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Cited by 119Neuroendocrine regulation and behaviorOlfactory and Sensory Function StudiesStress Responses and Cortisol

Sex, Receptors, and Attachment: A Review of Individual Factors Influencing Response to Oxytocin

Open access
MacDonald, Kai S.·2013·Frontiers in Neuroscience
DOI 10.3389/fnins.2012.00194PMC PMC3541513
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Abstract

As discussed in the larger review in this special issue (MacDonald and Feifel), intranasal oxytocin (OT) is demonstrating a growing potential as a therapeutic agent in psychiatry. Importantly, research suggests that a variety of individual factors may influence a person's response to OT. In this mini-review, I provide a review of three: (1) sex and hormonal status; (2) genetic variation in aspects of the OT system (i.e., OT receptors); and (3) attachment history. Each of these factors will be important to monitor as we strive to develop a richer understanding of OT's role in human development, brain-based disease, and the potential for individualized, OT-targeted treatments.

Verified 2026-10-09 · 1 reference not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This mini-review argues that sex and hormonal status, genetic variation in the oxytocin system (OTR and CD38), and early attachment history are individual factors that may moderate response to intranasal oxytocin. It concludes that clinical evidence for these moderators is sparse and requires larger therapeutic trials.

Key findings

  • Sex and hormonal status: animal and human evidence indicates sex-specific oxytocin effects; in a randomized, double-blind, within-subjects crossover trial of intranasal oxytocin (40 IU BID for 3 weeks) in generalized anxiety disorder, there was a trend-level dose-by-gender effect, with males showing significant HAM-A improvement on oxytocin while females showed higher HAM-A scores during treatment. Three multi-week schizophrenia studies had male-biased recruitment (62 males treated vs. 13 females) and none showed a sex-by-drug effect.
  • Genetic variation: OTR and CD38 variants have been linked to personality, social behavior, stress/maltreatment responses, brain anatomy/function, and disease states such as schizophrenia and autism; however, no published studies have examined genetic variation in the OT system in relation to clinical response to oxytocin in psychiatrically ill patients. Examples include moderation of subjective responses to infant faces by OTR rs53576G, associations of OTR rs53576, rs2254298, and rs2228485 with Reading the Mind in the Eyes Test performance, and modulation of neural responses to emotional faces by OXTR rs2268498.
  • Attachment history: early attachment experiences may shape the central OT system through epigenetic and neuroplastic changes, and intranasal oxytocin effects can be moderated by parental love-withdrawal and attachment representations. The only published clinical study cited in this area found that patients with borderline personality disorder and anxious attachment showed less trust than those with more secure attachment after intranasal oxytocin.
  • Overall, the review presents these three factors as candidate moderators of oxytocin response, but emphasizes that clinical trial evidence remains limited.

Methods

  • Design: narrative mini-review of three individual factors influencing response to intranasal oxytocin: sex and hormonal status, genetic variation in aspects of the OT system (OTR and CD38), and attachment history.
  • Data or sample: no primary data or new sample; the paper synthesizes animal studies, human neurotypical studies, genetic and imaging studies, and clinical trials, including cited trials in generalized anxiety disorder, schizophrenia, and borderline personality disorder.
  • Main analysis: narrative synthesis of cited literature; no systematic search, meta-analysis, or new statistical analysis is reported.

Limitations

  • The paper states that given the paucity of clinical trials with intranasal oxytocin, the suggestion that these factors moderate clinical response should be viewed with circumspection, and larger-scale therapeutic trials are needed.
  • The paper states that no published studies have examined genetic variation in the OT system in relation to clinical response to oxytocin in psychiatrically ill patients, and that evidence for early experience impacting OT response in clinical populations is sparse, with only one published study in borderline personality disorder.
  • Evident from the text: as a mini-review, it does not report a systematic search or formal quality appraisal, and it notes replicability and effect-size concerns, including failed associations in some OTR studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fnins.2012.00194

Cites

141 of 146 references verified4 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 90 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In humans, testosterone seems from one perspective to decrease trust, generosity, and empathy.

    “testosterone seems from one perspective to have opposite behavioral effects to the prosocial impact classically associated with OT: decreasing trust, generosity, empathy (van Honk and Schutter, 2007; Zak et al., 2009; Bos et al., 2010)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites van Honk and Schutter, 2007

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    • cites Zak et al., 2009

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    • cites Bos et al., 2010

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  • Premisecitation

    Men and women show differences in plasma oxytocin levels.

    “men and women show differences in plasma OT levels (Ozsoy et al., 2009; Gordon et al., 2010; Holt-Lunstad et al., 2011; Weisman et al., 2012b)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ozsoy et al., 2009

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    • cites Gordon et al., 2010

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    • cites Holt-Lunstad et al., 2011

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  • Premisecitation

    Many other single-dose studies have not found an effect of sex.

    “many other single-dose studies have not found an effect of sex (see Bartz et al., 2011b for review).”
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    • cites Bartz et al., 2011b

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  • Interpretationreasoning

    A variety of individual factors may influence a person's response to oxytocin.

    “Importantly, research suggests that a variety of individual factors may influence a person’s response to OT.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Other studies in this area have failed to find a sex bias in oxytocin receptor associations.

    “though other studies in this area have failed to find a sex bias (Rodrigues et al., 2009; Saphire-Bernstein et al., 2011; Feldman et al., 2012).”
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    • cites Rodrigues et al., 2009

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    • cites Saphire-Bernstein et al., 2011

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    • cites Feldman et al., 2012

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  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 1

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    Premisecitation

    The histological structure for oxytocin neurons is sexually dimorphic, suggesting that sex steroids play a role in early morphogenesis of this system.

    “the histological structure for OT neurons is sexually dimorphic, suggesting that sex steroids play a role in early morphogenesis of this system (de Vries, 2008).”
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    • cites de Vries, 2008

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    Premisecitation

    Scheele et al. found in 86 normal heterosexual males that intranasal oxytocin preferentially stimulated men in a monogamous relationship, but not single males, to maintain more personal space from women but not men.

    “Scheele et al. (2012) found in a group of 86 normal heterosexual males that IN OT preferentially stimulated men in a monogamous relationship – but not single males – to maintain more personal space from women (but not men).”
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    • cites Scheele et al., 2012

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    Premisecitation

    Testosterone promotes oxytocin receptor binding in the hypothalamus and production of arginine vasopressin.

    “testosterone promotes both OTR binding in the hypothalamus (Johnson et al., 1991) as well as production of AVP (Delville et al., 1996)”
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    • cites Johnson et al., 1991

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    • cites Delville et al., 1996

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    Premisecitation

    Estrogen upregulates oxytocin and oxytocin receptor production.

    “Estrogen upregulates OT and OT receptor (OTR) production (Patisaul et al., 2003; Windle et al., 2006; Choleris et al., 2008)”
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    • cites Patisaul et al., 2003

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    • cites Windle et al., 2006

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    • cites Choleris et al., 2008

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  • The quote only partly states this claim.

    Interpretationnone given

    Genetic variation in aspects of the oxytocin system, including the oxytocin receptor and CD38, is one individual factor that may influence a person's response to oxytocin.

    “In this mini-review, I provide a review of three: (1) sex and hormonal status; (2) genetic variation in aspects of the OT system (i.e., OT receptors); and (3) attachment history.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Feifel et al.'s 2011 trial in generalized anxiety disorder demonstrated a trend-level dose-by-gender effect such that males treated with oxytocin showed significant clinical improvement in HAM-A scores with oxytocin, whereas females showed higher HAM-A scores during 3 weeks of treatment.

    “This trial demonstrated a trend level dose-by-gender effect such that males treated with OT showed a significant clinical improvement in HAM-A scores with OT, whereas females showed higher HAM-A scores during 3 weeks of treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Feifel et al., 2011

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    Premisecitation

    In neurotypical subjects, genetic differences in the oxytocin system impact positive personality factors and social behavior, differential responses to stress and maltreatment, brain anatomy, and function of stress and emotion-related brain areas.

    “in neurotypical subjects, genetic differences in the OT system impacts positive personality factors and social behavior (Bakermans-Kranenburg and van Ijzendoorn, 2008; Rodrigues et al., 2009; Montag et al., 2011; Saphire-Bernstein et al., 2011; Walter et al., 2012)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bakermans-Kranenburg and van Ijzendoorn, 2008

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    • cites Rodrigues et al., 2009

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    • cites Montag et al., 2011

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    Premisecitation

    Female oxytocin receptor rs4813625 carriers demonstrated greater stress-induced dopamine release, higher attachment and trait anxiety, and lower emotional well-being scores.

    “female OTR (rs4813625) carriers demonstrated greater stress-induced dopamine release, higher attachment and trait anxiety, and lower emotional well-being scores (Love et al., 2012).”
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    • cites Love et al., 2012

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    Premisecitation

    Retinoids can be used to increase CD38 expression, providing an alternative way to stimulate the oxytocin system or potentially augment intranasal oxytocin treatment.

    “retinoids (vitamin-A related compounds) can be used to increase CD38 expression (Riebold et al., 2011), thus providing an alternative way to stimulate the OT system or potentially augment IN OT treatment (Ebstein et al., 2011).”
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    • cites Riebold et al., 2011

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    • cites Ebstein et al., 2011

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    Premisecitation

    Three extant studies using multiple weeks of oxytocin treatment in patients with schizophrenia demonstrated a male bias in recruitment (62 males treated vs. 13 females), though none showed a sex-by-drug effect.

    “The three extant studies using multiple weeks of OT treatment in patients with schizophrenia demonstrated a male bias in recruitment (62 males treated vs. 13 females), though none showed a sex-by-drug effect (Feifel et al., 2010; Pedersen et al., 2011; Modabbernia et al., 2012).”
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    • cites Modabbernia et al., 2012

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    Premisecitation

    Hormone levels, menstrual phase, and oral contraceptive status may impact oxytocin levels and psychiatric symptoms.

    “these parameters may impact OT levels (Salonia et al., 2005, but, see Rubin et al., 2011) and psychiatric symptoms (Rubin et al., 2010).”
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    Premisecitation

    CD38 knock-out mice forget the location of their pups and previous social encounters, and synthesize but do not properly secrete oxytocin.

    “These socially hapless mice forget the location of their pups as well as previous social encounters, and synthesize, but don’t properly secrete OT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Differences in baseline and dynamic levels of oxytocin release in the brain and/or secretion into the plasma, and differences in regional oxytocin receptor and AVPR receptor density, are potential contributors to neuropeptidergic individuality.

    “other potential contributors to neuropeptidergic individuality include: (1) differences in baseline and dynamic levels of OT release in the brain and/or secretion into the plasma, the latter found to correlate with personality and brain structure (Andari et al., 2012)”
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    • cites Andari et al., 2012

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    Premisecitation

    In humans, variants in the CD38 gene have been tied to oxytocin secretion, social processing, sensitive parenting, and potentially autism.

    “In humans, variants in the CD38 gene have been tied to OT secretion (Kiss et al., 2011), social processing (Higashida et al., 2012a; Sauer et al., 2012), sensitive parenting (Feldman, 2012), and potentially autism (Higashida et al., 2011, 2012b for review).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kiss et al., 2011

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    • cites Higashida et al., 2012a

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    • cites Sauer et al., 2012

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    Premisecitation

    Genetic variation in the oxytocin system has been implicated in schizophrenia and autism.

    “genetic variation in the OT system has been implicated in several of the disease states where OT has shown the most therapeutic promise: schizophrenia (Teltsh et al., 2011; Montag et al., 2012) and autism (Ebstein et al., 2012).”
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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Given the paucity of clinical trials with intranasal oxytocin, the suggestion that the above factors may be moderators of clinical response to intranasal oxytocin should be viewed with circumspection.

    “Given the paucity of clinical trials with IN OT, the suggestion that the above factors may be moderators of clinical response to IN OT should be viewed with circumspection.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: No published studies have examined the role of genetic variation in the oxytocin system to a psychiatrically ill person's clinical response to oxytocin.
    • Rests on an assumption: Evidence that early experience impacts oxytocin response in clinical populations is sparse.

  • May combine two claims.

    Premisecitation

    Aversive early attachment experiences and attachment style impact stress systems, CSF, and plasma oxytocin levels as well as later response to intranasal oxytocin.

    “aversive early attachment experiences and attachment style impact stress systems, CSF, and plasma OT levels (Heim et al., 2009; Strathearn et al., 2009, 2012; Bertsch et al., 2012; Weisman et al., 2012a) as well as later response to IN OT”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Heim et al., 2009

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    • cites Strathearn et al., 2009

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    • cites Huffmeijer et al., 2011

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  • The paper relies on this without support.

    No published studies have examined the role of genetic variation in the oxytocin system to a psychiatrically ill person's clinical response to oxytocin.

    “Though no published studies have examined the role of genetic variation in the OT system to a psychiatrically ill person’s clinical response to OT”

  • The paper relies on this without support.

    Evidence that early experience impacts oxytocin response in clinical populations is sparse.

    “To date, in keeping with the general trend noted throughout this and the accompanying larger review (MacDonald and Feifel, this issue) the evidence that early experience impacts OT response in clinical populations is sparse.”
2 of 2

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Related

Authors
MacDonald, K. S.
Affiliations
University of California San Diego (US)
Corresponding author
MacDonald, Kai S.
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2013
Volume
6
Pages
194-194
ISSN
  • 1662-453X (ISSN-L)
  • 1662-4548
DOI
10.3389/fnins.2012.00194
PMC
PMC3541513
OpenAlex
W2134862200
Semantic Scholar
ad3697e908167c192241d32b8a01114f0f6fff84
Cited by
119
References
143
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 10 · 2017: 7 · 2016: 19 · 2015: 15 · 2014: 14 · 2013: 12
FWCI
30.02
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
oxytocin, intranasal oxytocin, oxytocin receptor, sex differences, hormonal status, genetic variation, attachment history, individual differences in treatment response, human development

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