independently of the stage of the menstrual cycle. Eight females were tested with 2 males, and every female gained access faster with 1 male (i.e, preferred partner). For all 8 females, the preferred male was the one that spent more time grooming the female. For 5 females, the preferred partner was also the one that ejaculated more frequently. For 4 females, where agonistic interactions with males could be evaluated, the preferred male was the one that elicited fewer submissive behavioral patterns. These results indicate that the operant behavior of female rhesus monkeys is positively reinforced by social and sexual factors and negatively reinforced by agonistic interactions and may thus provide a measure of the strength of consort bonds. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intrasexual interactions among female golden hamsters (Mesocricetus auratus) over the estrous cycle.

Examined social interactions of cycling female golden hamsters paired with ovariectomized animals (N?=?96) in large enclosures. Interactions were primarily agonistic and intense over the 4-day estrous cycle, as indicated by frequent occurrences of chase and flight behavior. Dominant and subordinate social ranks were established in the majority of pairs (96%) tested, and even Ss in sexual heat were capable of attacking and dominating their rivals. Furthermore, cycling Ss exhibited significantly more aggressive acts than ovariectomized opponents 1 day prior to sexual receptivity. No differences in fighting patterns were found between Ss on the other 3 days of the estrous cycle. Additional analyses revealed clear differences in agonistic elements, including flank marking, between dominant and subordinate Ss, regardless of whether they were gonadectomized or intact. Analyses also show that dominant Ss frequently chased and bit opponents during encounters within their nesting area. Data are examined for implications on the adaptive organization of female hamster agonistic behavior and the neuroendocrine regulation of species-typical behavior over the estrous cycle. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

alpha-Tocopherol concentrations in plasma but not in lipoproteins fluctuate during the menstrual cycle in healthy premenopausal women

Because premenopausal women experience cyclic fluctuations of plasma carotenoids and their lipoprotein carriers, it was hypothesized that plasma alpha-tocopherol (A-T) fluctuates by phase of the menstrual cycle. Twelve free-living women, with a confirmed ovulatory cycle, were given a controlled diet for two consecutive menstrual cycles. Blood was drawn during the menses, early follicular, late follicular and luteal phases to simultaneously measure serum hormones, plasma lipoproteins and A-T concentrations, and A-T distribution in the lipoprotein fractions. Plasma A-T concentrations were significantly lower during menses than during the luteal phase by approximately 12% in each controlled diet cycle (P < 0.001). Adjustment for serum cholesterol and triglyceride concentrations did not alter these findings. The distributions of A-T in lipoprotein cholesterol fractions were not significantly different by menstrual phase. From 61 to 62% of A-T was concentrated in the LDL fraction, with another 9-14% in HDL2, 17-22% in HDL3 and the remaining 6-8% in VLDL+ IDL. There were no significant differences in lipoprotein cholesterol fractions by menstrual phase, except for a significant increase (P = 0.03) in HDL2 cholesterol from the early follicular to the late follicular phase. Spearman rank correlations from data during the second controlled diet month showed A-T in HDL2 in the late follicular phase was positively correlated with HDL cholesterol in the early follicular (r = 0.88), late follicular (r = 0.86) and luteal phases (r = 0.86) and with luteal apolipoprotein (ApoA-1) level (r = 0.90), and luteal HDL2 cholesterol (r = 0.83). A-T in HDL3 in the early follicular phase was negatively correlated with HDL2 cholesterol (r = -0.96) and ApoA-1 (r = -0.85), whereas luteal A-T in HDL3 was correlated with luteal HDL3 cholesterol (r = -0.79). Late follicular A-T in VLDL was positively correlated with early follicular HDL3 cholesterol and late follicular HDL3 cholesterol (r = 0.83). Fluctuations of A-T concentrations by phase of the menstrual cycle should be taken into consideration in future research concerning premenopausal women and the risk of chronic disease.     

Developmental changes in intestinal globule leukocytes of normal rats

The relationship between sex hormone concentrations and female genital swelling during the menstrual cycle in the monogamous gibbon was comparable with that of polygamous female primates, such as the chimpanzee, which live in multimale groups and have larger swellings. The data, therefore, support the hypothesis proposed by C. R. Carpenter more than 50 years ago, that the gibbon's genital swelling, like that of other female primates, reflects basic physiological processes associated with progress of the menstrual cycle. Genital swelling increased during the follicular phase with increasing concentrations of oestradiol and oestrone glucuronide, reached maximal swelling in association with the mid-cycle peaks in the oestrogens and LH and began detumescence with the initial increases in progesterone during the luteal phase. The data also suggest that the menstrual cycle of the gibbon is shorter than previously reported, since cycles of 19-22 days exhibited hormone patterns that are consistent with ovulation. The genital swelling of the female gibbon is a useful marker for monitoring progress of the menstrual cycle and the presumptive time of ovulation.     

Regional and temporal separation of serotonergic activity mediating social stress

Stressful aggressive interaction stimulates central serotonergic activation in telencephalon as well as brainstem. Social roles can be distinguished by monoamine activity following aggression. Pairs of male lizards, Anolis carolinensis, were allowed to fight and form dominant/subordinate relationships. In micropunched regions of telencephalon, the greatest serotonergic changes occur in subordinate males. In hippocampal cortex and nucleus accumbens, subordinate males have increased 5-hydroxyindoleacetic acid/serotonin at 1 h following the fight. In these areas the ratio gradually decreases over a week of cohabitation, as was previously reported for brainstem. Medial and lateral amygdala develop increased serotonergic activity more slowly, with the greatest increase being evident following a week of interaction. Turnover, serotonin and 5-hydroxyindoleacetic acid levels in amygdala escalate over the first week of interaction in subordinate males, and return to baseline by one month. In dominant males, the pattern is accelerated, with the most extensive serotonin system activity present at 1 h, then decreasing over a month. The patterns of serotonergic activation are so similar in hippocampus, nucleus accumbens and brainstem that a co-ordinated response may be involved in mediating short-term social stress and aggression. Similarly, medial and lateral amygdala exhibit corresponding, but delayed patterns in subordinate males, suggesting a co-ordinated response in these regions mediating longer-term stress responses. These data are consistent with rapid neuroendocrine stress modulation in dominant individuals, and delayed serotonergic activity changes in subordinate males.     

Thermic effect of food during each phase of the menstrual cycle

The effect of the menstrual cycle on the thermic effect of food (TEF) was examined in eight healthy, normal-weight [mean +/- SD: 56.1 +/- 5.6 kg and body mass index (in kg/m2) 21.3 +/- 1.8] women aged 22-38 y. Their lean body mass and fat mass were 39.4 +/- 2.7 kg and 16.9 +/- 6.5 kg, respectively. TEF was measured on 4 separate days selected to match the four phases of a menstrual cycle: early follicular, follicular, luteal, and late luteal. The volunteers consumed a 3138-kJ liquid meal (54.5% carbohydrate, 14.0% protein, and 31.5% fat) on each test day. Resting metabolic rate was measured for 55 min before the meal and every 30 min after the start of the meal for 205 min. Although resting metabolic rate remained unchanged, there was a significant difference (P < 0.01 by ANOVA) in mean (+/- SEM) values for TEF among the four phases of the cycle: 0.94 +/- 0.05 kJ/min during the early follicular phase, 0.86 +/- 0.09 kJ/min during the follicular phase, 0.70 +/- 0.10 kJ/min during the luteal phase, and 0.76 +/- 0.07 kJ/min during the late luteal phase. TEF decreased significantly (P < 0.025 by paired t test) during postovulation (average of luteal and late luteal phases), when it was 0.73 +/- 0.07 kJ/min, compared with preovulation (average of early follicular and follicular phases), when it was 0.90 +/- 0.06 kJ/min. In conclusion, TEF decreased during the luteal phase of the menstrual cycle, possibly as a result of impairment of glucose uptake and slower transit of food through the upper gastrointestinal tract.     

Auditory event-related potentials, auditory digit span, and clinical symptoms in chronic schizophrenic men on neuroleptic medication

The Intervet Symposium 'Control and Regulation of Folliculogenesis' took place at the Annual Conference of the Society for the Study of Fertility in University College, Dublin in July, 1995. Five papers were presented, of which abstracts have been published. Discussion centred on monotocous species and principally addressed the question 'How is the ovulatory follicle selected and nurtured?' Many follicles start to develop simultaneously, but most become atretic. During the luteal phase of the cycle, several waves of follicles are initiated, and although one in each wave gains dominance, all ultimately atrophy. The dominant follicle in the wave produced towards the end of the luteal phase ovulates. The biochemical characteristics of dominant and subordinate follicles were contrasted, and the endocrine environment in which they waxed and waned was analysed. Interaction of autocrine and paracrine effectors, principally with FSH, LH and their receptors, ultimately determines follicular destiny.     

Macrophages, cell proliferation, and cell death in the human menstrual corpus luteum

We studied the presence and numbers of macrophages in the different compartments of the human menstrual corpus luteum (CL) in relation to the proliferative activity and apoptosis in luteal cells. Macrophages were recognized by immunohistochemical demonstration of the lysosome-associated glycoprotein CD68, and proliferating cells by immunohistochemical detection of the cell cycle-related protein Ki67 and by counting mitotic cells. In general, changes in the number of macrophages were parallel to the functional activity of the CL. Macrophage numbers increased up to the end of the early luteal phase, remained relatively unchanged during the midluteal phase, and decreased at the late luteal phase. Furthermore, macrophages showed prominent morphological changes during the cycle. They showed round or elongated cytoplasm during the early and late luteal phases, and dendritic features in the midluteal phase. Proliferating cells were very abundant on Days 15-16 and showed a significant decrease thereafter. Most proliferating cells corresponded to stromal (mainly vascular) cells. However, about 5% of granulosa-lutein cells and about 15% of theca-lutein cells were proliferating during the early and midluteal phases. Regression of the CL at the late luteal phase was associated with both a decrease in the number of proliferating cells and an increase in the number of apoptotic cells, which were highly increased on Days 25-27 of the cycle. The number of macrophages was not related to cell proliferation nor to cell death during the luteal phase. The observed changes in both macrophage number and morphology suggest the existence of a bidirectional communication between macrophages and steroidogenic cells in the human CL, or regulation of both cell populations by similar mechanisms.     

Tobacco withdrawal in women and menstrual cycle phase.

Because negative mood is a characteristic of both tobacco withdrawal and menstrual discomfort, withdrawal may vary by menstrual cycle phase. Tobacco withdrawal, mood, and menstrual discomfort were assessed in premenopausal women who quit smoking during either the follicular (Days 1–14 postmenstrual onset; n?=?41) or luteal (Day 15 or longer postmenstrual onset; n?=?37) phase of the menstrual cycle and maintained biochemically verified smoking abstinence during the postquit week. Women quitting during the luteal phase reported significantly greater increases in tobacco withdrawal and self-reported depressive symptoms than women quitting during the follicular phase. These results indicate that selecting a quit-smoking day early in the follicular phase may attenuate withdrawal and negative affect in premenopausal female smokers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired steroidogenesis in the luteal phase of the reproductive cycle and during pregnancy in rhesus monkeys immunized with the beta-subunit of ovine luteinizing hormone

Monkeys immunized with the beta-subunit of ovine luteinizing hormone (oLH beta) develop antibodies which cross react with rhesus chorionic gonadotropin (rhCG) and luteinizing hormone (rhLH). Immunization causes shortened menstrual cycles and reduced fertility. Fertility can be restored by administration of medroxyprogesterone acetate (MPA) during the first 5 weeks of pregnancy. In the present study, we have measured the effects of circulating oLH beta-antibodies on peripheral estradiol, progesterone and 17 alpha OH-progesterone (17OH-P) concentrations throughout the menstrual cycle and during gestation in monkeys which became pregnant following MPA-treatment. Progesterone concentrations were markedly reduced during the luteal phase in cycling animals and the luteal phase of the cycle was significantly shorter as compared to non-immunized controls. Concentrations of estradiol and 17OH-P in the peripheral circulation were not affected by the oLH beta-antibodies. In immunized monkeys which became pregnant following MPA-treatment, progesterone and 17OH-P levels were consistently lower and estradiol concentrations were increased during the second and third trimesters. Our results show that circulating antibodies to oLH beta have multiple endocrinological effects. Corpus luteum function is impaired in cycling monkeys and during the early part of pregnancy. In addition, the pattern of steroid secretion remains abnormal in pregnant monkeys even after the luteal-placental shift.     

Influence of female's sexual cycle on aggressiveness in male rats

Two experiments examined the relationship between the female's stage of estrus and agonistic behavior among males. Socially subordinate male albino rats were exposed to an inaccessible female and then given equal numbers of free-choice and forced-choice trials to a more aggressive "target" male or to an empty compartment. The submissive males were more aggressive following exposure to an estrous female than following exposure to a diestrous female. Furthermore, the probability of approaching the more aggressive male increased. This heightened level of aggressiveness was accompanied by a comparable increase in hostile behaviors by the dominant target males of Experiment 1. However, in the second experiment the increase in submissive-male aggressiveness was sufficient to reduce the social distance between the submissive subjects and their moderately aggressive target males.     

Effect of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonin agonist m-chlorophenylpiperazine in women with premenstrual syndrome and controls

To evaluate the potential role of serotonin in the premenstrual syndrome (PMS), we investigated the effects of menstrual cycle phase on neuroendocrine and behavioral responses to the serotonergic agent m-chlorophenylpiperazine (m-CPP) in women with PMS and controls. A single oral dose of m-CPP (0.5 mg/kg) was administered to 10 PMS patients and 10 healthy controls during the follicular and luteal phases of the menstrual cycle. We observed the following. m-CPP administration during the luteal phase resulted in an acute improvement of PMS symptoms; the plasma cortisol and ACTH responses to m-CPP were blunted in both menstrual cycle phases in PMS patients compared with controls. These data provide evidence for the acute efficacy of m-CPP in the treatment of PMS. Although there is additional evidence for dysregulation of either the hypothalamic-pituitary-adrenal axis or serotonin control of the hypothalamic-pituitary-adrenal axis in women with PMS, there is little evidence for luteal phase-specific serotonergic dysfunction. These findings, nonetheless, implicate the serotonin system as a modulating (not causal) factor in PMS.     

Adrenergic receptors in premenstrual dysphoric disorder: I. Platelet alpha 2 receptors: Gi protein coupling, phase of menstrual cycle, and prediction of luteal phase symptom severity

BACKGROUND: Abnormal alpha 2-adrenergic receptor (AR) function is implicated in anxiety and depressive disorders. Premenstrual dysphoric disorder (PMDD) is characterized by anxiety and depressive symptoms, which may be associated with changes in alpha 2AR function. Previous studies on alpha 2AR function during phases of the menstrual cycle in controls and PMDD patients are inconsistent. METHODS: alpha 2AR function was examined in 16 PMDD patients and 15 controls during the follicular phase, and in 10 PMDD patients during late luteal phase. Antagonist-measured maximum binding capacity, agonist-measured receptor density in high- and low-conformational states, and agonist affinity to both states were measured. Coupling efficiency to Gi protein was estimated. RESULTS: There were no significant differences in coupling efficiency. PMDD patients had significantly low antagonist affinity; there were no differences in other binding parameters. There were no changes in alpha 2AR binding parameters between phases of menstrual cycle in PMDD women. alpha 2AR density and symptom severity were inversely related during the follicular phase in controls and patients. During luteal phase, alpha 2AR density correlated positively with symptom severity in patients. High follicular alpha 2AR density predicted more severe luteal symptoms in PMDD patients. CONCLUSIONS: These findings are discussed in view of the molecular biology of alpha 2AR, and their role in PMDD, anxiety, and depressive disorders.     

Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases

BACKGROUND: Retrospective studies show significant improvements in survival among women who had breast cancer resected during the luteal phase of their menstrual cycle compared with the follicular phase. We hypothesised that tumour tissue would show cyclical changes in expression of genes whose products might contribute to metastatic potential. METHODS: We studied 32 premenopausal women with operable breast cancer. We assayed hormones to define more accurately the menstrual phase during which surgery was done. We used northern blot analysis of RNA from fresh-frozen tumour specimens to study the patterns of expression of genes for proteolytic enzymes (cysteine proteinase cathepsin L and aspartyl proteinase cathepsin D; matrix metalloproteinases MMP-9 and MMP-2), tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2, and TP53. RESULTS: There was a significantly higher level of expression of RNA for cathepsin L, MMP-9, and TP53 (p=0.005, 0.03, 0.03, respectively) in tumours that were resected during the follicular and periovulatory phases of the menstrual cycle than at other times in the cycle. A similar but non-significant trend was seen for MMP-2 and cathepsin D. A non-significant trend in the opposite direction was seen for TIMP-1 and TIMP-2. INTERPRETATION: We found that tumour expression of genes that may contribute to proliferative capacity and metastatic potential can change in breast cancer during the course of the menstrual cycle. The finding could provide a molecular explanation for the reports of improved survival in some breast-cancer patients whose tumours were removed during the luteal phase of the menstrual cycle. Larger studies are required to extend our study, assess mechanisms of gene regulation, and verify any relevant influence in long-term survival.