Article Influence of Menstrual Cycle Length and Age at Menarche on Symptoms, Cognition, Social Cognition, and Metacognition in Patients with First-Episode Psychosis Paula Barrau-Sastre 1,2,3 , Irene Birulés 2,3 , Marina Verdaguer-Rodríguez 1,2 , Raquel López-Carrilero 1,2,4 , Marta Ferrer-Quintero 1,2,3,4 , Helena García-Mieres 1,2,4 , Luciana Díaz-Cutraro 1,2,5 , Eva Grasa 4,6,7 , Esther Pousa 4,6,7,8,9 , Ester Lorente 4,10 , Trinidad Peláez 2,4 , María Luisa Barrigón 11 , Isabel Ruiz-Delgado 12 , Fermín González-Higueras 13 , Jordi Cid 14 , Alfonso Gutiérrez-Zotes 4,15 , Daniel Cuadras 16 , Judith Usall 1,2 , Regina Vila-Badia 1,2,4 , Ana Barajas 17,18, Susana Ochoa 1,2,4,* and on behalf of the Spanish Metacognition Group † 1 Etiopatogènia I Tractament dels Trastorns Mentals Greus (MERITT), Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain; paula.barrau@sjd.es (P.B.-S.); marina.verdaguer@sjd.es (M.V.-R.); raquel.lopezc@sjd.es (R.L.-C.); marta.ferrerq@sjd.es (M.F.-Q.); helena.garcia@sjd.es (H.G.-M.); luciana.diaz@sjd.es (L.D.-C.); judit.usall@sjd.es (J.U.); regina.vilab@sjd.es (R.V.-B.) 2 Parc Sanitari Sant Joan de Déu, Doctor Antoni Pujadas 42, 08830 Sant Boi de Llobregat, Spain; irene.birules@sjd.es (I.B.); mtrinidad.pelaez@sjd.es (T.P.) 3 Facultat de Psicologia, Universitat de Barcelona, Passeig de la Vall d’Hebron, 71, 08035 Barcelona, Spain 4 Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain; egrasa@santpau.cat (E.G.); epousa@santpau.cat (E.P.); esterlorente@hotmail.com (E.L.); gutierreza@peremata.com (A.G.-Z.) 5 Psychology Department, FPCEE Blanquerna, Universitat Ramon Llull, 08022 Barcelona, Spain Citation: Barrau-Sastre, P.; Birulés, I.; 6 Department of Psychiatry, Institut d’Investigació Biomèdica-Sant Pau (IIB-Sant Pau), Hospital de la Santa Verdaguer-Rodríguez, M.; Creu i Sant Pau, 08041 Barcelona, Spain 7 Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona, López-Carrilero, R.; Ferrer-Quintero, M.; García-Mieres, H.; Díaz-Cutraro, Cerdanyola del Vallès, 08193 Barcelona, Spain 8 Salut Mental Parc Taulí. Sabadell, Hospital Universitari, UAB Universitat Autònoma de Barcelona, Sabadell, L.; Grasa, E.; Pousa, E.; Lorente, E.; 08208 Barcelona, Spain et al. Influence of Menstrual Cycle 9 Neuropsiquiatria i Addicions, Hospital del Mar. IMIM (Hospital del Mar Medical Research Institute), Length and Age at Menarche on 08003 Barcelona, Spain Symptoms, Cognition, Social 10 Psychiatry Service, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain Cognition, and Metacognition in 11 Departamento de Psiquiatría, Hospital Universitario Virgen del Rocio, 41013 Sevilla, Spain; marisabe@gmail.com Patients with First-Episode Psychosis. 12 Unidad de Salud Mental Comunitaria Málaga Norte, UGC Salud Mental Carlos Haya, Servicio Andaluz de Salud, Women 2022, 2, 135–146. https:// 29014 Málaga, Spain; isabelruizdelgado@hotmail.com 13 Comunidad Terapéutica Jaén Servicio Andaluz de Salud, 23001 Jaén, Spain; pablofermingh78@gmail.com doi.org/10.3390/women2020015 14 Mental Health & Addiction Research Group, IdiBGi—Institut d’Assistencia Sanitària, 17119 Girona, Spain; Academic Editor: Mary V. Seeman jordi.cid@telefonica.net 15 Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari Institut Pere Mata, Received: 7 February 2022 Universitat Rovira i Virgili, 43206 Reus, Spain Accepted: 31 May 2022 16 Statistical Unit, Fundació Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain; daniel.cuadras@sjd.es Published: 2 June 2022 17 Serra Húnter Programme, Department of Clinical and Health Psychology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain; ana.barajas@uab.cat Publisher’s Note: MDPI stays neutral 18 Centre d’Higiene Mental Les Corts, Department of Research, 08029 Barcelona, Spain with regard to jurisdictional claims in * Correspondence: susana.ochoa@sjd.es published maps and institutional affil- † Membership of the Spanish Metacognition Study Group is provided in the Acknowledgments. iations. Abstract: A protective effect has traditionally been attributed to estrogen in psychotic disorders. The aim of this study was to investigate cumulative lifetime estrogen by assessing the menstrual cycle Copyright: © 2022 by the authors. length, age at menarche, and years of difference between the onset of psychotic symptoms and the age Licensee MDPI, Basel, Switzerland. of menarche, measuring their effects on symptoms, cognition, social cognition, and metacognition. This article is an open access article As it was not possible to directly measure cumulative estrogen levels over the lifetime of a patient, distributed under the terms and the study sample was composed of 42 women with first-episode psychosis; estrogen levels were conditions of the Creative Commons inferred by the menstrual cycle length, age at menarche, and years of difference between the onset of Attribution (CC BY) license (https:// psychotic symptoms and menarche. All patients were assessed with a battery of questionnaires using creativecommons.org/licenses/by/ the BDI, PSYRATS, PANSS, STROOP, TAVEC, WSCT, IPSAQ, and BCIS questionnaires. The results 4.0/). Women 2022, 2, 135–146. https://doi.org/10.3390/women2020015 https://www.mdpi.com/journal/women Women 2022, 2 136 related to menstrual cycle length showed a relationship with memory; specifically, shorter cycles with semantic strategies (p = 0.046) and longer cycles with serial strategies in the short term (p = 0.005) as well as in the long term (p = 0.031). The results also showed a relationship with perseverative errors (p = 0.035) and self-certainty (p = 0.049). Only personalized bias (p = 0.030) was found to be significant in relation to the age at menarche. When analyzing the differences in years of difference between the age at menarche and the onset of psychotic symptoms, the results indicated lower scores in women with a smaller difference between both events in memory (short-term (p = 0.050), long-term (p = 0.024), intrusions (p = 0.013), and recognition (p = 0.043)) and non-perseverative errors (p = 0.024). No relationship was found between symptoms and menstrual characteristics. The investigatory outcomes seem to indicate a relationship between estrogen cumulative effects and the memory domain. More in-depth investigations in the field are necessary in order to improve personalized treatment in women with psychosis. Keywords: schizophrenia; first psychotic episode; hormonal cycle; reproductive cycle; estrogen; memory 1. Introduction The course of schizophrenia, its expression, and the response to treatment varies widely among patients [1], although it is commonly a highly incapacitating disease that entails a considerable societal burden [2]. Nonetheless, the prognosis of psychotic disorders is still partially unknown [3,4]; first-episode psychosis (FEP) is a five-year critical period in which social development deteriorates. At present, the course of the illness can be determined based on cognitive and social cognition functioning [5–7]. Additionally, substance misuse and abuse in women with FEP is being discussed as a possible oxidative factor that can cause further cognitive deficits and negative symptomatology [8,9]. Cumulative evidence has established that cognition, social cognition, and metacogni- tion are among the best predictors of functional outcomes in psychosis [7,10–13]. People with psychosis often present important deficits in these three constructs, which are stable and appear prior to the onset of the disorder [10,14,15]. However, a growing body of literature suggests that psychological interventions aiming to improve cognition, social cognition, and metacognition have potential for promoting recovery [7,16]. A body of research has focused on understanding the sex differences in psychosis. Commonly, studies have found a lower prevalence and better recovery in females [17], which has led to the estrogenic hypothesis. This hypothesis suggests a protective effect of estrogen [18–21]. Estrogen plays several roles in females, from the development of secondary sexual characteristics to the regulation of the menstrual cycle. However, this effect is not exclusive to females as estrogen has recently been linked to anti-inflammatory, neuroprotective, and cognitive effects in males [22,23]. The duration of the menstrual cycle is associated with the length of the follicular phase, meaning that shorter follicular phases indicate shorter cycles [24]. Additionally, shorter menstrual cycles are usually associated with lower estradiol levels per cycle, but with a larger cumulative concentration over time [25]. On the other hand, shorter and longer cycles have been related to an increased probability of chronic anovulation and, consequently, a lower exposure to estrogen [25,26]. A delayed age at menarche has also been associated with negative and positive events in adulthood such as worse psychosocial functioning and a greater cardiovascular risk. Conversely, it has a protective effect against breast and endometrial cancer [25,27]. Emerging research indicates that early menarche correlates with higher estrogen levels [28]. In the case of women with psychosis, there seems to be an association between early puberty and a later onset of symptoms, which is consistent with the estrogenic hypothesis [29,30]. Furthermore, symptoms seem to fluctuate throughout the menstrual cycle and are heightened during the late luteal and early follicular phases. Interestingly, Women 2022, 2 137 this association is also present in patients with mood disorders [26,30–32]. In addition, postpartum and menopause psychosis have been related to the abrupt decrease in estrogen after these events [26,30,33]. Compared with healthy populations, women with psychosis have lower estrogen levels [33]. Recent studies have suggested that selective estrogen receptor modulators (SERMs) can improve cognitive symptoms in men and women with psychosis [34,35]. However, how estrogen cumulative effects influence symptoms, cognition, social cognition, and metacognition is still unknown, although a pharmacological treatment with SERMs seems to provide results. Therefore, the present study intended to obtain preliminary data on how pubertal and menstrual characteristics influence the expression of the illness and whether the protective effect of estrogen can be detected. The length of the cycle, age at menarche, and time elapsed since the age at menarche as well as the onset of symptoms could be variables that help us to indirectly deduce the level of estrogen. The aim of this work was to conduct an exploratory analysis of the clinical, cognitive, social cognitive, and metacognitive differences according to the length of the menstrual cycle, age at menarche, and years of difference between the onset of psychosis and age at menarche in women with FEP. We hypothesized that these indicators could be related to clinical, cognitive, social cognitive, and metacognitive variables with a positive relationship between them and the inferred estrogen levels. An exploratory analysis was performed based on these data because these were the only data that were available as we did not count hormone levels. 2. Method and Materials The sample of this study was composed of 42 women recruited through the following Spanish outpatient mental health centers between the years 2012 and 2017: The Health Assistance Institute of Girona; Sant Pau Hospital (Barcelona); Andalusian Service of Jaén; Andalusian Service of Málaga Pere Mata’s Institute (Reus); Jiménez Díaz Foundation (Madrid); Mental Health Hygiene Centre of Les Corts (Barcelona); Mental Health Centre of Healthcare and University Corporation of Parc Taulí (Sabadell); Clínic Hospital of València; and Parc Sanitari Sant Joan de Déu (PSSJD). The inclusion criteria were women between the age of 18 and 45 years with FEP having a diagnosis of schizophrenia, an unspecified psychotic disorder, a schizoaffective disorder, a delusional disorder, a brief psychotic disorder, or a schizophreniform disorder based on DSM-V criteria in addition to psychopathological stability over the previous 3 months (meaning no changes in medication) and having obtained 3 or above on the delusion, grandiosity, or suspicion items on The Positive and Negative Syndrome Scale (PANSS). The exclusion criteria established were an intellectual disability (premorbid IQ inferior or equal to 70), the presence of a cranioencephalic traumatism, a substance abuse disorder, amenorrhea, or the use of hormonal contraceptives, having obtained 5 or above on the hostility and absence of cooperation items and a score of 6 on the suspiciousness item on the PANSS in order to facilitate adherence and collaboration during the evaluation. Three variables were used to conduct the analysis. To start with, the cycle duration was defined as the average number of days that the menstrual cycle lasted. This variable was subjectively reported by participants, who had to choose which of the three groups they belonged to: short menstrual cycle (<28 days); mean (28–30 days); or long (>30 days). This classification was previously defined in the research protocols used in other studies. The second variable, age at menarche, was defined as the age of first menstruation and was asked of participants or reported based on their clinical history. The age at menarche was divided into three groups: early menarche (aged 9–12); mean (aged 13); or late menarche (aged 14–16). These groups were organized considering the distribution of the sample using the mean and conceptual information. In this case, the age of most women (50%) at menarche was at 13 years; therefore, we used this as the middle group. Those above and below the median formed the other two groups. For the last variable, if 0–5.99, 6–19.99, or >20 years passed between the age at menarche and illness onset, it was defined as the Women 2022, 2 138 time when symptoms were reported for the first time. This group was divided considering the proximity to hormonal changes; below 5 years between the onset and menarche age was considered to be close to developmental changes and more than 20 years was considered to be hormonal maturation changes. Regarding the assessment, the data were gathered during the inclusion of the study and through clinical histories; clinical, cognitive, social cognition, and metacognition evaluations were based on a clinical interview and the questionnaires from Table 1. Table 1. Questionnaires. Symptom Evaluation • The Beck Depression Inventory (BDI) was used to evaluate depressive symptoms as it has a high internal consistency and content validity. Higher scores indicate worse symptomatology [36–38]; • The Psychotic Symptom Rating Scales (PSYRATS) was used to assess the severity of hallucinations and delusions in psychotic patients as it has demonstrated its validity as a complement in order to evaluate these dimensions. Higher scores indicate a greater presence of hallucinations and delusions [39]; • The Positive and Negative Syndrome Scale (PANSS) is a semi-structured interview that allows for differentiating between positive, negative, and general symptoms. Higher scores mean a greater symptom severity [40,41]. Cognitive Evaluation • The Stroop Test was used for its reliability in evaluating executive functioning, measuring cognitive inhibition, and flexibility [42–44]; • The Test de Aprendizaje Verbal España-Complutense (TAVEC), the Spanish version of the California Verbal Learning Test, assesses learning capacity, memory domains, and strategies used in addition to counting with reliability and validity. Higher scores indicate a better performance [45–47]; • The Wisconsin Card Sorting Test (WSCT) is an executive functioning test used to evaluate problem solving and the ability to change tasks and response maintenance, and it measures these constructs well. A good development on this test is reflected by high scores [48]. Social Cognition Evaluation • The Hinting Task, used to evaluate the theory of mind, was chosen because of its strong psychometric properties. In our study, we used the abbreviated version; the higher the punctuation, the higher this ability [49,50]; • The Emotion Recognition Face Test consists of a set of different pictures that represent different emotions and the patient must choose between two options. We selected this test because of its reliability in detecting deficits, even though it reaches ceiling performance scores [51,52]; • The Internal, Situational, and Personal Attributions Questionnaire (IPSAQ), which has supported internal reliability [53], is used to describe the causal locus of the thinking of a person. High results reflect the attributional style they tend to use and whether it is a personalizing or externalizing bias style [54]. Metacognitive Evaluation • The Beck Cognitive Insight Scale (BCIS) is a self-assessed scale that evaluates the capacity of the patient to think about their own behavior and includes two scales: self-certainty and self-reflectivity. The higher the punctuations obtained on each scale, the more developed their capacity. This scale was chosen because its assessment is based on good psychometric properties [55]. 2.1. Ethical Aspects The present study was approved by the Ethical Committee of Sant Joan de Déu (coordinator center) (protocol code: PIC-73-11; date of approval: 22 November 2011) and the ethical committee of each of the participant centers, following the guidelines of the Declaration of Helsinki. In addition, each participant was provided with an informative sheet and signed an informed consent form. Women 2022, 2 139 2.2. Statistical Analysis The data analysis was performed using the ANOVA descriptive test and partial eta squared (η2 ) to calculate the effect size. We considered a p-value equal to or less than 0.05 to be statistically significant. Regarding the effect size, the following criteria were used: less than 0.1 indicated a small effect; between 0.1 and 0.15, a medium one; and larger than 0.15, a high effect size [56]. Multiple analysis corrections were not applied based on the effect size because we were performing an exploratory analysis [57]. We also performed a multimodal regression analysis that compared the three categories of each of the three main variables with the significant variables in the bivariate analysis. Moreover, we included age as a covariant. The reference category of menstrual cycle length was the middle group; in menarche age, the reference group was also the middle group. However, in the difference between the age at menarche and the onset of the illness, the reference group was the first one. 3. Results Table 2 contains a description of the sociodemographic variables of the sample. The mean age of the patients was 31 years with a standard deviation of 8.06. As can be seen, 76.2% of our sample were single and 69.1% were not working (i.e., 28.6% unemployed; 21.4% inactive; 14.3% permanently or temporarily sick leave and 4.8% pensioners). Table 2. Sociodemographic characteristics of the sample. Variables Categories N % Single 32 76.2 Married or living with a partner 4 9.5 Marital status Separated 4 9.5 Divorced 1 2.4 Widowed 1 2.4 Incomplete 1 2.4 Primary Complete 6 14.3 Incomplete 7 16.7 Study level Secondary Complete 11 26.2 Incomplete 6 14.3 University Complete 11 26.2 Active occupied 5 11.9 Active unemployed 12 28.6 Student 6 14.3 Working situation Housework 2 4.8 Pensioner 2 4.8 Permanent or temporary sick leave 6 14.3 Inactive 9 21.4 Schizophrenia 9 21.4 Unspecified psychotic disorder 11 26.2 Schizoaffective disorder 8 19.0 Principal diagnostic Delusional disorder 4 9.5 Brief psychotic disorder 5 11.9 Schizophreniform disorder 5 11.9 <28 days 15 35.7 Menstrual cycle description 28–30 days 20 47.6 >30 days 5 11.9 9–12 years 12 28.6 Age at menarche 13 years 21 50.0 14–16 years 9 21.4 Difference in age at 0–5.99 years 8 19.0 menarche and age of 6–19.99 years 20 47.6 symptom onset >20 years 14 33.3 Women 2022, 2 140 Regarding the variables studied, most patients had a 28–30 day menstrual cycle (47.6%). On the other hand, 35.7% had shorter ones (<28 days); only 11.9% were longer (>30 days). The mean menarche age was 12.31 with a standard deviation of 1.62 and the mean difference in years between the menarche age and the age of symptom onset was 15.14 with a standard deviation of 7.71. We found no relationship between the age at menarche and the age of illness onset (r = 0.137; p = 0.388). When analyzing the cycle length (Table 3), we found statistically significant differences with high effect sizes between the groups primarily in relation to memory and specifically in terms of semantic strategies (p = 0.046) and serial strategies with short-term (p = 0.005) and long-term (p = 0.031) memory. We also found a relationship between the cycle length and perseverative errors (p = 0.035) and self-certainty (p = 0.049). Table 3. Relationship between cycle length and symptoms, cognition, social cognition, and metacognition. <28 Days 28–30 Days >30 Days p-Value Partial Eta Squared M SD M SD M SD BDI 14.87 7.43 15.00 11.20 13.40 8.17 0.944 0.003 Hallucinations 1.62 5.82 5.00 9.44 5.20 11.63 0.523 0.037 PSYRATS Delusions 9.00 7.20 4.45 5.66 4.20 4.92 0.107 0.120 Symptoms PANSS: positive 13.73 7.35 13.40 4.16 12.00 5.24 0.839 0.009 PANSS: negative 13.80 4.51 13.85 6.43 15.00 5.05 0.909 0.005 PANSS: general 29.27 7.24 28.75 9.75 28.20 9.58 0.969 0.002 Word 44.87 11.82 42.00 9.52 39.80 8.26 0.577 0.031 Color 40.93 8.65 34.89 7.54 35.40 7.47 0.096 0.125 STROOP Word–color 49.93 13.80 40.11 10.73 40.40 8.65 0.059 0.149 Interference 56.67 10.53 50.72 6.37 50.40 6.43 0.106 0.120 Short-term free recall 44.64 11.90 38.13 11.56 36.54 16.21 0.245 0.075 Short-term recall with keys 43.71 11.56 37.83 15.02 33.22 14.25 0.266 0.071 Long-term free recall 43.73 10.76 39.42 16.09 35.59 16.42 0.488 0.039 Long-term recall with keys 41.77 12.67 36.20 15.50 32.75 15.89 0.386 0.052 Semantic strategy on 50.39 10.50 42.73 6.94 43.81 9.22 0.046 0.158 short-term recall with keys Cognition TAVEC Semantic strategy on 48.48 10.10 42.26 8.22 43.96 9.82 0.156 0.098 long-term recall with keys Serial strategy on short-term 44.19 0.52 50.04 6.51 47.46 4.07 0.005 0.256 recall with keys Serial strategy on long-term 45.60 4.12 53.34 10.83 47.46 5.73 0.031 0.176 recall with keys Perseverations 44.48 7.82 49.32 9.03 56.57 11.24 0.035 0.110 Total intrusions on recall 52.65 13.17 49.11 10.70 54.91 21.33 0.598 0.028 with keys Total intrusions on free recall 49.57 8.28 45.59 4.85 47.49 9.52 0.268 0.071 Hits on recognition 48.93 11.89 43.76 16.04 41.52 20.27 0.511 0.037 Hits 75.00 11.70 70.39 8.28 75.75 15.71 0.406 0.053 Total errors 45.43 7.50 40.61 6.00 44.00 6.22 0.135 0.100 WSCT Perseverative errors 46.29 9.19 40.44 8.26 46.75 5.32 0.122 0.120 Non-perseverative errors 44.57 7.47 41.22 5.97 40.50 8.39 0.336 0.064 Hinting task 1.68 0.36 1.70 0.24 1.73 0.28 0.930 0.004 Emotion recognition facial test 18.33 1.11 17.65 1.42 17.20 1.64 0.183 0.088 Social cognition Externalization bias 2.47 3.83 1.00 3.88 3.00 3.16 0.404 0.048 IPSAQ Personalizing bias 0.89 0.50 1.26 0.68 1.45 0.88 0.149 0.100 Self-reflectivity 13.14 4.19 14.50 6.91 16.00 6.25 0.629 0.025 Metacognition BCIS Self-certainty 7.64 3.54 6.90 3.23 11.40 4.56 0.049 0.155 The results for the menarche age can be found in Table 4. The only statistically significant result found was for personalizing bias (p = 0.030) with a high effect size (η2 = 0.168). The group with a later menarche was the one that obtained worse scores. Regarding the years of difference between the onset of psychotic symptoms and menarche age (Table 5), the results indicated lower scores in women with the smallest difference between both events in memory (short-term (p = 0.050), long-term (p = 0.024), intrusions (p = 0.013), and recognition (p = 0.043)) and non-perseverative errors (p = 0.024); all of them had a high effect size. Women 2022, 2 141 Table 4. Relationship between the age at menarche and symptoms, cognition, social cognition, and metacognition. 9–12 Years 13 Years 14–16 Years p-Value Partial Eta Squared M SD M SD M SD BDI 12.00 8.07 20.40 12.26 15.56 8.53 0.072 0.130 Hallucinations 3.37 7.08 8.91 12.67 0.00 0.00 0.063 0.142 PSYRATS Delusions 4.80 5.84 9.27 7.73 4.89 5.27 0.152 0.097 Symptoms PANSS: positive 11.95 3.32 16.27 8.73 13.00 3.12 0.094 0.114 PANSS: negative 13.55 5.81 16.18 6.87 14.56 4.39 0.481 0.037 PANSS: general 28.41 6.15 32.37 13.98 27.89 5.69 0.431 0.042 Word 40.82 7.80 43.25 12.26 45.89 7.67 0.648 0.023 Color 37.36 8.41 37.00 9.68 38.33 5.48 0.934 0.004 STROOP Word–color 43.75 13.17 43.45 13.37 43.44 10.27 0.997 0.000 Interference 53.35 10.56 54.00 7.48 48.67 4.82 0.341 0.056 Short-term free recall 39.60 14.27 42.22 8.56 39.10 11.65 0.816 0.011 Short-term recall with keys 37.97 15.44 39.75 12.36 38.05 15.01 0.943 0.003 Long-term free recall 38.62 15.25 42.62 12.42 39.76 14.54 0.757 0.015 Long-term recall with keys 35.93 15.47 37.54 15.14 37.62 15.93 0.944 0.003 Semantic strategy on 45.24 10.70 46.08 7.42 45.31 8.24 0.970 0.002 short-term recall with keys Cognition TAVEC Semantic strategy on 42.84 10.89 45.36 8.58 45.98 8.10 0.654 0.022 long-term recall with keys Serial strategy on short-term 46.99 5.21 49.80 6.85 46.83 3.63 0.335 0.056 recall with keys Serial strategy on long-term 50.74 11.06 50.22 7.25 48.12 4.59 0.768 0.014 recall with keys Perseverations 48.15 8.10 50.18 12.20 46.11 8.60 0.634 0.027 Total intrusions on recall 51.96 12.47 44.17 1.63 56.97 17.92 0.071 0.130 with keys Total intrusions on free recall 48.59 7.63 43.97 4.68 48.37 6.48 0.171 0.089 Hits on recognition 42.35 15.95 48.83 8.62 44.51 19.79 0.532 0.033 Hits 77.27 9.28 71.26 9.57 70.25 13.08 0.747 0.017 Total errors 42.75 5.82 45.20 8.36 41.13 7.40 0.569 0.032 WSCT Perseverative errors 43.05 8.16 45.30 9.65 42.63 9.47 0.763 0.015 Non-perseverative errors 42.25 5.34 45.20 8.35 40.50 8.14 0.335 0.061 Hinting task 1.70 0.28 1.68 0.28 1.70 0.36 0.988 0.001 Emotion recognition facial test 17.91 1.31 17.45 1.44 17.78 1.64 0.687 0.019 Social cognition Externalization bias 1.95 4.02 2.00 2.93 0.33 4.21 0.527 0.032 IPSAQ Personalizing bias 1.01 0.54 1.07 0.61 1.68 0.82 0.030 0.168 Self-reflectivity 14.14 6.66 14.27 5.83 14.75 4.27 0.970 0.002 Metacognition BCIS Self-certainty 8.50 3.80 7.55 3.56 6.63 4.00 0.465 0.039 Table 5. Relationship between the difference in age at menarche and age of onset of psychosis and symptoms, cognition, social cognition, and metacognition. 0–5.99 Years 6–19.99 Years >20 Years p-Value Partial Eta Squared M SD M SD M SD BDI 16.00 8.50 15.45 10.91 13.15 8.98 0.757 0.015 Hallucinations 5.71 10.36 4.80 10.05 2.17 5.13 0.635 0.025 PSYRATS Delusions 3.88 6.15 5.85 6.78 7.83 6.12 0.408 0.047 Symptoms PANSS: positive 13.75 3.66 13.95 6.83 12.14 3.92 0.625 0.024 PANSS: negative 14.50 4.54 15.75 6.97 12.57 4.27 0.299 0.060 PANSS: general 29.63 6.57 30.85 11.39 26.93 4.34 0.445 0.041 Word 36.57 7.66 46.37 8.66 42.14 11.91 0.082 0.127 Color 35.00 4.80 37.89 8.37 37.93 9.97 0.717 0.018 STROOP Word–color 42.57 8.72 43.16 10.76 44.71 16.07 0.915 0.005 Interference 54.00 7.09 49.47 6.55 55.79 11.17 0.111 0.112 Short-term free recall 32.98 17.01 39.62 10.82 44.63 10.18 0.112 0.109 Cognition Short-term recall with keys 28.73 16.94 37.66 13.96 44.49 10.80 0.050 0.146 Long-term free recall 28.74 18.60 39.49 12.89 46.19 10.15 0.024 0.179 TAVEC Long-term recall with keys 26.64 16.41 36.10 15.59 42.68 11.38 0.066 0.133 Semantic strategy on 42.72 9.74 45.55 8.90 46.76 9.76 0.648 0.023 short-term recall with keys Semantic strategy on 39.57 10.60 45.33 9.59 44.92 9.24 0.382 0.049 long-term recall with keys Serial strategy on short-term 46.74 3.34 47.80 4.17 48.06 7.70 0.872 0.007 recall with keys Women 2022, 2 142 Table 5. Cont. 0–5.99 Years 6–19.99 Years >20 Years p-Value Partial Eta Squared M SD M SD M SD Serial strategy on long-term 50.18 7.99 48.78 5.18 51.74 13.06 0.645 0.023 recall with keys Perseverations 50.05 9.99 49.89 9.66 45.00 8.23 0.282 0.073 Total intrusions on recall TAVEC 63.34 20.58 47.48 8.58 49.77 9.93 0.013 0.204 with keys Cognition Total intrusions on free recall 52.05 10.50 45.98 4.88 46.83 6.66 0.124 0.104 Hits on recognition 31.83 25.32 48.16 9.78 45.79 12.99 0.043 0.153 Hits 72.33 12.72 71.84 9.40 74.38 11.44 0.799 0.013 Total errors 39.67 6.02 44.00 7.40 43.23 6.33 0.499 0.039 WSCT Perseverative errors 43.33 8.82 43.58 9.13 43.62 8.58 0.998 0.000 Non-perseverative errors 36.17 6.08 44.74 6.30 42.62 6.49 0.024 0.193 Hinting task 1.81 0.24 1.62 0.28 1.73 0.33 0.276 0.065 Emotion recognition facial test 17.38 1.41 17.75 1.59 18.00 1.11 0.610 0.025 Social cognition Externalization bias 0.88 4.64 1.25 3.43 2.57 3.84 0.511 0.034 IPSAQ Personalizing bias 1.39 0.88 1.22 0.71 0.98 0.38 0.370 0.051 Self-reflectivity 16.25 6.78 14.68 4.75 12.64 6.81 0.369 0.051 Metacognition BCIS Self-certainty 8.88 4.61 7.58 3.49 7.71 3.79 0.711 0.018 When performing the multimodal regression analysis concerning the menstrual cycle length, age (p = 0.009), serial strategy on short-term recall with keys (p = 0.002), and self- certainty (p = 0.023) were included in the model. However, in the analysis of each subgroup, we only found a tendency toward a significance regarding the lowest cycle and middle cycle in the serial strategy on short-term recall with keys (B = 0.118; p = 0.088). Considering the results of the age at menarche, hallucinations measured by the PSYRATS (p = 0.013), a positive PANSS (p = 0.048), and personalized bias (p < 0.001) were included in the model. In this case, personalized bias had a tendency to differ between subgroups 1 and 2 (B = 0.074; p = 0.061). A positive PANSS (B = 1.769; p = 0.098) and personalized bias (B = 38.845; p = 0.051) had a tendency to differ between subgroups 2 and 3. Finally, regarding the difference between the age at menarche and the age of onset, the only variable included in the model was hits on recognition (p = 0.032), which was significant between subgroups 1 and 2 (B = 0.902; p = 0.046). 4. Discussion In the present study, we have suggested differences based on the length of the cycle, the time elapsed since the age at menarche and the onset of symptoms, and the age at menarche following the expected protective estrogen hypothesis, indicating that these could be relevant indicators. Our first finding was that the duration of the menstrual cycle was significantly associ- ated with the different domains of memory. We observed that the semantic strategy was the least used in women with an average cycle length whereas the serial strategy was used more often. Patients with psychosis often present deficits in semantic processing; thus, they tend to rely more on serial memory. According to our results, patients with shorter and longer cycles performed better on semantic processing, indicating a better performance on memory; other authors have suggested that this is related to less severe symptoms [58,59]. Our results were in line with the estrogen levels associated with cycle length reported by Mumford et al. [25], and were also consistent with those in previous studies that reported an association between memory and processes of encoding and recalling [60–62]. They are also in line with the estrogen synthesis of the brain, which takes place mostly in the hippocampus and temporal regions [63,64]. Another significant result was that we found that women with shorter menstrual cycles appeared to have more cognitive flexibility and a greater inhibition capacity. These results were consistent with previous studies that reported that the interaction between estrogen and the dopaminergic system modulates executive functions [22,60]. Furthermore, an association between total estradiol and cognitive function in women has been observed [65]. Women 2022, 2 143 The women with mean menstrual cycles showed less self-certainty, which was also consistent with a reported association between estrogen levels and cycle length [25]. Self- certainty is a metacognitive construct that has been associated with the emergence and maintenance of delusions [66,67] as well as neurocognitive performance [13] The age at menarche was associated with personalized bias, a cognitive bias directly implicated in the emergence and maintenance of delusions [68,69]. This suggested that women with lower estrogen levels may attribute others with the consequences of negative events. This result followed our expectations although it was the only significant variable. Similar to previous studies, we did not find a relationship between the age at menarche and the onset of illness [29]. Nonetheless, a more complex relationship between these factors has already been proposed in a previous study [70] and it is possible that there is a critical period in which estrogen exerts its effects [22,60]. Moreover, an early age at menarche has been associated with an increased risk of suffering a mental illness post- menarche [71]. An early age at menarche has also been associated with various factors during prenatal and childhood development such as body weight, trauma, or exposure to certain chemicals [71,72]. Based on the time elapsed since the age at menarche and the onset of symptoms, we also observed important differences in cognition. More precisely, short-term recall with keys and free long-term recall exhibited a larger period of time between both successes and an improved performance. This fact could indicate a better conservation of memory strategies [22,62,73,74], which may be due to the neuroprotective effects of estrogen [60]. We observed significant differences in intrusions, recognition, and non-perseverative errors; unexpectedly, the best performance was seen in the middle group. The worst performance was seen in the shortest period group, indicating that the shorter this time was, the worse the development was, thereby suggesting that a lack of estrogen implies a poorer performance [26,61]. The results obtained indicated a possible association between a few pubertal and menstrual characteristics on account of the protective influence of estrogen. However, the results of our study must be interpreted in the light of several limitations. First, we had a limited sample size, which should be larger in prospective research. Moreover, we based our groups on predefined characteristics and the distribution of the sample and conceptual knowledge. We did not have access to the blood measures of the hormonal parameters. Finally, the fact that correction analyses for multiple testing were not included should also be noted as a limitation. Notwithstanding these limitations, our results highlighted a possible relationship between menarche age, the menstrual cycle, and social cognitive, metacognitive, and neurocognitive performance in women with FEP. In the absence of re- search on the menstrual and pubertal characteristics of women with FEP, we only intended to conduct an exploratory analysis to guide future investigations on this subject. Therefore, our findings suggest a relationship between the length of the cycle, the age at menarche, and the time elapsed since the age at menarche and the onset of symptoms with cognitive and metacognitive performance in women with FEP. In the future, it may be worth monitoring menstrual cycle characteristics and hormone blood levels as they are easy indicators to compile and could be useful tools to modulate medication and offer more individualized and personalized treatment. Further studies need to be performed with bigger sample sizes, continuous menstrual monitoring, and blood test analytics to corroborate this relationship. Author Contributions: Conceptualization, P.B.-S., S.O. and I.B.; methodology, P.B.-S., S.O. and I.B.; validation, S.O. and I.B.; formal analysis, P.B.-S. and S.O.; investigation, P.B.-S.; resources, I.B., M.V.-R., R.L.-C., H.G.-M., M.F.-Q., L.D.-C., E.G., E.P., E.L., T.P., M.L.B., I.R.-D., F.G.-H., J.C., A.G.-Z., D.C. and the Spanish Metacognition Group; data curation, R.L.-C.; writing—original draft preparation, P.B.-S.; writing—review and editing, P.B.-S., I.B., S.O., H.G.-M., M.F.-Q., L.D.-C., J.U. and R.V.-B.; visualization, P.B.-S.; supervision, S.O. and I.B.; project administration, A.B. and S.O.; funding acquisition, S.O. All authors have read and agreed to the published version of the manuscript. Women 2022, 2 144 Funding: This research was funded by the Instituto de Salud Carlos III, Spanish Government (grant no. PI11/01347, PI14/00044, and PI18/00212); the Fondo Europeo de Desarrollo Regional (FEDER); the Health Department of Catalonia; PERIS call (grant no. SLT006/17/00231); the Progress and Health Foundation of the Andalusian Regional Ministry of Health (grant no. PI-0634/2011 and PI-0193/2014); Obra Social La Caixa (RecerCaixa call 2013); CERCA Programme/Generalitat de Catalunya; Obra Social Sant Joan de Déu (BML); and FI19/00062 (Ayudas para la Contratación de Personal Predoctoral). L.D.-C was the beneficiary of a Predoctoral Training Grant in Health Research for this project. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Research and Ethics Committees of Sant Joan de Déu (protocol code: PIC-73-11; date of approval: 22 November 2011). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: Data are not available upon request due to restrictions (e.g., privacy or ethical). The data presented in this study are available upon request from the corresponding author. 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