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. 2025 Oct 26;13(5):qfaf086. doi: 10.1093/sexmed/qfaf086

Abnormal grey matter in identifying primary intravaginal anejaculation patients from healthy controls: a voxel-based morphometry analysis

Qingqiang Gao 1, Heng Wang 2, Youfeng Han 3, Jiaming Lu 4, Peining Niu 5,✉, Jianhuai Chen 6,✉
PMCID: PMC12554162  PMID: 41146973

Abstract

Introduction

Abnormal spontaneous neural activity has been detected in the brain of anejaculation patients. It has been confirmed that anejaculation may be associated with altered regional activation in the brain.

Aim

This study aimed to explore the changes of grey matter in the brain of anejaculation patients.

Methods

Structural magnetic resonance imaging data were collected from 20 primary intravaginal anejaculation (PIAJ) patients and 16 matched healthy controls (HCs). The 3D high resolution T1 weighted images were processed to calculate the grey matter volume and density by the method of voxel-based morphometry analysis.

Outcomes

Differences of grey matter volume and density were compared between groups, and receiver operating characteristic curve was performed to evaluate the values of altered brain regions in distinguishing PIAJ from HCs.

Results

PIAJ patients showed increased grey matter volume in the right supplementary motor area, right inferior temporal gyrus, right superior and inferior occipital gyrus, part of the left precuneus and decreased grey matter grey matter in another part of the left precuneus. In addition, increased grey matter density of the right supplementary motor area, right postcentral gyrus, right inferior temporal gyrus, left middle frontal gyrus, left inferior temporal gyrus and decreased grey matter density of the left precuneus were revealed in PIAJ patients. Both abnormal grey matter volume and altered grey matter density exhibited satisfactory performance in distinguishing PIAJ from HCs.

Clinical Implications

These findings suggested that increased microstructural changes of grey matter might be associated with the increased inhibiting effect of the brain on ejaculation.

Strengths & Limitations

This study provided new insights into the pathological mechanism underlying PIAJ, These findings are exploratory and that future longitudinal or comparative studies (eg, PIAJ vs. premature ejaculation) will be necessary to clarify whether these changes are predisposing, consequential, or potentially modifiable.

Conclusion

These findings indicated that patients suffering from PIAJ might exhibit abnormal grey matter volume and density in some brain regions, which might be linked to the inability to ejaculate intravaginally. PIAJ patient showed more increased indicators of grey matter when compared with premature ejaculation patients, which often had decreased brain function.

Keywords: ejaculation dysfunction, primary intravaginal anejaculation, grey matter volume, grey matter density, voxel-based morphometry

Introduction

Anejaculation is a relatively uncommon sexual dysfunction and is one of the important causes of male infertility.1 Primary intravaginal anejaculation (PIAJ) is a type of anejaculation, where ejaculation cannot occur during the first vaginal intercourse, but can be achieved through masturbation or other methods, which is often accompanied by negative emotion such as anxiety and depression, affecting marital relationships and partner fertility.2 It was hypothesized that PIAJ might be related to psychological factors and inappropriate masturbation during adolescence.3 However, the pathogenesis of PIAJ is complex and its specific etiology is unknown. The diagnosis mainly relies on the self-evaluation method of intravaginal ejaculation latency (IELT), which is highly subjective and lacks objective biological indicators.4 Therefore, a deep understanding of the neuropathological mechanism of PIAJ is of great significance for ejaculation dysfunction.

Ejaculation is considered as a complex physiological and psychological process, which is under the control of multiple systems in the human body.5 This behavior has been proven to be a process of neurophysiological reflexes, which is regulated by brain and can be affected by psychological factors.6-8 It has reported that the process of ejaculation can be facilitated by the high dopamine level and increased spontaneous neural activity of regions located in the brain dopaminergic system while it can be inhibited by the high 5-hydroxytryptamine level and decreased activity of regions located in the serotonergic system.9-13 Previous studies have demonstrated that human cerebral cortex belongs to the high-level nerve center, which is influenced by emotional states.14-16 It not only regulates cognitive and emotional states, but also participates in controlling human sexual activities.17,18 In addition, the successful use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of premature ejaculation (PE) further confirmed the importance of brain in the process of ejaculation.19,20

With the application of neuroimaging method in previous studies, it has been found that ejaculation dysfunction may be associated with abnormalities of the central nervous system.21,22 Based on T1-weighted structural magnetic resonance imaging (MRI) data, atrophy patterns of grey matter had been found in the subcortical structures of brain in patients with psychogenic erectile dysfunction, which suggested that atrophy of abnormal brain structure played a key role in psychogenic erectile dysfunction.23 In addition, abnormalities of grey matter volume had been identified in the prefrontal-cingulate-thalamic areas of PE patients by the method of voxel-based morphometry (VBM).24 VBM is an MRI analysis technique that allows voxel-wise comparison of local gray matter volume or concentration across the whole brain. It involves spatial normalization of individual brain images into a standard space, segmentation into tissue classes (gray matter, white matter, cerebrospinal fluid), and statistical analysis at the voxel level. VBM is commonly used to identify regional structural differences between groups or associations with clinical or behavioral variables, without requiring a priori specification of regions of interest. These structural brain abnormalities were related to the development of PE, as well as its clinical characteristics, and might be helpful for distinguishing PE patients from healthy controls (HCs).24 However, no neuroimaging studies have investigated the microstructural changes of grey matter in PIAJ patients.

Based on the aforementioned studies, we speculated that PIAJ patients might exhibit abnormal grey matter including its volume and density when compared with HCs, which might be associated with the inability to ejaculate intravaginally. In order to test this hypothesis, structural MRI data were acquired from 20 PIAJ patients and 16 matched HCs in this study. The method of VBM was applied to calculate the measures of grey matter volume and density, which were compared between groups to evaluate the microstructural changes of grey matter in PIAJ patients. Moreover, receiver operating characteristic (ROC) curve was performed to evaluate the values of altered brain regions in distinguishing PIAJ from HCs.

Materials and methods

Participants

This study was approved by the ethical committee of Hospital. In addition, this study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each eligible participant. According to previous study,2 the diagnosis of PIAJ was based on the following criteria: (1) patients were unable to achieve intravaginal ejaculation from the first vaginal intercourse; (2) patients were able to achieve intravaginal ejaculation through masturbation or other methods; (3) patients had normal nocturnal emissions; (4) patients were accompanied by negative emotion related to PIAJ, such as anxiety and depression. These clinical data including medical and sexual history were collected through a face-to-face questionnaire interview. All participants had normal level of fasting blood glucose and sex hormone. Moreover, the level of depression and anxiety were evaluated by the scales of Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS).

All subjects should meet the following inclusion criteria: right-handed; aged from 20 to 45 years; educated for at least 9 years; had regular weekly sexual intercourses, normal sexual desire and erection in a stable sexual relationship for at least 6 months. Participants were excluded if they had any one of the following conditions: malformation or trauma of the genitalia; abnormal level of sex hormones; current or history of serious and instable medical disease, psychiatric or neurological diseases; structural brain abnormalities identified by conventional clinical MRI assessment; substance abuse/dependence; sexual dysfunction-associated treatment; any contraindications to MRI. Finally, 20 PIAJ patients and 16 matched HCs were enrolled in this study.

MRI data acquisition and preprocessing

MRI data were obtained using a 3.0 Tesla scanner (Achieva 3.0 T TX, Philips Medical Systems, Eindhoven, Netherlands). The 3D high resolution T1 weighted images were acquired with the following parameters: repetition time = 7600 ms; echo time = 3400 ms; slice thickness = 1 mm; field of view = 256 × 256 mm2; matrix = 256 × 256; flip angle = 8°.

MRI data preprocessing was carried out by Data Processing Assistant for Resting-State fMRI (DPARSF)25 based on MATLAB Platform. The detailed preprocessing procedures were as follows: (1) converting raw data from DICOM into NIFTI format; (2) reorientation of T1-weighted images; (3) segmenting the T1-weighted images into gray matter, white matter and cerebrospinal fluid using New Segment+DARTAL setting in DPARSF; (4) gray matter images were normalized to the averaging structural template of the patients/control group; (5) normalized gray matter images were transformed to the Montreal Neurological Institute (MNI) standard space; (6) voxels of normalized gray matter images were modulated by the Jacobian determinants derived from the normalization, to preserve the tissue volume following warping; (7) finally, modulated gray matter images were smoothed using a 4 mm full-width half-maximum Gaussian filter.

Statistical analysis

Between-group differences of demographic and clinical data were evaluated using two-sample t-tests by Statistical Package for the Social Sciences. The significant level was set at P < 0.05. Moreover, between-group differences of grey matter volume and density were compared by two-sample t-tests using Resting-State fMRI Data Analysis Toolkit (REST).26 The AlphaSim method in REST software was utilized for the correction of multiple comparisons. The significance threshold was set at P < 0.001 and minimum cluster size was set at 6 voxels. Moreover, ROC curve was performed to evaluate the values of altered brain regions in distinguishing PIAJ from HCs.

Results

Comparison of demographic and clinical data

No significant between-group differences were found in the age, BMI, educational level, IIEF-5, and PEDT scores (Table 1).

Table 1.

Demographic and clinical data of PIAJ patients and HCs.

PIAJ (n = 20) HCs (n = 16) t P
Age (years) 28.25 ± 3.945 30.69 ± 4.95 −1.65 0.11
BMI (kg/m  2) 24.88 ± 2.50 23.38 ± 3.23 1.58 0.12
Educational level (years) 15.05 ± 2.04 15.25 ± 1.61 −0.32 0.75
IIEF-5 (scores) 22.10 ± 1.17 22.63 ± 1.41 −1.22 0.23
PEDT (scores) 2.35 ± 1.76 3.00 ± 2.61 −0.85 0.40
IELT (minutes) - 12.06 ± 8.43 - -
SDS (scores) 37.44 ± 10.94 35.80 ± 12.23 0.42 0.68
SAS (scores) 36.19 ± 9.03 34.00 ± 10.62 0.66 0.52
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PIAJ: primary intravaginal anejaculation; HCs: healthy controls. BMI: body mass index; IIEF-5: international index of erectile function-5; PEDT: premature ejaculation diagnostic tool; IELT: intravaginal ejaculatory latency time; SDS: Self-rating Depression Scale; SAS: Self-rating Anxiety Scale. P values were obtained by two-sample t-tests. The significant level was set at P < 0.05.

Brain regions showed altered grey matter volume

Compared with HCs, PIAJ patients showed increased grey matter volume in the right supplementary motor area, right inferior temporal gyrus, right superior and inferior occipital gyrus, part of the left precuneus and decreased grey matter grey matter in another part of the left precuneus (Table 2; Figure 1).

Table 2.

Brain regions showed altered grey matter in primary intravaginal anejaculation patients.

Peak MNI coordinates Clusters Peak T values P
x y z
Grey matter volume
Right supplementary motor area 4 −2 50 8 4.39 P < 0.001
Right inferior temporal gyrus 48 −56 −10 16 5.06 P < 0.001
Right superior occipital gyrus 28 −78 46 11 4.56 P < 0.001
Right inferior occipital gyrus 42 −76 −16 6 3.84 P < 0.001
Left precuneusa −6 −44 80 10 3.81 P < 0.001
Left precuneusb −10 −48 48 12 -4.61 P < 0.001
Grey matter density
Right supplementary motor area 4 −2 50 12 5.03 P < 0.001
Right postcentral gyrus 52 −4 26 6 4.07 P < 0.001
Right inferior temporal gyrusa 48 −58 −10 10 4.52 P < 0.001
Right inferior temporal gyrusb 46 −16 −28 6 4.84 P < 0.001
Left middle frontal gyrus −24 0 56 7 4.80 P < 0.001
Left inferior temporal gyrus −46 −16 −28 11 4.57 P < 0.001
Left precuneus −10 −48 48 11 −4.54 P < 0.001
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P values were obtained by two-sample t-tests. The AlphaSim method in REST software was utilized for the correction of multiple comparisons. The significance threshold was set at P < 0.001 and minimum cluster size was set at 6 voxels.

Figure 1.

Figure 1

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Brain regions showed altered grey matter volume in primary intravaginal anejaculation patients. P values were obtained by two-sample t-tests. The AlphaSim method in REST software was utilized for the correction of multiple comparisons. The significance threshold was set at P < 0.001 and minimum cluster size was set at 6 voxels.

Brain regions showed altered grey matter density

In addition, increased grey matter density of the right supplementary motor area, right postcentral gyrus, right inferior temporal gyrus, left middle frontal gyrus, left inferior temporal gyrus and decreased grey matter density of the left precuneus were revealed in PIAJ patients when compared with HCs (Table 2; Figure 2).

Figure 2.

Figure 2

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Brain regions showed altered grey matter density in primary intravaginal anejaculation patients. P values were obtained by two-sample t-tests. The AlphaSim method in REST software was utilized for the correction of multiple comparisons. The significance threshold was set at P < 0.001 and minimum cluster size was set at 6 voxels.

ROC curve analysis abnormal brain region for distinguishing PIAJ from and HCs

The ROC curve analysis using increased grey matter volume revealed an area under curve (AUC) of 0.90 with a sensitivity of 90% and a specificity of 88% in distinguishing PIAJ from HCs. Decreased grey matter volume could distinguish PIAJ from HCs with AUC 0.76, and the sensitivity and specificity were 75% and 81%, respectively (Figure 3).

Figure 3.

Figure 3

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ROC curve analysis abnormal brain region for distinguishing PIAJ from and HCs. ROC: receiver operating characteristic; PIAJ: primary intravaginal anejaculation; HCs: healthy controls.

Moreover, increased grey matter density revealed an AUC of 0.91 with a sensitivity of 85% and a specificity of 88% in distinguishing PIAJ from HCs. Decreased grey matter density could distinguish PIAJ from HCs with AUC 0.77, and the sensitivity and specificity were 70% and 81%, respectively (Figure 3).

Discussion

To the best of our knowledge, this is the first structural MRI study exploring the differences of grey matter volume and density between PIAJ patients and HCs. The results demonstrated that PIAJ patients exhibited increased grey matter volume and density in several brain regions with the exception of left precuneus, which showed decreased grey matter volume and density. The increased microstructural changes of grey matter might be associated with increased inhibiting effect of the brain on the process of ejaculation, which might be associated with the inability to ejaculate intravaginally. Both abnormal grey matter volume and altered grey matter density exhibited satisfactory performance in distinguishing PIAJ from HCs. In addition, PE and PIAJ represent clinically opposite syndromes, and the neurobiological mechanisms may differ substantially despite overlapping brain regions being implicated. From the results of the depression and anxiety scale scores, it can be seen that the subjects included in this study did not exhibit symptoms of depression and anxiety, meaning that PIAJ may not be related to abnormal emotions or stress, but only related to abnormal gray matter structure in the brain.

The supplementary motor area can provide efferent signals for sensory suppression, which then produce the suppression of neural activity in sensory areas.27 In addition, it has been found that the supplementary motor area is involved in the automatic suppression of manual motor plans.28 For the supplementary motor area, increased voxel-mirrored homotopic connectivity values in this region might be associated with shorter vaginal ejaculation latency and lower ejaculation control ability.29 In addition, increased long-range functional connectivity density in the bilateral supplementary motor area could be considered as biomarkers for evaluating the severity of PE.30 Moreover, the right supplementary motor area showed increased functional connectivity with the middle temporal gyrus, which might be also associated with PE.31 In patients with low ejaculation suppression ability, the enhancement of brain area activity or functional connectivity is likely a compensatory manifestation. These patients subconsciously try to change the situation of PE, and with this, the function of these brain regions increases, but in reality, they have not exerted the corresponding effect. In this study, increased grey matter volume and density were found in the right supplementary motor area of PIAJ patients. The change in this indicator seems to be similar in directionality to PE, but due to the more stable feature of microstructure, it has a corresponding inhibitory effect in sexual behavior. Therefore, the increased grey matter volume and density in the right supplementary motor area might be associated with the increased inhibition of brain over ejaculation.

Neurons of the inferior temporal cortex can reduce their response when the stimulus is repeated, which is regarded as adaptation or repetition suppression.32 For the inferior temporal gyrus, shorter vaginal ejaculation latency and lower ejaculation control ability were associated with decreased amplitude of low-frequency fluctuations (ALFF) in the bilateral inferior temporal gyrus, decreased fractional ALFF in the left inferior temporal gyrus and decreased regional homogeneity (ReHo) in the right inferior temporal gyrus, which suggested decreased strength and consistency of activation in the inferior temporal gyrus.33 The inferior temporal gyrus also exhibited decreased functional connectivity with the insula, and decreased functional connectivity with insula was related to dapoxetine treatment.34 From the structural perspective of brain, decreased global efficacy in the inferior temporal gyrus of the structural brain network related to PE.35 In a previous structural study, anejaculation patients showed decreased clustering coefficient in the right inferior temporal gyrus.36 In this study, increased grey matter volume and density were found in the inferior temporal gyrus of PIAJ patients. We speculated that the increased grey matter volume and density of right inferior temporal gyrus might be associated with increased inhibiting effect of the brain on ejaculation, which might be linked to the inability to ejaculate intravaginally. In PE patients, this brain region did not show any compensatory functional increase, while in PIAJ patients, this brain region still showed an increase in structure, suggesting that this brain region may have more characteristic significance in distinguishing PIAJ from PE.

In addition, increased grey matter volume was detected in the right superior, inferior occipital gyrus and left precuneus of PIAJ patients while increased grey matter density was revealed in the right postcentral gyrus, left middle frontal gyrus and left inferior temporal gyrus of PIAJ patients. Decreased ALFF values in the left middle frontal gyrus and inferior temporal gyrus were associated with PE.33 PE patients with depression showed decreased nodal participation in the right postcentral gyrus.37 The resting-state functional connectivity of right postcentral gyrus is altered in PE patients.38 In previous studies, both decreased activation in the right inferior occipital gyrus and decreased betweenness centrality of the right superior occipital gyrus in the structural brain network were associated with PE.33,39 The simultaneous decline in structure and function suggests that these brain regions may be characteristic changes of PE. Moreover, PE patients had decreased ALFF in the right postcentral gyrus when compared with anejaculation patients.21 The direct comparison between PE and PIAJ patients can better reflect the fundamental pathological differences between the two disorders. The cortical thickness of left middle frontal cortex was negatively correlated with the Premature Ejaculation Diagnostic Tool scores.40 The decreased functional connectivity of inferior temporal gyrus could be normalized by dapoxetine.34 From the perspective of clinical features and treatment, these brain regions are more closely related to the assessment of clinical symptoms and the mechanism of drug effects. Therefore, increased grey matter volume and density of these brain regions might be also involved in the development of PIAJ, which might also be related to clinical symptoms and drug efficacy.

The precuneus belongs to the default mode network (DMN) in the brain, which are significantly correlated with the sexual function and psychosocial status of patients.41 In this study, both decreased and increased grey matter volume was discovered in the left precuneus while decreased grey matter density was observed in the left precuneus of PIAJ patients. From the overall results of this study, it can be seen that only the precuneus exhibits indicators of both structural increase and decline, suggesting that structural changes in the precuneus may be more complex or exhibit dynamic changes in PIAJ. Lifelong PE patients showed increased functional connectivity in the precuneus.42 Increased long-range functional connectivity density was identified in the bilateral precuneus of PE patients.30 PE patients showed increased degree centrality values in the precuneus.43 Increased ALFF values were identified in the bilateral precuneus while decreased ReHo values were found in the right precuneus,33 which suggested that the changes of precuneus might be complex in PE patients. In addition, PE patients showed altered brain activation in the DMN and PE patients with high sympathetic activity had decreased activity in the DMN, which highlighted the significances of DMN in the pathophysiology of sexual dysfunction.44 From these previous research results, it is found that the changes in the precuneus in PE patients are also inconsistent and complex. Therefore, we speculated that the precuneus might be an abnormal brain region shared by PE and PIAJ, and altered grey matter of the left precuneus might play an important role in the central pathological mechanism of PIAJ.

Conclusion

In conclusion, this structural MRI study showed PIAJ patient exhibited increased grey matter volume and density in several brain regions involved in the process of ejaculation. In addition, these patients had microstructural abnormalities in the left precuneus including increased and decreased changes. Both abnormal grey matter volume and altered grey matter density could be helpful for distinguishing PIAJ from HCs. These findings suggested that increased microstructural changes of grey matter might be associated with the increased inhibiting effect of the brain on ejaculation, which provided new insights into the pathological mechanism underlying PIAJ. Finally, information of patient partners (eg, relationship duration) might also be relevant to the results. However, this influencing factor was not taken into account in this study, and further large-scale studies were needed to validate the findings of this study in the future.

Acknowledgments

Not applicable.

Contributor Information

Qingqiang Gao, Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.

Heng Wang, Department of Urology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215003, China.

Youfeng Han, Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.

Jiaming Lu, Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.

Peining Niu, Department of Andrology, Siyang Traditional Chinese Medicine Hospital, Suqian 223700, China.

Jianhuai Chen, Department of Andrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.

Author contributions

Q.G., J.C., and Y.H.: Designed the experiments. Q.G., Y.H., and J.L.: Contributed to clinical data collection and assessment. Q.G., J.C., H.W., Y.H., and P.N.: Analyzed the results. Q.G., J.C., H.W., Y.H., and P.N.: Wrote the manuscript. All authors approved the final manuscript.

Qingqiang Gao, Heng Wang, and Youfeng Han are the co-first authors.

Funding information

The work was supported by the grants of: Nanjing Medical Technology Development Project (No. YKK19059); Jiangsu Traditional Chinese Medicine Science and Technology Development Plan Project (No. MS2022023); Key Project of Natural Science Foundation of Nanjing University of Chinese Medicine (No. XZR2024015); Excellent Young Doctor Training Program of Jiangsu Province Hospital of Chinese Medicine (No. 2023QB0126).

Conflict of interest

All authors declared that they had no conflict of interest.

Data availability

The data of this study are available from the corresponding author upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data of this study are available from the corresponding author upon request.

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