Clinical Practice & Epidemiology in Mental Health




ISSN: 1745-0179 ― Volume 15, 2019
RESEARCH ARTICLE

Sex-Related Differences in Plasma Oxytocin Levels in Humans



Donatella Marazziti1, *, Stefano Baroni1, Federico Mucci1, Armando Piccinni1, Ilenia Moroni1, Gino Giannaccini2, Claudia Carmassi1, Enrico Massimetti3, Liliana Dell’Osso1
1 Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
2 Dipartimento di Farmacia, University of Pisa, Pisa, Italy
3 ASST, Bergamo Ovest, SSD Servizio Psichiatrico diagnosi e cura, Treviglio, Italy

Abstract

Background:

Increasing evidence supports a key role of Oxytocin (OT) as a modulator of social relationships in mammals.

Objective:

The aim of the present study was to investigate possible sex-related differences in plasma OT levels in human beings.

Methods:

Forty-five healthy men and 45 women (mean age: 34.9 ± 6.2 years), were included in the study. Plasma preparation, peptide extraction and OT radioimmunoassay were carried out according to standardized methods.

Results:

The results showed that OT plasma levels (pg ̸ ml, mean ± SD) were significantly higher in women than in men (4.53 ± 1.18 vs 1.53 ± 1.19, p ˂ 0.001).

Conclusions:

The present finding demonstrates sex-related differences in plasma OT levels in humans. It is tempting to hypothesize that such differences might be related to behaviours, attitudes, as well as susceptibility to stress response, resilience and social emotions specific of women and men.

Keywords: Dymorphic changes, Humans, Oxytocin, Plasma levels, Social emotions, AVP receptors.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 15
First Page: 58
Last Page: 63
Publisher Id: CPEMH-15-58
DOI: 10.2174/1745017901915010058

Article History:

Received Date: 23/01/2019
Revision Received Date: 19/02/2019
Acceptance Date: 22/02/2019
Electronic publication date: 26/03/2019
Collection year: 2019

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© 2019 Marazziti et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Dr. Donatella Marazziti, Dipartimento di Medicina Clinica e Sperimentale, Section of Psichiatry, University of Pisa, Via Roma, 67, 56100 Pisa, Italy; Tel: +39 050 2219768;Fax: +39 050 2219787; E-mail: dmarazzi@psico.med.unipi.it




1. INTRODUCTION

Oxytocin (OT) is produced in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and is released in the blood stream by the posterior pituitary gland [1Amico JA, Robinson G. Oxytocin: Clinical and laboratory studies 1985.]. Although related to other peptides present in all vertebrates, OT appears to be an exclusive mammalian hormone, and it plays a key role in labor and lactation, as well as in the onset and in the maintenance of a wide range of social behaviours [2Pedersen CA, Prange AJ Jr. Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA 1979; 76(12): 6661-5.[http://dx.doi.org/10.1073/pnas.76.12.6661] [PMID: 293752] ]. The evidence of an intimate connection between OT and the development of complex social behaviours is rising: as a matter of fact, OT has been reported to promote social approach, pair bonding and copulation throughout a modulation of neuroendocrine and behavioural responses to social stress [3Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35(11): 649-59.[http://dx.doi.org/10.1016/j.tins.2012.08.004] [PMID: 22974560] ]. Not surprisingly, currently OT is supposed to be one of the main mediators of the development of attachment in childhood, pair bonding, as well as to relating social signals with cognition, behaviours and reward [4Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000; 85(Spec No): 111S-24S.[http://dx.doi.org/10.1111/j.1469-445X.2000.tb00014.x] [PMID: 1079 5913] -7Panksepp J. Primary process affects and brain oxytocin. Biol Psychiatry 2009; 65(9): 725-7.[http://dx.doi.org/10.1016/j.biopsych.2009.02.004] [PMID: 19348835] ]. Besides the animal data, converging findings are accumulating highlighting the increasing role of OT as a prosocial mediator in human beings [6Uvnås-Moberg K, Petersson M. [Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing]. Z Psychosom Med Psychother 2005; 51(1): 57-80.[http://dx.doi.org/10.13109/zptm.2005.51.1.57] [PMID: 15834840] -8Jones C, Barrera I, Brothers S, Ring R, Wahlestedt C. Oxytocin and social functioning. Dialogues Clin Neurosci 2017; 19(2): 193-201.[PMID: 28867943] ]. Some authors found out that early social experiences in humans are capable of influencing the OT system but also the Arginine-vasopressin (AVP, another hypothalamic protein hormone that might be exerting opposite functions to OT) system [9Heim C, Owens MJ, Plotsky PM, Nemeroff CB. Persistent changes in corticotropin-releasing factor systems due to early life stress: relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacol Bull 1997; 33(2): 185-92.[PMID: 9230630] , 10Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 2004; 7(8): 841-6.[http://dx.doi.org/10.1038/nn1290] [PMID: 15273691] ]. In particular, the available evidence suggests that proper development of the OT and AVP systems may be critically impaired by a lack of the essential care in young children. Furthermore, a dysfunctional functioning of those systems seems to result in a disruption of the typical calming and comforting effects provided from the caregivers [11Carter CS. Developmental consequences of oxytocin. Physiol Behav 2003; 79(3): 383-97.[http://dx.doi.org/10.1016/S0031-9384(03)00151-3] [PMID: 12954 433] , 12Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci USA 2005; 102(47): 17237-40.[http://dx.doi.org/10.1073/pnas.0504767102] [PMID: 16303870] ]. Not surprisingly, comforting physical contact, familiar smells and other socially pleasant sensory experiences are capable of raising the levels of OT and AVP [4Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000; 85(Spec No): 111S-24S.[http://dx.doi.org/10.1111/j.1469-445X.2000.tb00014.x] [PMID: 1079 5913] , 11Carter CS. Developmental consequences of oxytocin. Physiol Behav 2003; 79(3): 383-97.[http://dx.doi.org/10.1016/S0031-9384(03)00151-3] [PMID: 12954 433] , 12Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci USA 2005; 102(47): 17237-40.[http://dx.doi.org/10.1073/pnas.0504767102] [PMID: 16303870] ].

Interestingly, the OT system and some of its parameters show some sex-related differences depending on the brain region and species. In rats, the density of OT-immunoreactive axons tends to be higher in females [13Cushing BS, Carter CS. Peripheral pulses of oxytocin increase partner preferences in female, but not male, prairie voles. Horm Behav 2000; 37(1): 49-56.[http://dx.doi.org/10.1006/hbeh.1999.1558] [PMID: 10712858] ]. It was also observed that OT Receptor (OTR) binding seems to be increased up to 40% by a high maternal licking and grooming in females, while AVP receptors of type 1a (APVRs) are more evident in males [14Macbeth AH, Stepp JE, Lee HJ, Young WS III, Caldwell HK. Normal maternal behavior, but increased pup mortality, in conditional oxytocin receptor knockout females. Behav Neurosci 2010; 124(5): 677-85.[http://dx.doi.org/10.1037/a0020799] [PMID: 20939667] ]. The results of different studies carried out on several animal species, which show more prominent effects of OT in females and more significant effects of AVP in males, appear congruent with the dimorphic effects on OTR and V1a receptors [15Carter CS. Oxytocin and sexual behavior. Neurosci Biobehav Rev 1992; 16(2): 131-44.[http://dx.doi.org/10.1016/S0149-7634(05)80176-9] [PMID: 1630727] , 16Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci USA 1992; 89(13): 5981-5.[http://dx.doi.org/10.1073/pnas.89.13.5981] [PMID: 1321430] ]. Similarly, pair bonding in monogamous praire voles seems apparently to depend on OT in females and on AVP in males, at variance with polygamous montane voles [13Cushing BS, Carter CS. Peripheral pulses of oxytocin increase partner preferences in female, but not male, prairie voles. Horm Behav 2000; 37(1): 49-56.[http://dx.doi.org/10.1006/hbeh.1999.1558] [PMID: 10712858] , 16Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci USA 1992; 89(13): 5981-5.[http://dx.doi.org/10.1073/pnas.89.13.5981] [PMID: 1321430] -19Smeltzer MD, Curtis JT, Aragona BJ, Wang Z. Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles. Neurosci Lett 2006; 394(2): 146-51.[http://dx.doi.org/10.1016/j.neulet.2005.10.019] [PMID: 16289323] ]. The different behaviours are possibly the result of the interaction of OT and AVP with steroid hormones, such as estradiol and progesterone: in particular estradiol enhances OTR affinity, while progesterone decreases it, especially in the amygdala [20Bale TL, Dorsa DM, Johnston CA. Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle. J Neurosci 1995; 15(7 Pt 1): 5058-64.[http://dx.doi.org/10.1523/JNEUROSCI.15-07-05058.1995] [PMID: 7623134] -22Gimpl G, Wiegand V, Burger K, Fahrenholz F. Cholesterol and steroid hormones: modulators of oxytocin receptor function 2002; 139: 43-55.[PMID: 12436925] ].

Data in humans are more limited and mainly indirect. The administration of intranasal OT enhanced the recognition of kinship in women and of competition in men [23Fischer-Shofty M, Levkovitz Y, Shamay-Tsoory SG. Oxytocin facilitates accurate perception of competition in men and kinship in women. Soc Cogn Affect Neurosci 2013; 8(3): 313-7.[http://dx.doi.org/10.1093/scan/nsr100] [PMID: 22446301] ]. Moreover, this procedure seems to reduce amygdala activation in men and to increase it in women when observing emotional facial expressions [24Domes G, Lischke A, Berger C, et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2010; 35(1): 83-93.[http://dx.doi.org/10.1016/j.psyneuen.2009.06.016] [PMID: 19632787] ]. Generally, women consider all human faces more positive and appealing than men, while showing a preference for facial beauty of children and elderly people [25Proverbio AM. Sex differences in social cognition: The case of face processing. J Neurosci Res 2017; 95(1-2): 222-34. [doi: 10.1002/jnr.23817]. [PMID: 27870403].[http://dx.doi.org/10.1002/jnr.23817] [PMID: 27870403] ]. Gender differences in the neural and behavioural response to OT administration during human social interaction have been also reported [26Rilling JK, Demarco AC, Hackett PD, et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2014; 39: 237-48.[http://dx.doi.org/10.1016/j.psyneuen.2013.09.022] [PMID: 24157401] ]. In men performing cooperative interactions, OT and AVP were shown to enhance brain areas abundant in OTRs and AVPRs and/or related to reward, social bonding, arousal and memory. By contrast, in women, OT and AVP showed decreased activity or no effect in these areas. Somehow, OT treatment turned neural responses of men more similar to those of women in the placebo group and vice-versa [27Turner RA, Altemus M, Yip DN, et al. Effects of emotion on oxytocin, prolactin, and ACTH in women. Stress 2002; 5(4): 269-76.[http://dx.doi.org/10.1080/1025389021000037586-1] [PMID: 12475 731] ]. The increase of OT levels while facing interpersonal distress or psychological stress is also more marked in women and possibly mediated by sex hormones, as estrogens are supposed to up-regulate the OT system with a resulting enhancement of social interest and approach behaviours [22Gimpl G, Wiegand V, Burger K, Fahrenholz F. Cholesterol and steroid hormones: modulators of oxytocin receptor function 2002; 139: 43-55.[PMID: 12436925] , 27Turner RA, Altemus M, Yip DN, et al. Effects of emotion on oxytocin, prolactin, and ACTH in women. Stress 2002; 5(4): 269-76.[http://dx.doi.org/10.1080/1025389021000037586-1] [PMID: 12475 731] ]. For this reason, they are considered an index of stressful relationships in women, but not in men, where AVP would play a major role [28Taylor SE, Saphire-Bernstein S, Seeman TE. Are plasma oxytocin in women and plasma vasopressin in men biomarkers of distressed pair-bond relationships? Psychol Sci 2010; 21(1): 3-7.[http://dx.doi.org/10.1177/0956797609356507] [PMID: 20424014] ]. Indirect support derives also from the clinical evidence of a female prevalence of both major depression and social anxiety disorder, highly associated with social–emotional stress [3Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35(11): 649-59.[http://dx.doi.org/10.1016/j.tins.2012.08.004] [PMID: 22974560] , 29Kirsch P, Esslinger C, Chen Q, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005; 25(49): 11489-93.[http://dx.doi.org/10.1523/JNEUROSCI.3984-05.2005] [PMID: 16339 042] , 30Panksepp J. Oxytocin effects on emotional processes: separation distress, social bonding, and relationships to psychiatric disorders. Ann N Y Acad Sci 1992; 652: 243-52.[http://dx.doi.org/10.1111/j.1749-6632.1992.tb34359.x] [PMID: 1626 832] ].

Taken together, we may reasonably speculate that the OT system could act distinctly in men and women through the possible mediations of sex hormones [31Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron 2008; 58(4): 639-50.[http://dx.doi.org/10.1016/j.neuron.2008.04.009] [PMID: 18498743] -33Singer T, Snozzi R, Bird G, et al. Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion 2008; 8(6): 781-91.[http://dx.doi.org/10.1037/a0014195] [PMID: 19102589] ].

The limited literature on the topic of dymorphism of OT system in humans is with no doubt related to the lack of reliable peripheral parameters reflecting its central functioning. Plasma OT levels are considered a reliable marker of the CNS concentrations of this neurohormone [4Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000; 85(Spec No): 111S-24S.[http://dx.doi.org/10.1111/j.1469-445X.2000.tb00014.x] [PMID: 1079 5913] , 27Turner RA, Altemus M, Yip DN, et al. Effects of emotion on oxytocin, prolactin, and ACTH in women. Stress 2002; 5(4): 269-76.[http://dx.doi.org/10.1080/1025389021000037586-1] [PMID: 12475 731] , 34Madden JR, Clutton-Brock TH. Experimental peripheral administration of oxytocin elevates a suite of cooperative behaviours in a wild social mammal. Proc Biol Sci 2011; 278(1709): 1189-94.[http://dx.doi.org/10.1098/rspb.2010.1675] [PMID: 20926437] , 35Knobloch HS, Charlet A, Hoffmann LC, et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 2012; 73(3): 553-66.[http://dx.doi.org/10.1016/j.neuron.2011.11.030] [PMID: 22 325206] ], although disagreements do exist [16Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci USA 1992; 89(13): 5981-5.[http://dx.doi.org/10.1073/pnas.89.13.5981] [PMID: 1321430] ]. However, a series of reports on parallel changes in OT levels in plasma and in the brain [4Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000; 85(Spec No): 111S-24S.[http://dx.doi.org/10.1111/j.1469-445X.2000.tb00014.x] [PMID: 1079 5913] , 27Turner RA, Altemus M, Yip DN, et al. Effects of emotion on oxytocin, prolactin, and ACTH in women. Stress 2002; 5(4): 269-76.[http://dx.doi.org/10.1080/1025389021000037586-1] [PMID: 12475 731] , 34Madden JR, Clutton-Brock TH. Experimental peripheral administration of oxytocin elevates a suite of cooperative behaviours in a wild social mammal. Proc Biol Sci 2011; 278(1709): 1189-94.[http://dx.doi.org/10.1098/rspb.2010.1675] [PMID: 20926437] ] would suggest common regulatory processes and, thus, support the use of the peripheral OT as a mirror of the central one [35Knobloch HS, Charlet A, Hoffmann LC, et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 2012; 73(3): 553-66.[http://dx.doi.org/10.1016/j.neuron.2011.11.030] [PMID: 22 325206] ].

Therefore, due to the limited available data, this study aimed at measuring and comparing plasma OT levels in a sample of healthy men and women.

2. MATERIALS AND METHODS

Forty-five men (mean age: 35.1 ± 7.5 years) and 45 women (mean age: 34.9 ± 6.2 years), recruited amongst medical and nursing staff at the Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa. All subjects who volunteered for the study underwent a detailed medical interview, conducted by senior psychiatrists (DM and AP). None of the subjects had any personal or family history of major psychiatric disorders or medical diseases. No subjects reported any regular intake of psychotropic or other medical compounds. Finally, none of them reported to be a heavy cigarette smoker or alcohol drinker. All subjects were within the normal body/mass index (BMI) range. All women had a normal menstrual cycle and did not take any contraceptive pills; all their blood samples were collected in the early follicular phase (between the second and the fifth day of the menses). No past history or current signs/symptoms of hypogonadism or disease of genital system was detected in men. Thirty-nine men and 30 women were involved in a love relationship, of whom ten and twelve, respectively, were married, while two were separated/divorced, and the remaining were single. All subjects had completed the high school, 25 men and 23 women were graduated and/or PhD. All the information derived from the medical history collected by one of the authors (DM).

All subjects provided the written informed consent to participate in the study previously approved by the Ethics Committee at Pisa University.

2.1. Plasma Preparation

In the periods January-March, and between 8 and 10 am, 10 ml of blood was withdrawn three times from an antecubital vein from fasting subjects who were sitting and relaxing in the same setting at a constant temperature of about 19° C. The blood (10 ml) was collected in vacutainers with EDTA as anti-coagulant, transferred to centrifuge tubes containing aprotinin (Sigma, Milan, Italy) (0.6 TIU/ml of blood), and gently mixed several times to inhibit the activity of proteinases. Blood was then centrifuged at 1,600 x g for 15 min at 4°C and the ensuing plasma was collected and kept at -70°C until the assay.

2.2. Extraction of Peptides from Plasma

6 ml of plasma was acidified with 6 ml of buffer A (1% trifluoroacetic acid in H2O), centrifuged at 17,000 × g for 20 min at 4°C and the ensuing supernatant was collected. C-18 sep-columns were equilibrated with 1 ml of buffer B (60% acetonitrile in 1% trifluoroacetic acid) followed by buffer A (3 ml, 3 times). Acidified plasma solution was loaded into the pre-treated C-18 Sep-column washed with buffer A (3 ml, twice). Oxytocin was then eluted with buffer B (3 ml, once) and collected into a polystyrene tube. The eluate was evaporated in a Speedvac centrifugal concentrator, and the remaining product was lyophilized by a freeze dryer.

2.3. Oxytocin Radioimmunoassay

Radioimmunoassay (RIA) was performed by a Phoenix Pharmaceuticals Oxytocin RIA kit (Belmont, California, USA) according to our method [36Marazziti D, Dell’Osso B, Baroni S, et al. A relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health 2006; 2: 28.[http://dx.doi.org/10.1186/1745-0179-2-28] [PMID: 17034623] ]. The assay sensitivity, measured as IC50, was 10-30 pg/tube, and intra-assay and inter-assay values were 9% and 11%, respectively. Lyophilized samples and standard OT were rehydrated with RIA buffer, and dilutions of standard oxytocin were prepared (from 1 to 128 pg/tube). Primary rabbit anti-OT antibodies were added to both sample and standard, and subsequently, the mixtures were stored for 24 hours at 4°C. 125I-Oxytocin was then added to mixtures that were stored for 24 hrs at 4°C. Goat anti-rabbit IgG serum and normal rabbit serum were added to each tube. Afterwards, tubes were centrifuged at 1700 × g for 20min at 4°C. All the supernatant was carefully aspirated and the pellets were counted by a gamma-counter (Wizard, Perkin Elmer, Milan, Italy). All samples were assayed in duplicate. Standard curve and calculations of unknown samples were performed by means of Graphpad Prism3 software.

2.4. Statistical Analyses

The Student t-test (two-tailed unpaired) was used to assess the intergroup difference of age and OT levels, by means of the SPSS, Version 12.0.1 (SPSS Inc., 2003).

3. RESULTS

The plasma OT levels (pg/ml, mean ± SD) were significantly (p < 0.001) higher in women (range between 2.34 ± 0.02 and 6.59 ± 0.01, mean ± SD: 4.53 ± 1.18) than in men (range between 0.14 ± 0.02 and 2.59 ± 0.01, mean ± SD: 1.53 ± 1.19) each single value represented the mean of three evaluations performed within one hour (Table 1).

Table 1
Demographic data and plasma oxytocin (OT) levels in healthy men (M) and women (W).


Plasma OT levels were not different in married or single subjects, while, for the small sample size, no comparisons could be performed in individuals with and without a partner.

4. DISCUSSION

Given the paucity of information, this study aimed at investigating the possible existence of sex-related differences in OT plasma levels in humans. The ensuing findings indicate that women showed higher OT levels than men. To our knowledge, this is one of the first demonstrations of a clear-cut difference in peripheral OT between the two sexes in humans. Previously, in most cases, no sex differences were found [36Marazziti D, Dell’Osso B, Baroni S, et al. A relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health 2006; 2: 28.[http://dx.doi.org/10.1186/1745-0179-2-28] [PMID: 17034623] -39Graugaard-Jensen C, Hvistendahl GM, Frøkiaer J, Bie P, Djurhuus JC. Urinary concentration does not exclusively rely on plasma vasopressin. A study between genders. Gender and diurnal urine regulation. Acta Physiol (Oxf) 2014; 212(1): 97-105.[http://dx.doi.org/10.1111/apha.12337] [PMID: 24965868] ], but there is also evidence of elevated levels in men [40Floyd K, Pauley PM, Hesse C. State and trait affectionate communication buffer adults stress reactions. Commun Monogr 2010; 77(4): 618-36.[http://dx.doi.org/10.1080/03637751.2010.498792] ]. Only one study [41Imamura Y, Mizoguchi Y, Nabeta H, et al. An association between belief in life after death and serum oxytocin in older people in rural Japan. Int J Geriatr Psychiatry 2017; 32(1): 102-9.[http://dx.doi.org/10.1002/gps.4453] [PMID: 26898770] ] reported higher OT levels in older women than in men.

Our data, with the limits of a peripheral, albeit reliable parameter, can be considered in agreement with those mainly gathered in animals, while supporting the notion that behavioural differences in social and relationship contexts between the two sexes might be related to OT concentrations, functioning or processing [13Cushing BS, Carter CS. Peripheral pulses of oxytocin increase partner preferences in female, but not male, prairie voles. Horm Behav 2000; 37(1): 49-56.[http://dx.doi.org/10.1006/hbeh.1999.1558] [PMID: 10712858] , 18Insel TR, Young LJ. Neuropeptides and the evolution of social behavior. Curr Opin Neurobiol 2000; 10(6): 784-9.[http://dx.doi.org/10.1016/S0959-4388(00)00146-X] [PMID: 11240 290] , 19Smeltzer MD, Curtis JT, Aragona BJ, Wang Z. Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles. Neurosci Lett 2006; 394(2): 146-51.[http://dx.doi.org/10.1016/j.neulet.2005.10.019] [PMID: 16289323] , 42Anacker AM, Beery AK. Life in groups: the roles of oxytocin in mammalian sociality. Front Behav Neurosci 2013; 7: 185.[http://dx.doi.org/10.3389/fnbeh.2013.00185] [PMID: 24376404] -44Macdonald K, Macdonald TM. The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 2010; 18(1): 1-21.[http://dx.doi.org/10.3109/10673220903523615] [PMID: 20047458] ]. Another limitation of our study was that estradiol levels were not evaluated while being a potentially confounding variable. Again, the sample size was small, with all subjects belonging to the same environment, with similar educational level and lifestyle: these characteristics may limit the generalizability of our findings.

Until now, the available evidence in humans has been mainly indirect and based on a few observations of behavioural and emotional differences between men and women of in kinship, competition skills or facial recognition following intranasal OT challenges [23Fischer-Shofty M, Levkovitz Y, Shamay-Tsoory SG. Oxytocin facilitates accurate perception of competition in men and kinship in women. Soc Cogn Affect Neurosci 2013; 8(3): 313-7.[http://dx.doi.org/10.1093/scan/nsr100] [PMID: 22446301] -25Proverbio AM. Sex differences in social cognition: The case of face processing. J Neurosci Res 2017; 95(1-2): 222-34. [doi: 10.1002/jnr.23817]. [PMID: 27870403].[http://dx.doi.org/10.1002/jnr.23817] [PMID: 27870403] ]. In addition, it should be noted that generally previous studies are affected by a sex bias, as a large majority of them included only men as participants [26Rilling JK, Demarco AC, Hackett PD, et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2014; 39: 237-48.[http://dx.doi.org/10.1016/j.psyneuen.2013.09.022] [PMID: 24157401] ].

It is conceivable that OT might have refined gender-specific functional roles within the context of human sociality: it is noteworthy that intranasal OT administration has been shown to increase amygdala activation in men facing aggressive individuals, while in women it occurs when they observe individuals approving somebody else. Therefore, according to this result, it was concluded that OT plays a specific role in promoting the positive and negative salience of a social encounter, respectively, in women and in men [45Gao S, Becker B, Luo L, et al. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci USA 2016; 113(27): 7650-4.[http://dx.doi.org/10.1073/pnas.1602620113] [PMID: 27325780] ].

Reported sex differences have been attributed to the interactive effect of OT with sex steroid hormones, particularly estrogens [46Jezová D, Juránková E, Mosnárová A, Kriska M, Skultétyová I. Neuroendocrine response during stress with relation to gender differences. Acta Neurobiol Exp (Warsz) 1996; 56(3): 779-85.[PMID: 8917906] ]. Previous studies demonstrated that neuro-endocrine activation depends on the stressor and on many other factors including the individual's sex [47Steinman MQ, Duque-Wilckens N, Greenberg GD, et al. Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin. Biol Psychiatry 2016; 80(5): 406-14.[http://dx.doi.org/10.1016/j.biopsych.2015.10.007] [PMID: 26620251] ]. Some authors claimed that, since OTRs exhibit a diverse expression within the rodent brain, the receptors might play a complementary or opposing role in the gender-specific regulation of social behaviour [48Dumais KM, Veenema AH. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 2016; 40: 1-23.[http://dx.doi.org/10.1016/j.yfrne.2015.04.003] [PMID: 25951955] ].

Indeed, a properly regulated OT system has been suggested to enhance resilience and to act as a hurdle against the development of mental disorders and/or substance abuse [49Johnson JL, Buisman-Pijlman FT. Adversity impacting on oxytocin and behaviour: timing matters. Behav Pharmacol 2016; 27(8): 659-71.[http://dx.doi.org/10.1097/FBP.0000000000000269] [PMID: 27755 016] , 50Kovács GL, Sarnyai Z, Szabó G. Oxytocin and addiction: a review. Psychoneuroendocrinology 1998; 23(8): 945-62.[http://dx.doi.org/10.1016/S0306-4530(98)00064-X] [PMID: 9924 746] ]. Accumulating evidence suggests a role for OT in the pathophysiology of different psychopathological conditions, mainly in those characterized by social and emotional deficits [3Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35(11): 649-59.[http://dx.doi.org/10.1016/j.tins.2012.08.004] [PMID: 22974560] , 29Kirsch P, Esslinger C, Chen Q, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005; 25(49): 11489-93.[http://dx.doi.org/10.1523/JNEUROSCI.3984-05.2005] [PMID: 16339 042] , 30Panksepp J. Oxytocin effects on emotional processes: separation distress, social bonding, and relationships to psychiatric disorders. Ann N Y Acad Sci 1992; 652: 243-52.[http://dx.doi.org/10.1111/j.1749-6632.1992.tb34359.x] [PMID: 1626 832] , 51Kirsch P. Oxytocin in the socioemotional brain: implications for psychiatric disorders. Dialogues Clin Neurosci 2015; 17(4): 463-76.[PMID: 26869847] , 52Marazziti D, Catena Dell’osso M. The role of oxytocin in neuropsychiatric disorders. Curr Med Chem 2008; 15(7): 698-704.[http://dx.doi.org/10.2174/092986708783885291] [PMID: 18336283] ], such as depression [53Bell CJ, Nicholson H, Mulder RT, Luty SE, Joyce PR. Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence. J Psychopharmacol (Oxford) 2006; 20(5): 656-60.[http://dx.doi.org/10.1177/0269881106060512] [PMID: 16401658] -56McQuaid RJ, McInnis OA, Abizaid A, Anisman H. Making room for oxytocin in understanding depression. Neurosci Biobehav Rev 2014; 45: 305-22.[http://dx.doi.org/10.1016/j.neubiorev.2014.07.005] [PMID: 25025 656] ], social phobia [57Hoge EA, Pollack MH, Kaufman RE, Zak PJ, Simon NM. Oxytocin levels in social anxiety disorder. CNS Neurosci Ther 2008; 14(3): 165-70.[http://dx.doi.org/10.1111/j.1755-5949.2008.00051.x] [PMID: 18801 109] ], anxiety disorders [3Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35(11): 649-59.[http://dx.doi.org/10.1016/j.tins.2012.08.004] [PMID: 22974560] ], autism spectrum disorders [58Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007; 61(4): 498-503.[http://dx.doi.org/10.1016/j.biopsych.2006.05.030] [PMID: 16904652] , 59Carter CS. Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 2007; 176(1): 170-86.[http://dx.doi.org/10.1016/j.bbr.2006.08.025] [PMID: 17000015] ], OCD [60Leckman JF, Goodman WK, North WG, et al. Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder. Comparison with Tourette’s syndrome and healthy controls. Arch Gen Psychiatry 1994; 51(10): 782-92.[http://dx.doi.org/10.1001/archpsyc.1994.03950100030003] [PMID: 7524462] , 61Marazziti D, Baroni S, Giannaccini G, et al. Plasma oxytocin levels in untreated adult obsessive-compulsive disorder patients. Neuropsycho- biology 2015; 72(2): 74-80.[http://dx.doi.org/10.1159/000438756] [PMID: 26509891] ], post traumatic stress disorders [9Heim C, Owens MJ, Plotsky PM, Nemeroff CB. Persistent changes in corticotropin-releasing factor systems due to early life stress: relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacol Bull 1997; 33(2): 185-92.[PMID: 9230630] ], and other conditions [61Marazziti D, Baroni S, Giannaccini G, et al. Plasma oxytocin levels in untreated adult obsessive-compulsive disorder patients. Neuropsycho- biology 2015; 72(2): 74-80.[http://dx.doi.org/10.1159/000438756] [PMID: 26509891] -63Heim C, Young LJ, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol Psychiatry 2009; 14(10): 954-8.[http://dx.doi.org/10.1038/mp.2008.112] [PMID: 18957940] ] almost all characterized by a female preponderance [64Steel Z, Marnane C, Iranpour C, et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol 2014; 43(2): 476-93.[http://dx.doi.org/10.1093/ije/dyu038] [PMID: 24648481] , 65Sundström Poromaa I, Comasco E, Georgakis MK, Skalkidou A. Sex differences in depression during pregnancy and the postpartum period. J Neurosci Res 2017; 95(1-2): 719-30.[http://dx.doi.org/10.1002/jnr.23859] [PMID: 27870443] ]. Again, sex-related OT differences have been related to emotional distress [28Taylor SE, Saphire-Bernstein S, Seeman TE. Are plasma oxytocin in women and plasma vasopressin in men biomarkers of distressed pair-bond relationships? Psychol Sci 2010; 21(1): 3-7.[http://dx.doi.org/10.1177/0956797609356507] [PMID: 20424014] , 66Ebner NC, Chen H, Porges E, et al. Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendo- crinology 2016; 69: 50-9.[http://dx.doi.org/10.1016/j.psyneuen.2016.03.013] [PMID: 27032063] ] and to the anxiety of a love relationship [36Marazziti D, Dell’Osso B, Baroni S, et al. A relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health 2006; 2: 28.[http://dx.doi.org/10.1186/1745-0179-2-28] [PMID: 17034623] , 67Simpson JA, Steven Rholes W. Adult attachment, stress, and romantic relationships. Curr Opin Psychol 2017; 13: 19-24.[http://dx.doi.org/10.1016/j.copsyc.2016.04.006] [PMID: 27135049] ]. Recently, a common OTR gene (rs53576) polymorphism has been associated with empathic concern and emotional aspects of empathy, with women showing higher empathy scores than men [68Huetter FK, Bachmann HS, Reinders A, et al. Association of a common oxytocin receptor gene polymorphism with self-reported ‘empathic concern’ in a large population of healthy volunteers. PLoS One 2016; 11(7): e0160059.[http://dx.doi.org/10.1371/journal.pone.0160059] [PMID: 27467763] ].

CONCLUSION

It is tempting to speculate that OT might be considered as one of the main modulators of some specific behaviours and attitudes (stress response, social skills, altruism, trust, empathy, love) that may be different in the two sexes [31Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron 2008; 58(4): 639-50.[http://dx.doi.org/10.1016/j.neuron.2008.04.009] [PMID: 18498743] , 69Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005; 435(7042): 673-6.[http://dx.doi.org/10.1038/nature03701] [PMID: 15931222] -71Carter CS. The oxytocin-vasopressin pathway in the context of love and fear. Front Endocrinol (Lausanne) 2017; 8: 356.[http://dx.doi.org/10.3389/fendo.2017.00356] [PMID: 29312146] ]. Interestingly, salivary OT has been positively related to generosity in young girls [72Fujii T, Schug J, Nishina K, Takahashi T, Okada H, Takagishi H. Relationship between salivary oxytocin levels and generosity in preschoolers. Sci Rep 2016; 6: 38662.[http://dx.doi.org/10.1038/srep38662] [PMID: 27929138] ].

In any case, although our sample size was small and quite homogenous, the present findings would indicate that women show higher plasma OT concentrations than men. Further studies are needed to replicate or not this finding in larger samples composed by more heterogeneous subjects, as well as to evaluate if differences in OT concentrations represent an indicator of a different susceptibility to stress response, resilience and social emotions that are, however, functional for creating and sustaining an optimal biosocial environment.

LIST OF ABBREVIATIONS

AVP = Arginine-vasopressin
AVPR(s) = AVP Receptor(s)
BMI = Body/Mass Index
EDTA = Ethylenediaminetetraacetic Acid
OT = Oxytocin
OTR (s) = OT Receptor (s)
RIA = Radio-immuno Assay

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study was approved by the Ethics Committee of University of Pisa (CEAVNO), Pisa, Italy.

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

Informed consent was obtained from all individual participants included in the study.

CONFLICT OF INTEREST

The authors declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Donatella Marazziti, Stefano Baroni, Armando Piccinni, Liliana Dell’Osso planned the study, wrote and revised the paper. Donatella Marazziti, Armando Piccinni, Federico Mucci, Enrico Massimetti, Claudia Carmassi and Ilenia Moroni selected the subjects to be included in the study. Stefano Baroni, Lionella Palego and Gino Giannaccini carried out the biological assays and the statistical analyses. All the authors revised and approved the final version of the paper.

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