Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.

A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FH-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta=0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7, a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.

Chromosome 2 (2p16) abnormalities in Carney complex tumours.

Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22-24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region, that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumours. Both thyroid and adrenal tumours constitute part of CNC indicating that the responsible gene(s) in this area may indeed be involved in both inherited and sporadic endocrine tumour pathogenesis and/or progression.

Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.

The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin alpha-subunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C>G, and two in exon 2, 3998G>A and 4088G>A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-beta; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.

The human vitamin D receptor gene (VDR) is localized to region 12cen-q12 by fluorescent in situ hybridization and radiation hybrid mapping: genetic and physical VDR map.

The vitamin D receptor (VDR) is a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The VDR gene was previously mapped to human chromosome 12q13-12q14, but its precise physical and genetic localization are unknown. The present study reports the mapping of the human VDR gene by radiation hybrid (RH) analysis, the isolation of a bacterial artificial chromosome (BAC) containing this gene, and physical mapping of the VDR gene by fluorescent in situ hybridization (FISH). RH analysis placed the VDR gene locus at chromosome 12cen-q12, flanked by Stanford Human Genome Center (SHGC) 30216 and SHGC 9798 (D12S1892) markers. FISH analysis of a BAC containing the VDR gene confirmed its centromeric location. Thus, we have identified a BAC and genetic markers which can be used in the genetic analysis of the VDR gene and investigation of its involvement in osteoporosis and related disorders. We conclude that the VDR gene is centromeric to its previously reported locus on chromosome 12.

Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503).

Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal (and one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized.

Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3.

Aldosterone synthase (AS) is encoded by the CYP11B2 gene, a candidate for familial hypertension. CYP11B2 was previously mapped to chromosome 8q but its precise localization is necessary for genetic studies of hypertension. The present study reports the genetic mapping of the human CYP11B2 gene by radiation hybrid (RH) analysis, the isolation of a bacterial artificial chromosome (BAC) containing this gene and its physical mapping by fluorescent in situ hybridization (FISH). The CYP11B2 locus is on the most distal segment of the long arm of chromosome 8, proximal to the microsatellite polymorphic marker D8S1704. This location, which was confirmed by FISH, is approximately 60cM telomeric to the currently listed human gene locus (chromosome 8q21-22) and corresponds to cytogenetic band 8q24.3. The BACs containing the gene and a high-resolution map of the CYP11B2 locus are useful for genetic studies of hypertension and other endocrine disorders.

Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy.

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome (OMIM 160980, http://www.ncbi.nlm.nih.gov/omim) with features overlapping those of other multiple endocrine neoplasias and hamartomatoses, Peutz-Jeghers syndrome (PJS) in particular. Although a number of patients with CNC and ovarian tumors have been described in individual patient reports, it is unclear whether ovarian lesions constitute a component of the syndrome or are coincidental events. We investigated 18 women with CNC [age at first evaluation, 31.3+/-12.1 yr (mean +/- SD)] prospectively for the development of ovarian tumors over a period of 35.7+/-30.6 months by physical examination and pelvic ultrasonography. They were compared with 11 women (age at first evaluation, 32.9+/-17 yr) who were enrolled under the same protocol (follow up, 32.3+/-25.1 months) and served as a control group. In addition, a registry of 178 women from among a total of 309 patients with CNC was searched retrospectively for any having ovarian tumors. Seven available histological specimens were rereviewed. None of the CNC patients had ovarian tumors analogous to those of PJS. Two patients with CNC in the prospective group developed ovarian tumors and were operated upon. One had bilateral oophorectomy for asynchronous serous cystadenomas. The second patient had a unilateral serous cystadenoma. Resected tumor tissue from both patients was tested for genetic abnormalities of the chromosomal regions to which CNC genetic loci have been mapped. Both showed genomic amplification of chromosomal region 2p16. An additional 10 patients had at least 1 sonogram positive for ovarian cysts. Only 1 of the patients in the control group was found to have a persistent, simple ovarian cyst by ultrasonography. The registry of 178 CNC patients included 4 who had undergone surgery for ovarian tumors. The diagnoses included endometrioid adenocarcinoma (1 patient) and metastatic mucinous adenocarcinoma (the primary site was probably ovarian; 1 patient). In addition, 7 of 12 patients (58%) with CNC, who died of other causes, had ovarian lesions at autopsy. In conclusion, although the same stromal tumor, large-cell calcifying Sertoli cell tumor, affects the testes in CNC and PJS, we did not find such tumors in a small population of CNC patients that was studied prospectively or a larger group of CNC patients that was studied retrospectively. The results of our study also suggested that women with CNC commonly develop ovarian cysts and may be at risk for ovarian carcinoma. The chromosome 2p16 CNC locus was involved in ovarian pathology with apparent copy number gain, suggesting that at least molecularly there is some involvement of the CNC gene(s) in these lesions. Although ovarian tumors do not seem to be a major manifestation of CNC, sonography of the ovaries may be part of the initial evaluation for this genetic syndrome in women with CNC; follow-up of any identified lesion is recommended because of the possible risk for malignancy.

Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.

Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21-8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance (theta) of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21-8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21-8qtel most likely does not harbor the genetic defect in this kindred.

Mutational analysis of the PRL receptor gene in human breast tumors with differential PRL receptor protein expression.

PRL is a major growth and differentiating hormone in the human breast, with activation of the PRL-PRL receptor complex increasingly recognized as an important mechanism in the induction and progression of mammary tumors. Although constitutive activation of various hormone and growth factor receptors is newly recognized as a common cause of tumor development, the PRL receptor gene has not been analyzed for similar aberrations in breast and other tumors. Therefore, using bacterial artificial chromosomes containing the PRL receptor gene and intron-spanning PCR, we determined the exon-surrounding intron sequences providing primers for the first analysis of the entire coding region of the human PRL receptor gene. We examined the presence of PRL receptor in 41 breast tumors by immunohistochemistry and attempted a correlation of its expression to pathological grading of the disease. Then tumor cells were isolated by laser capture microdissection to examine DNA from 30 patients for PRL receptor mutations. The PRL receptor immunoreactive score did not correlate to the tumor size, histopathological grading, age, or family history of patients. PRL receptor immunoreactivity was predominantly found in steroid hormone receptor-positive tumors, but without overall correlation of immunoreactive score. In both PRL receptor-positive and PRL receptor- negative breast cancer cells, direct sequencing of the coding sequence of the PRL receptor gene did not detect any somatic or hereditary gene aberrations. In conclusion, PRL receptor mutations do not appear to be common in human breast cancer, suggesting that constitutive activation of the PRL receptor can be excluded as a major cause of mammary tumor genesis. The molecular structure of the PRL receptor seems to remain intact in tumor tissue, and systemic and local production of PRL may participate in tumor cell growth and proliferation through functional receptors.

Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.

Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance. A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders. We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than 2 and/or by haplotype analysis. LOH for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%. We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19q13) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families.

Adrenocorticoid hormones and the development and expression of mammalian monogamy.

Based on research with prairie voles, we hypothesize that the unusual patterns of reproduction and social behavior associated with mammalian monogamy may arise as a consequence of normal developmental exposure to high levels of glucocorticoids and/or other hormones of the HPA axis. Increased HPA activity could functionally inhibit some of the masculinizing processes expected during the perinatal period. We hypothesize that the unique behavioral, physiological, and anatomical changes associated with monogamy may reflect the adaptive consequences of reduced exposure to the masculinizing actions of HPG hormones, such as testosterone. Reproductively naive, unpaired adult prairie voles also show unusual patterns of adrenal activity, including a marked decline in corticosterone levels within minutes following exposure to novel animals of the opposite sex. In females, this decline in corticosterone may contribute to pair bonding, since corticosterone injections inhibit, and adrenalectomy is associated with a facilitation of pair bond formation. In males, corticosterone injections facilitate pair bonding and adrenalectomy has the opposite effect. In animals from established social pairs corticosterone levels also fluctuate according to the social environment of the animal; the absence of a familiar partner is associated with increased corticosterone secretion, and in the presence of the familiar partner corticosterone levels tend to decline. Prairie voles may offer a valuable source of information regarding the behavioral, anatomical, and physiological consequences of long-term and short-term exposure to high levels of adrenal activity in the absence of pathology.

Conditioned release of corticosterone by contextual stimuli associated with cocaine is mediated by corticotropin-releasing factor.

Elevated blood concentrations of corticosterone (CORT), an adrenal steroid associated with stress responses, is one of the endocrine correlates of cocaine treatment. Experiment 1 confirmed and extended previous findings that chronic cocaine treatment does not alter corticosteroid responses to cocaine. In Experiment 2, conditioned endocrine effects of cocaine were examined in three groups of rats after 7 consecutive days of treatment. Cocaine-induced conditioning was achieved using a simple contextual design. In group 1 (paired), rats were injected with cocaine (30 mg/kg), then immediately placed into a locomotor activity chamber for 30 min. One hour after the rats were returned to their home cages, they received an injection of saline. In group 2 (unpaired), rats were injected with saline, then immediately placed into a locomotor activity chamber for 30 min. One hour after the rats were returned to their home cages, they received an injection of cocaine (30 mg/kg). Rats in group 3 (control) received only saline injections, but otherwise were treated as animals in the other treatment groups. On the test day (Day 8), all rats were placed immediately into the locomotor apparatus for 30 min prior to collection of a blood sample. Blood CORT concentrations and locomotor activity in the paired group were significantly higher than in the unpaired and control groups. However, pretreatment of the rats in Experiment 3 with the corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF9-41 (1 microg, i.c.v.), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent conditioned increase in blood CORT concentrations. These data represent the first demonstration of classical conditioning of a steroid hormone response to stimuli associated with a psychoactive drug in rats and suggest that the effect is mediated by endogenous CRF. Because the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in modulating the actions of cocaine, it is plausible that such conditioned increases in CORT release by cocaine-associated cues may further predispose an organism to the reinforcing effects of the drug or enhance the susceptibility to drug-taking behavior. Alternatively, such conditioned effects may be related to the anxiogenic properties of cocaine. Further understanding of the conditioned effects of hormones in the development and expression of addictive behaviors may provide new insights into treatment of drug addiction.

Structure of the gene coding for calcineurin B (PPP3R1) and mapping to D2S358-D2S1778 (chromosomal region 2p15).

Calcineurin is a protein phosphatase with an important role in signal transduction; its calcium-binding regulatory subunit, calcineurin B, is widely present in the brain and is coded by the PPP3R1 gene which was mapped recently to human chromosome 2. Calcineurin has long been considered a candidate for psychiatric and/or monogenic brain disorders. The present study reports the intron-exon structure of the PPP3R1 gene with the proximal intronic sequences, its genetic mapping to D25358-D251778 on chromosome 2p15, and its exclusion in a genetic disorder mapped proximal to this locus.

Social cues influence growth and sexual maturation of the male musk shrew (Suncus murinus).

Musk shrews were maintained from weaning (20 days of age) for 20 or 40 days in one of several social conditions. In Exp. 1, young males housed with adult females gained more weight and had heavier sex accessory organs than did young males housed with an adult male or reared alone. In Exp. 2 this same pattern of accelerated growth and sexual maturation was found when males were reared directly with an adult female or in a split cage where a wire barrier served to separate the male and his adult female cagemate. In Exp. 3, males were reared in cages containing clean or soiled bedding: soiled bedding was taken once every 5 days from the cage of an adult male, or a female. Under these conditions differences in the weights of reproductive tissues showed minimal variation with housing condition after 20 days of treatment. At that time males reared in soiled bedding taken from the cage of an adult female had accelerated development compared with control males. In Exp. 4, males were housed alone or in a split cage with an adult female which was separated by a wire mesh or a solid, opaque barrier. Males separated by a solid barrier from their female cagemates for 40 days had reproductive tissue weights equivalent to those measured in males reared alone. Taken together these results suggest that the presence of an adult female has dramatic effects on body growth and development of reproductive target tissues in young male musk shrews. Male-female social interactions could play an important role in the timing of puberty in this opportunistically breeding tropical mammal.

The effects of stress on social preferences are sexually dimorphic in prairie voles.

Prairie voles (Microtus ochrogaster) are monogamous rodents that form pair bonds characterized by a preference for a familiar social partner. In male prairie voles, exposure to either the stress of swimming or exogenous injections of corticosterone facilitate the development of a social preference for a female with which the male was paired after injection or swimming. Conversely, adrenalectomy inhibits partner preference formation in males and the behavioral effects of adrenalectomy are reversed by corticosterone replacement. In female prairie voles, swim stress interferes with the development of social preferences and corticosterone treatments inhibit the formation of partner preferences, while adrenalectomized females form preferences more quickly than adrenally intact controls. Because sex differences in both behavior and physiology are typically reduced in monogamous species, we initially predicted that male and female prairie voles would exhibit similar behavioral responses to corticosterone. However, our findings suggest an unanticipated sexual dimorphism in the physiological processes modulating social preferences. This dimorphic involvement of stress hormones in pair bonding provides a proximate mechanism for regulating social organization, while permitting males and females to adapt their reproductive strategies in response to environmental challenges.