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Age at menarche predicts age at onset of major affective and anxiety disorders
European Psychiatry 39 (2017) 80–85
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Original article
Age at menarche predicts age at onset of major affective and anxiety disorders L. Tondo a,c,*, M. Pinna c, G. Serra a,d,e, L. De Chiara d, R.J. Baldessarini a,b a
International Consortium for Psychotic & Mood Disorders Research, Mailman Research Center, McLean Hospital, Belmont, MA, USA Department of Psychiatry, Harvard Medical School, Boston, MA, USA c Lucio Bini Mood Disorder Centers, Cagliari and Rome, Italy d NESMOS Department of Psychiatry, Faculty of Medicine, University (Sapienza) of Rome, Rome, Italy e Child Neuropsychiatry Unit, Department of Neuroscience, IRCCS Children Hospital Bambino Gesu`, Rome, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2016 Received in revised form 31 July 2016 Accepted 1st August 2016 Available online
Background: Menarche age has been associated inconsistently with the occurrence, timing or severity of major depressive disorder (MDD), but rarely studied in women with bipolar (BDs) or anxiety disorders. Methods: We investigated women patients at a Sardinian mood disorder center for associations of age at menarche with age at illness onset for major affective or anxiety disorders, year of birth, and other selected factors, using bivariate comparisons and multivariate regression modeling. Results: Among women (n = 1139) with DSM-IV MDD (n = 557), BD-I (n = 223), BD-II (n = 178), or anxiety disorders (n = 181), born in 1904–1998, of mean age 42.9 years, menarche age averaged 12.8 [CI: 12.7– 12.9] years. Illness onset age averaged 30.9 [30.1–31.8] years, ranking: BD-I, 25.8; anxiety disorders, 28.0; BD-II, 30.3; MDD, 34.1 years. Menarche age declined secularly over birth years, and was associated with younger illness-onset, having no or fewer siblings, more psychiatrically ill first-degree relatives, living in rural environments, being suicidal, substance abuse, and being unemployed. Earlier menarche and earlier illness-onset were significantly associated for onset age groups of 20, 20–39, and > 40 years. Menarche age versus diagnosis ranked: BD-II < BD-I < anxiety disorders < MDD. Conclusions: Age at menarche in Sardinia, as elsewhere, has declined over the past decades. It was strongly associated with age at onset of bipolar and anxiety, as well as major depressive disorders across the age range, suggesting sustained effects of biological maturational factors. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Anxiety Bipolar disorders Major depression Menarche Onset age
1. Introduction In many countries, average age at menarche falls within a limited range (11–14 years), but with some differences between regions and ethnic groups. International average age at menarche in general populations samples is 12.8 [CI: 12.5–13.0] years [1–15]. Studies from several countries have found a consistent secular decline in age at menarche throughout the past century [1,5,6,10,12–14,16–21], including a study reporting data from the end of the 18th century to 1981 [22]. Relatively early age at menarche has been associated with several psychopathological conditions. These include overall worse mental health indicated by multiple morbidity indices [23], as well as anxiety disorders [24–28], abuse of alcohol or other substances [25,29–31], conduct or oppositional-defiant disorder * Corresponding author. Mailman Research Center 3, McLean Hospital, 115, Mill Street, Belmont, MA 24768-9106, USA. Tel.: +1 617 855 3201. E-mail address: [email protected] (L. Tondo). http://dx.doi.org/10.1016/j.eurpsy.2016.08.001 0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.
[24], disruptive or violent behavior [32], eating disorders [30,33] and attention-deficit hyperactivity disorder (ADHD) [34], as well as cyclothymic or depressive temperaments in women diagnosed with bipolar disorder (BD) [35]. In contrast, later menarche has been associated with later onset of schizophrenia [36] and its more favorable clinical outcome [37]. Findings concerning an association between age at menarche and depression are inconsistent. Some studies found a significant association of early menarche and early onset of major depressive disorder (MDD) [30,37–42]; another did not [43]. In addition, greater risk of depression [35,44], and more severe depression sometimes were associated with earlier menarche [44–46], but not in certain ethnic subgroups, including African-American and Hispanic women in the US [47]. Moreover, menarche itself has been proposed as a possible triggering factor for depressive disorders [48,49]. Studies addressing associations of menarche age with BD have been rare. Among 50 women, BD began before menarche in 32% and in another 18% (total, 50%) within a year after menarche [50],
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whereas recurrent, endogenous MDD began before or at menarche in only 3% of 70 women [51]. Early menarche was more prevalent among women diagnosed with BD or MDD than among healthy women: menarche at or before age 11 was found in 25.7% of women with mood disorders (27.8% with BD, 23.3% with MDD) versus only 13.9% of healthy controls (x2 = 25.9; P < 0.0001) [51]. Seemingly inconsistently, however, earlier menarche was found in patients with onset of BD after age 16 more than with earlier illness onset [52]. This background indicates a striking paucity of studies of menarche age in relation to age at onset of specific mood disorders, particularly BD. Accordingly, we studied the relationship of age at menarche to age at illness onset among women diagnosed with DSM-IV BD-I or BD-II or MDD, compared to anxiety disorders, and considered covariates, and considered an expected secular trend in age of menarche. We hypothesized that earlier menarche would be associated with earlier illness onset, would decline over birth years, and might be associated with indicators of less successful adaptation.
Data are presented as means standard deviation (SD) or with (CI), or as medians with inter-quartile range (IQR); regression models are presented with slope functions (b) with their CI. Analyses employed commercial software: Statview.5 (SAS Institute, Cary, NC; for spreadsheets) and Stata.12 (StataCorp, College Station, TX) for analyses.
2. Methods
Age (years) at intake to the study site was lower in patients with anxiety disorders than those with mood disorders, but similar across mood disorders: anxiety disorders (40.1 [37.8–42.3]), BD-I (46.1 [44.1–48.2]), MDD (48.0 [46.5–49.5]), and BD-II (50.8 [48.6– 53.0]). Age at menarche in this sample of Sardinian women averaged 12.8 [CI: 14.7–12.9] (median: 13.0 [IQR: 12.0–14.0]; range: 7–20) years, overall, and was similar to the overall average for Italy, of 12.4 years [3,4]. Age at menarche was similar among the four diagnoses, ranking:
The study sample included all women diagnosed clinically with a major affective (BD-I, BD-II, or MDD) or anxiety disorder, with diagnoses updated to meet DSM-IV-TR criteria, evaluated and followed at the Lucio Bini Mood Disorders Center in Cagliari, Sardinia. We analyzed information from systematic clinical assessments of consecutive patients between 1976 and September 2015. All subjects underwent diagnostic and follow-up evaluations by the same mood-disorders expert (LT), based on semi-structured interviews at intake as well as during prospective, clinical follow-up. Diagnoses were updated to meet DSM-IVTR criteria after the year 2000. Written informed consent was obtained for collection and analysis of patient data to be presented anonymously in aggregate form, in accordance with the requirements of Italian law and following review by a local ethical committee. Data management complied with US federal Health Insurance Portability and Accountability Act (HIPAA) regulations pertaining to confidentiality of patient records. Required data were entered into a computerized database (by LD, MP, GS, and LT) in coded form to protect subject identity; all authors participated in literature searching, data analysis and reporting. Age at menarche (within six months) and estimated age at onset of illness were recorded routinely; included subjects had defined ages both at menarche and illness-onset. Analyses of the relationships of these measures and other factors of interest used standard bivariate comparisons of age at menarche with categorical (linear regression [slope or b]) and continuous measures (by ANOVA methods [F]), both tested with t-scores. Factors significantly associated with menarche age in bivariate analyses were subjected to multivariable linear regression modeling (to generate slope (b) functions and their 95% confidence intervals [CI]). For regression analyses of age at menarche versus birth year, we compared findings with data limited to subjects who had reached menarche by age 20 (the observed maximum age in the entire sample), so as to avoid biasing toward earlier menarche among younger women. In addition, for analyses of illness onset age versus age at menarche, we compared results with all subjects included to results limited to subjects with onset age 40 years and born before 1976. We also analyzed the age at menarche for three different age classes (< 20, 20–39, and 40 years) for illnessonset to compare possible differences in younger versus older women. We also applied Bayesian analysis (sensitivity, specificity, and positive predictive value) for the correlation of age at menarche and age at illness onset.
3. Results 3.1. Characteristics of study subjects The study involved 1139 women subjects born between 1904 and 1998, of mean age at intake at the study site of 42.9 [CI: 41.9–43.8] years. DSM-IV psychiatric diagnoses were:
unipolar MDD (n = 557; 48.9%); BD-I (n = 223; 19.6%); anxiety disorders (n = 181; 15.9%; BD-II (n = 178; 15.6% of subjects).
BD-I (12.7 [CI: 12.5–12.9]); anxiety disorders (12.8 [12.5–13.0]); BD-II (12.8 [12.6–13.1] years); MDD (12.8 [12.7–13.0]).
Age at onset for the four disorders overall averaged 30.9 [CI: 30.0–31.8] years, and ranked by diagnosis as: BD-I (25.8 [24.2– 27.4] years), anxiety disorders (28.0 [26.0–30.0]), BD-II (30.3 [28.4–32.2]), MDD (34.1 [32.7–35.5] years). 3.2. Association of age at menarche with year of birth We confirmed and extended an internationally reported secular decline of age at menarche over the years of birth (1904–1995; Table 1A). In particular, menarche age averaged 13.7 [CI: 13.1– 14.4] years in women born in 1904–1925, and 12.2 [11.8–12.6] years for those born in 1985–1995 (selected to account for the highest age at menarche of 20 years encountered in the entire sample); this 1.51-year decline in menarche age over 69 years (2.19%/year, or 2.59 months per decade) is highly significant (t = 4.48, P < 0.0001). 3.3. Association of age at menarche with age at illness onset There was a notable, highly significant, overall correlation of younger age at menarche with earlier onset of major mood or anxiety disorders (slope, b = 1.64 [CI: 1.09–2.15]; t = 5.89, P < 0.0001; Table 1A; Fig. 1). Owing to concern for potentially biased sampling of onset ages among patients sampled either at young ages or with late onsets, we repeated this analysis including only women who experienced illness onset before age 40 and were at least 40 years old when evaluated (born before 1976). Again, there was a highly significant correlation of earlier onset age with earlier menarche (slope [b] = 0.694 [CI: 0.320–1.07]; t = 3.64, P < 0.0001).
L. Tondo et al. / European Psychiatry 39 (2017) 80–85
82 Table 1 Factors associated with earlier age at menarche. Factor
A. Slope function (bivariate linear regression) [95% CI] More recent birth year (1904–1995)a Fewer siblings Younger at illness-onset Greater family history rate (%)b B. Mean age at menarche [95%CI] Only child Yes No Ever suicidalc Present Absent Location Urban Rural Employment Unemployed Employed Substance abuse Present Absent C. Slope function (multivariate linear regression) [95% CI]d More recent birth year Younger at illness-onset a b c d
Measures
t-score
P-value
0.020 [–0.025 to–0.014] 0.13 [0.09 to 0.18] 1.64 [1.09 to 2.18] –0.54 [ 1.01 to 0.07]
7.27 5.78 5.89 2.27
< 0.0001 < 0.0001 < 0.0001 0.02
2.54
0.01
2.47
0.01
12.1 [11.8–12.4] 12.7 [12.5–12.8] 12.7 [12.5–12.8] 12.9 [12.8–13.0] 2.39
0.02
12.6 [12.5–12.8] 12.9 [12.7–13.0] 12.4 [12.1–12.7]
2.19
0.03
12.8 [12.7–12.9] 12.5 [12.2–12.8]
1.99
0.05
3.85 3.41
< 0.0001 0.001
12.8 [12.7–12.9] 0.014 [ 0.021 to 0.007] 0.023 [0.010 to 0.037]
Limited to birth years < 1996, to allow for all ages at menarche (all 20 years). Percentage of first-degree relatives with any psychiatric diagnosis. Lifetime suicidal act or ideation. Limited to year 1996 and onset age < 41 years.
The latency from menarche to onset of illness averaged 18.1 [CI: 17.3–19.0] years. Only 4.13% of all cases began before menarche. Latency (years) from menarche to illness-onset ranked by diagnosis as: BD-I (13.2 [CI: 11.6–14.7]) < anxiety disorders (15.2 [13.3–17.2]) < BD-II (17.5 [15.6–19.3]) < MDD (21.3 [19.9– 22.6]). As expected from differences in onset ages, these latencies differ by diagnosis highly significantly (t = 4.47, P = 00001). The association of early illness-onset with younger age at menarche among all subjects was found across the range of onset ages, in the following order by statistical significance: ages 20–39 > 40 or older = less than 20 years (Table 2). This finding, remarkably, appears to indicate that early age at menarche may
predict age at illness onset at mid-adult and older ages as well as in adolescence or young adult years. Among specific diagnoses, we found a significant association of younger age at menarche with earlier illness onset of all illnesses except BD-II, with strength of association ranking as: MDD > anxiety disorder > BD-I, but not with BD-II (Table 3). We also found that the prevalence of illness-onset within two years of the age at menarche (peri-menarche) ranked as follows: BD-I > BD-II > MDD > anxiety disorders (Table 3). 3.4. Bayesian characteristics To evaluate the potential clinical value of menarche age as a predictor of age at illness onset, we considered Bayesian characteristics (sensitivity [early menarche among all cases of early illness-onset], specificity [late menarche with late illnessonset], and positive predictive value [early illness-onset among all cases of early menarche]), based on contrasting outcomes with menarche before versus after age 13 years. For all such subjects (n = 877) an illness onset of 25 versus >25 years of age, sensitivity was 68.9% (270/392), specificity only 47.8% (232/ 485 = 47.8%), and positive predictive value was 51.6% (270/523), with high statistical significance (x2 = 25.2, P < 0.0001). If illnessonset age was contrasted for < 20 versus 40 years, predictive performance improved somewhat: sensitivity 70.0% (171/243), specificity 51.5% (51.5%), and positive predictive value 63.1% (171/ 271), again with strong statistical significance (x2 = 22.2, P < 0.0001). Prediction was strongest for MDD (e.g., sensitivity = 71/99 = 71.7%; x2 = 10.7, P = 0.001), somewhat less for BD Table 2 Association of age at illness-onset versus age at menarche for onset age groups.
Fig. 1. Relationship of age at onset ( 95% CI) of major mood or anxiety disorders to age at menarche for 1139 women (by linear regression, slope [b] = 1.64 [CI: 1.09– 2.18]; t = 5.89, P < 0.0001).
Onset age (years)
Subjects (n)
Slope [95% CI]a
t-score
P-value
< 20 20–39 40
311 557 271
0.251 [0.021–0.481] 0.491 [0.196–0.787] 0.798 [0.079–1.52]
2.15 3.26 2.19
0.03 0.001 0.03
a
Based on bivariate linear regression for all 1139 subject.
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Table 3 Association of age at onset of affective illness versus age at menarche. Diagnosis
Peri-menarche onset (%)a
Subjects (n)
Slope [b] [95% CI]
t-score
P-value
Major depressive disorder Anxiety disorder Bipolar I disorder Bipolar II disorder Any disorder
3.41 1.66 8.52 4.49 4.30
557 181 223 178 1139
1.82 2.02 1.11 0.90 1.64
4.19 3.10 2.28 1.48 5.89
< 0.0001 0.002 0.02 0.14 < 0.0001
a
[0.97–2.67] [0.73–3.31] [0.15–2.07] [ 0.30 to 2.10] [1.09–2.18]
Within 1 year of menarche; x2 = 12.5, P = 0.003. Data are ranked by significance of the association of onset age with menarche age.
(sensitivity = 66/97 = 68.0%; x2 = 6.08, P = 0.005), and nonsignificant for anxiety disorders (sensitivity = 34/47 = 51.1%; x2 = 1.21, P = 0.27). 3.5. Factors associated with age at menarche In addition to the strong associations of age at menarche with year of birth and age at illness onset, we found seven other factors to be significantly associated with an earlier age at menarche, based on bivariate analyses (Table 1B). In order of their statistical significance, they included: [a] having fewer siblings (excluding singletons), or [b] being an only child, [c] having suicidal ideation or acts at any time, [d] living in a rural area, [e] having more firstdegree family members with a psychiatric illness, [f] not being employed, and [g] presence of substance abuse. When these factors were analyzed by multivariate linear regression modeling, two remained independently and statistically significantly associated with being younger at menarche: [a] more recent birth year, and [b] being younger at onset of major affective or anxiety disorders (Table 1C). Factors not significantly associated with age at menarche included: socioeconomic status, temperament type, body-mass index (BMI) at intake, birth order, month or season of birth, marital status, age at marriage, number of children, age at menopause, attention-hyperactivity disorder, type of first illness episode, and overall morbidity as episodes or proportion of months since onset in depression, mania, or any illness per year. 4. Discussion The observed age at menarche in this large clinical sample (mean, 12.8 years) is identical to that in general-population samples from 13 countries (12.8 years), and very similar to that for Italy (12.4 years), as reviewed above (Introduction). This similarity accords with the expectation that the timing of menarche is a highly biologically determined developmental landmark in both clinical and general-population samples. We confirmed that age at menarche declined highly significantly in the Sardinian study sample since the early 1900s, by approximately 2.2%/year (Table 1A). This study appears to be the first to find a strong, highly significant correlation between younger ages at menarche and at the onset of various mood or anxiety disorders even when menarche preceded illness onset by many years. The significant correlations also held when women were divided in age classes (< 20, 20–39, and 40 years) for illness onset. This association appears to accord with findings reviewed above (Introduction) that an early menarche was associated with earlier or greater psychopathology of various types. However, associations with depression have been somewhat inconsistent and studies involving bipolar or anxiety disorders have been rare. We also confirmed previous reports of increased risk of mood disorders emerging close to the age at menarche [50,53,54]. Such perimenarchal risk within two years of a first mensis was especially high in BD-I subjects, in whom it was 2.50-times (8.52%/3.41%) more likely than
with MDD (Table 3). We also confirmed reports that menarche occurred earlier among women with fewer ( 2) or no siblings [55]. In addition, risks for suicidal ideation or behavior, substance abuse, and unemployment all were associated with earlier menarche. Such tendencies suggest relatively unfavorable functional or adaptational status, which also may be associated with earlier or more severe affective illnesses. A new finding was of younger menarche among women with more dense family histories of psychiatric illnesses (% of first-degree relatives affected; Table 1A). This association, and the strong association of early menarche with early onset of mood or anxiety disorders – further indication of earlier menarche – is associated with a greater or earlier risk of psychopathology, and suggests operation of familial or genetic factors. Moreover, the presence of a higher rate of unemployment in women with early age at menarche is probably explained as the more likely presence of psychopathological difficulties in association with early onset of menstruation. It is unlikley that age at menarche itself would be influenced by occupational level which usually occurs at later ages. However, we did not find correlations with some other factors previously reported to be associated with younger menarche age, including season of birth (menarche age reportedly lowest in summer) [54], being earlier in birth-order among siblings [56,57], having greater body weight or BMI [58,59], presence of attentionhyperactivity disorder [34,60], and cyclothymic or depressive temperament type [35]. Moreover, in the present subjects, age at menarche was not associated with other social or reproductive factors, including marital status, age at marriage, or number of children. Age at menopause also has been related inconsistently with age at menarche [44,60,61], as has socioeconomic status [59,62,63], but we found no relationship of either factor with menarche age. In addition, we found no significant association of menarche age with several clinical factors including type of firstlifetime illness episode (specifically, manic versus depressive), and annual episode counts or proportion of time in depression, mania, or any psychiatric illness. It is important to emphasize that as a predictor of age of onset of mood disorders, menarche age was highly statistically significant, but probably of limited clinical value, based on Bayesian characteristics. Such limitations probably reflect the relatively narrowly determined age at menarche, even in the present clinical sample. Mechanisms involved in the relationship of ages at menarche and at the onset of mood disorders are not clear. Before puberty, the prevalence of depression is reportedly similar in boys and girls, but after that age, a sharp increase of depression in girls has been noted [64,65]. Depressive episodes in females are likely to be influenced by gonadal steroids — so-called ‘reproductive depressions’ [66] — which increase after menarche [67]. Too, early menarche has been associated with higher circulating concentrations of estrogen around the onset of puberty as well as in early adulthood [68]. A plausible relationship between depressive symptoms and circulating concentrations of estrogens is supported by findings that major cerebral neurotransmitter systems are
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responsive to gonadal hormones, including ability to modulate gene transcription and the synthesis of various enzymes and receptor proteins involved in neurotransmission [69]. In particular, fluctuations in estrogens may contribute to mood oscillations and neurotransmission mediated by serotonin, including by decreasing expression of serotonin receptors [69,70]. In addition, hormonal changes occurring around menarche may tend to dysregulate mood through the hypothalamic–pituitary–adrenal axis, at a time of heightened vulnerability to external stressors [65]. How early menarche might influence the onset of mood disorders later in adult life (Table 2) is less clear. 5. Limitations Recollection of age at menarche is likely to vary and to be less reliable in older women. However, variance in such recollection should be similarly distributed across the investigated diagnostic groups, whose current ages were similar. 6. Conclusions Age at menarche among affectively ill women in Sardinia, as elsewhere, has declined over the past century and was strongly associated with age at onset of major affective and anxiety disorders across the age range. Younger menarche also was associated with factors suggestive of less-adaptive functioning, including suicidal behavior, substance abuse, and unemployment. Though early menarche was very strongly associated with earlier illness-onset, especially of mood disorders, the association had limited power as a potential clinical predictive measure, though with best Bayesian performance in MDD and BD-I. Nevertheless, the strong association of earlier menarche with earlier illnessonset throughout life suggests that biological mechanisms, including those related to reproductive endocrinology, may play a role in determining the timing of onset of mood and anxiety disorders. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments Supported in part by a research award from the Aretaeus Foundation of Rome (to LT), a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychiatric Research Fund (to RJB). References [1] Hosokawa M, Imazeki S, Mizunuma H, Kubota T, Hayashi K. Secular trends in age at menarche and time to establish regular menstrual cycling in Japanese women born between 1930 and 1985. BMC Womens Health 2012;12:19. [2] Silva CML da, Gigante DP, Minten GC. Premenstrual symptoms and syndrome according to age at menarche in a 1982 birth cohort in southern Brazil. Cad Saude Publica 2008;24:835–44. [3] De Sanctis V, Bernasconi S, Bianchin L, Bona G, Bozzola M, Buzi F, et al. Onset of menstrual cycle and menses features among secondary school girls in Italy: a questionnaire study on 3,783 students. Indian J Endocrinol Metab 2014; 18(Suppl. 1):S84–92. [4] Rigon F, De Sanctis V, Bernasconi S, Bianchin L, Bona G, Bozzola M, et al. Menstrual pattern and menstrual disorders among adolescents: an update of the Italian data. Ital J Pediatr 2012;38:38. [5] Lalys L, Pineau J-C. Age at menarche in a group of French schoolgirls. Pediatr Int 2014;56:601–4. [6] Anderson SE, Dallal GE, Must A. Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart. Pediatrics 2003;111:844–50. [7] Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. J Pediatr Endocrinol Metab 2014;27:47–51.
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Original article
Age at menarche predicts age at onset of major affective and anxiety disorders L. Tondo a,c,*, M. Pinna c, G. Serra a,d,e, L. De Chiara d, R.J. Baldessarini a,b a
International Consortium for Psychotic & Mood Disorders Research, Mailman Research Center, McLean Hospital, Belmont, MA, USA Department of Psychiatry, Harvard Medical School, Boston, MA, USA c Lucio Bini Mood Disorder Centers, Cagliari and Rome, Italy d NESMOS Department of Psychiatry, Faculty of Medicine, University (Sapienza) of Rome, Rome, Italy e Child Neuropsychiatry Unit, Department of Neuroscience, IRCCS Children Hospital Bambino Gesu`, Rome, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2016 Received in revised form 31 July 2016 Accepted 1st August 2016 Available online
Background: Menarche age has been associated inconsistently with the occurrence, timing or severity of major depressive disorder (MDD), but rarely studied in women with bipolar (BDs) or anxiety disorders. Methods: We investigated women patients at a Sardinian mood disorder center for associations of age at menarche with age at illness onset for major affective or anxiety disorders, year of birth, and other selected factors, using bivariate comparisons and multivariate regression modeling. Results: Among women (n = 1139) with DSM-IV MDD (n = 557), BD-I (n = 223), BD-II (n = 178), or anxiety disorders (n = 181), born in 1904–1998, of mean age 42.9 years, menarche age averaged 12.8 [CI: 12.7– 12.9] years. Illness onset age averaged 30.9 [30.1–31.8] years, ranking: BD-I, 25.8; anxiety disorders, 28.0; BD-II, 30.3; MDD, 34.1 years. Menarche age declined secularly over birth years, and was associated with younger illness-onset, having no or fewer siblings, more psychiatrically ill first-degree relatives, living in rural environments, being suicidal, substance abuse, and being unemployed. Earlier menarche and earlier illness-onset were significantly associated for onset age groups of 20, 20–39, and > 40 years. Menarche age versus diagnosis ranked: BD-II < BD-I < anxiety disorders < MDD. Conclusions: Age at menarche in Sardinia, as elsewhere, has declined over the past decades. It was strongly associated with age at onset of bipolar and anxiety, as well as major depressive disorders across the age range, suggesting sustained effects of biological maturational factors. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Anxiety Bipolar disorders Major depression Menarche Onset age
1. Introduction In many countries, average age at menarche falls within a limited range (11–14 years), but with some differences between regions and ethnic groups. International average age at menarche in general populations samples is 12.8 [CI: 12.5–13.0] years [1–15]. Studies from several countries have found a consistent secular decline in age at menarche throughout the past century [1,5,6,10,12–14,16–21], including a study reporting data from the end of the 18th century to 1981 [22]. Relatively early age at menarche has been associated with several psychopathological conditions. These include overall worse mental health indicated by multiple morbidity indices [23], as well as anxiety disorders [24–28], abuse of alcohol or other substances [25,29–31], conduct or oppositional-defiant disorder * Corresponding author. Mailman Research Center 3, McLean Hospital, 115, Mill Street, Belmont, MA 24768-9106, USA. Tel.: +1 617 855 3201. E-mail address: [email protected] (L. Tondo). http://dx.doi.org/10.1016/j.eurpsy.2016.08.001 0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.
[24], disruptive or violent behavior [32], eating disorders [30,33] and attention-deficit hyperactivity disorder (ADHD) [34], as well as cyclothymic or depressive temperaments in women diagnosed with bipolar disorder (BD) [35]. In contrast, later menarche has been associated with later onset of schizophrenia [36] and its more favorable clinical outcome [37]. Findings concerning an association between age at menarche and depression are inconsistent. Some studies found a significant association of early menarche and early onset of major depressive disorder (MDD) [30,37–42]; another did not [43]. In addition, greater risk of depression [35,44], and more severe depression sometimes were associated with earlier menarche [44–46], but not in certain ethnic subgroups, including African-American and Hispanic women in the US [47]. Moreover, menarche itself has been proposed as a possible triggering factor for depressive disorders [48,49]. Studies addressing associations of menarche age with BD have been rare. Among 50 women, BD began before menarche in 32% and in another 18% (total, 50%) within a year after menarche [50],
L. Tondo et al. / European Psychiatry 39 (2017) 80–85
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whereas recurrent, endogenous MDD began before or at menarche in only 3% of 70 women [51]. Early menarche was more prevalent among women diagnosed with BD or MDD than among healthy women: menarche at or before age 11 was found in 25.7% of women with mood disorders (27.8% with BD, 23.3% with MDD) versus only 13.9% of healthy controls (x2 = 25.9; P < 0.0001) [51]. Seemingly inconsistently, however, earlier menarche was found in patients with onset of BD after age 16 more than with earlier illness onset [52]. This background indicates a striking paucity of studies of menarche age in relation to age at onset of specific mood disorders, particularly BD. Accordingly, we studied the relationship of age at menarche to age at illness onset among women diagnosed with DSM-IV BD-I or BD-II or MDD, compared to anxiety disorders, and considered covariates, and considered an expected secular trend in age of menarche. We hypothesized that earlier menarche would be associated with earlier illness onset, would decline over birth years, and might be associated with indicators of less successful adaptation.
Data are presented as means standard deviation (SD) or with (CI), or as medians with inter-quartile range (IQR); regression models are presented with slope functions (b) with their CI. Analyses employed commercial software: Statview.5 (SAS Institute, Cary, NC; for spreadsheets) and Stata.12 (StataCorp, College Station, TX) for analyses.
2. Methods
Age (years) at intake to the study site was lower in patients with anxiety disorders than those with mood disorders, but similar across mood disorders: anxiety disorders (40.1 [37.8–42.3]), BD-I (46.1 [44.1–48.2]), MDD (48.0 [46.5–49.5]), and BD-II (50.8 [48.6– 53.0]). Age at menarche in this sample of Sardinian women averaged 12.8 [CI: 14.7–12.9] (median: 13.0 [IQR: 12.0–14.0]; range: 7–20) years, overall, and was similar to the overall average for Italy, of 12.4 years [3,4]. Age at menarche was similar among the four diagnoses, ranking:
The study sample included all women diagnosed clinically with a major affective (BD-I, BD-II, or MDD) or anxiety disorder, with diagnoses updated to meet DSM-IV-TR criteria, evaluated and followed at the Lucio Bini Mood Disorders Center in Cagliari, Sardinia. We analyzed information from systematic clinical assessments of consecutive patients between 1976 and September 2015. All subjects underwent diagnostic and follow-up evaluations by the same mood-disorders expert (LT), based on semi-structured interviews at intake as well as during prospective, clinical follow-up. Diagnoses were updated to meet DSM-IVTR criteria after the year 2000. Written informed consent was obtained for collection and analysis of patient data to be presented anonymously in aggregate form, in accordance with the requirements of Italian law and following review by a local ethical committee. Data management complied with US federal Health Insurance Portability and Accountability Act (HIPAA) regulations pertaining to confidentiality of patient records. Required data were entered into a computerized database (by LD, MP, GS, and LT) in coded form to protect subject identity; all authors participated in literature searching, data analysis and reporting. Age at menarche (within six months) and estimated age at onset of illness were recorded routinely; included subjects had defined ages both at menarche and illness-onset. Analyses of the relationships of these measures and other factors of interest used standard bivariate comparisons of age at menarche with categorical (linear regression [slope or b]) and continuous measures (by ANOVA methods [F]), both tested with t-scores. Factors significantly associated with menarche age in bivariate analyses were subjected to multivariable linear regression modeling (to generate slope (b) functions and their 95% confidence intervals [CI]). For regression analyses of age at menarche versus birth year, we compared findings with data limited to subjects who had reached menarche by age 20 (the observed maximum age in the entire sample), so as to avoid biasing toward earlier menarche among younger women. In addition, for analyses of illness onset age versus age at menarche, we compared results with all subjects included to results limited to subjects with onset age 40 years and born before 1976. We also analyzed the age at menarche for three different age classes (< 20, 20–39, and 40 years) for illnessonset to compare possible differences in younger versus older women. We also applied Bayesian analysis (sensitivity, specificity, and positive predictive value) for the correlation of age at menarche and age at illness onset.
3. Results 3.1. Characteristics of study subjects The study involved 1139 women subjects born between 1904 and 1998, of mean age at intake at the study site of 42.9 [CI: 41.9–43.8] years. DSM-IV psychiatric diagnoses were:
unipolar MDD (n = 557; 48.9%); BD-I (n = 223; 19.6%); anxiety disorders (n = 181; 15.9%; BD-II (n = 178; 15.6% of subjects).
BD-I (12.7 [CI: 12.5–12.9]); anxiety disorders (12.8 [12.5–13.0]); BD-II (12.8 [12.6–13.1] years); MDD (12.8 [12.7–13.0]).
Age at onset for the four disorders overall averaged 30.9 [CI: 30.0–31.8] years, and ranked by diagnosis as: BD-I (25.8 [24.2– 27.4] years), anxiety disorders (28.0 [26.0–30.0]), BD-II (30.3 [28.4–32.2]), MDD (34.1 [32.7–35.5] years). 3.2. Association of age at menarche with year of birth We confirmed and extended an internationally reported secular decline of age at menarche over the years of birth (1904–1995; Table 1A). In particular, menarche age averaged 13.7 [CI: 13.1– 14.4] years in women born in 1904–1925, and 12.2 [11.8–12.6] years for those born in 1985–1995 (selected to account for the highest age at menarche of 20 years encountered in the entire sample); this 1.51-year decline in menarche age over 69 years (2.19%/year, or 2.59 months per decade) is highly significant (t = 4.48, P < 0.0001). 3.3. Association of age at menarche with age at illness onset There was a notable, highly significant, overall correlation of younger age at menarche with earlier onset of major mood or anxiety disorders (slope, b = 1.64 [CI: 1.09–2.15]; t = 5.89, P < 0.0001; Table 1A; Fig. 1). Owing to concern for potentially biased sampling of onset ages among patients sampled either at young ages or with late onsets, we repeated this analysis including only women who experienced illness onset before age 40 and were at least 40 years old when evaluated (born before 1976). Again, there was a highly significant correlation of earlier onset age with earlier menarche (slope [b] = 0.694 [CI: 0.320–1.07]; t = 3.64, P < 0.0001).
L. Tondo et al. / European Psychiatry 39 (2017) 80–85
82 Table 1 Factors associated with earlier age at menarche. Factor
A. Slope function (bivariate linear regression) [95% CI] More recent birth year (1904–1995)a Fewer siblings Younger at illness-onset Greater family history rate (%)b B. Mean age at menarche [95%CI] Only child Yes No Ever suicidalc Present Absent Location Urban Rural Employment Unemployed Employed Substance abuse Present Absent C. Slope function (multivariate linear regression) [95% CI]d More recent birth year Younger at illness-onset a b c d
Measures
t-score
P-value
0.020 [–0.025 to–0.014] 0.13 [0.09 to 0.18] 1.64 [1.09 to 2.18] –0.54 [ 1.01 to 0.07]
7.27 5.78 5.89 2.27
< 0.0001 < 0.0001 < 0.0001 0.02
2.54
0.01
2.47
0.01
12.1 [11.8–12.4] 12.7 [12.5–12.8] 12.7 [12.5–12.8] 12.9 [12.8–13.0] 2.39
0.02
12.6 [12.5–12.8] 12.9 [12.7–13.0] 12.4 [12.1–12.7]
2.19
0.03
12.8 [12.7–12.9] 12.5 [12.2–12.8]
1.99
0.05
3.85 3.41
< 0.0001 0.001
12.8 [12.7–12.9] 0.014 [ 0.021 to 0.007] 0.023 [0.010 to 0.037]
Limited to birth years < 1996, to allow for all ages at menarche (all 20 years). Percentage of first-degree relatives with any psychiatric diagnosis. Lifetime suicidal act or ideation. Limited to year 1996 and onset age < 41 years.
The latency from menarche to onset of illness averaged 18.1 [CI: 17.3–19.0] years. Only 4.13% of all cases began before menarche. Latency (years) from menarche to illness-onset ranked by diagnosis as: BD-I (13.2 [CI: 11.6–14.7]) < anxiety disorders (15.2 [13.3–17.2]) < BD-II (17.5 [15.6–19.3]) < MDD (21.3 [19.9– 22.6]). As expected from differences in onset ages, these latencies differ by diagnosis highly significantly (t = 4.47, P = 00001). The association of early illness-onset with younger age at menarche among all subjects was found across the range of onset ages, in the following order by statistical significance: ages 20–39 > 40 or older = less than 20 years (Table 2). This finding, remarkably, appears to indicate that early age at menarche may
predict age at illness onset at mid-adult and older ages as well as in adolescence or young adult years. Among specific diagnoses, we found a significant association of younger age at menarche with earlier illness onset of all illnesses except BD-II, with strength of association ranking as: MDD > anxiety disorder > BD-I, but not with BD-II (Table 3). We also found that the prevalence of illness-onset within two years of the age at menarche (peri-menarche) ranked as follows: BD-I > BD-II > MDD > anxiety disorders (Table 3). 3.4. Bayesian characteristics To evaluate the potential clinical value of menarche age as a predictor of age at illness onset, we considered Bayesian characteristics (sensitivity [early menarche among all cases of early illness-onset], specificity [late menarche with late illnessonset], and positive predictive value [early illness-onset among all cases of early menarche]), based on contrasting outcomes with menarche before versus after age 13 years. For all such subjects (n = 877) an illness onset of 25 versus >25 years of age, sensitivity was 68.9% (270/392), specificity only 47.8% (232/ 485 = 47.8%), and positive predictive value was 51.6% (270/523), with high statistical significance (x2 = 25.2, P < 0.0001). If illnessonset age was contrasted for < 20 versus 40 years, predictive performance improved somewhat: sensitivity 70.0% (171/243), specificity 51.5% (51.5%), and positive predictive value 63.1% (171/ 271), again with strong statistical significance (x2 = 22.2, P < 0.0001). Prediction was strongest for MDD (e.g., sensitivity = 71/99 = 71.7%; x2 = 10.7, P = 0.001), somewhat less for BD Table 2 Association of age at illness-onset versus age at menarche for onset age groups.
Fig. 1. Relationship of age at onset ( 95% CI) of major mood or anxiety disorders to age at menarche for 1139 women (by linear regression, slope [b] = 1.64 [CI: 1.09– 2.18]; t = 5.89, P < 0.0001).
Onset age (years)
Subjects (n)
Slope [95% CI]a
t-score
P-value
< 20 20–39 40
311 557 271
0.251 [0.021–0.481] 0.491 [0.196–0.787] 0.798 [0.079–1.52]
2.15 3.26 2.19
0.03 0.001 0.03
a
Based on bivariate linear regression for all 1139 subject.
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Table 3 Association of age at onset of affective illness versus age at menarche. Diagnosis
Peri-menarche onset (%)a
Subjects (n)
Slope [b] [95% CI]
t-score
P-value
Major depressive disorder Anxiety disorder Bipolar I disorder Bipolar II disorder Any disorder
3.41 1.66 8.52 4.49 4.30
557 181 223 178 1139
1.82 2.02 1.11 0.90 1.64
4.19 3.10 2.28 1.48 5.89
< 0.0001 0.002 0.02 0.14 < 0.0001
a
[0.97–2.67] [0.73–3.31] [0.15–2.07] [ 0.30 to 2.10] [1.09–2.18]
Within 1 year of menarche; x2 = 12.5, P = 0.003. Data are ranked by significance of the association of onset age with menarche age.
(sensitivity = 66/97 = 68.0%; x2 = 6.08, P = 0.005), and nonsignificant for anxiety disorders (sensitivity = 34/47 = 51.1%; x2 = 1.21, P = 0.27). 3.5. Factors associated with age at menarche In addition to the strong associations of age at menarche with year of birth and age at illness onset, we found seven other factors to be significantly associated with an earlier age at menarche, based on bivariate analyses (Table 1B). In order of their statistical significance, they included: [a] having fewer siblings (excluding singletons), or [b] being an only child, [c] having suicidal ideation or acts at any time, [d] living in a rural area, [e] having more firstdegree family members with a psychiatric illness, [f] not being employed, and [g] presence of substance abuse. When these factors were analyzed by multivariate linear regression modeling, two remained independently and statistically significantly associated with being younger at menarche: [a] more recent birth year, and [b] being younger at onset of major affective or anxiety disorders (Table 1C). Factors not significantly associated with age at menarche included: socioeconomic status, temperament type, body-mass index (BMI) at intake, birth order, month or season of birth, marital status, age at marriage, number of children, age at menopause, attention-hyperactivity disorder, type of first illness episode, and overall morbidity as episodes or proportion of months since onset in depression, mania, or any illness per year. 4. Discussion The observed age at menarche in this large clinical sample (mean, 12.8 years) is identical to that in general-population samples from 13 countries (12.8 years), and very similar to that for Italy (12.4 years), as reviewed above (Introduction). This similarity accords with the expectation that the timing of menarche is a highly biologically determined developmental landmark in both clinical and general-population samples. We confirmed that age at menarche declined highly significantly in the Sardinian study sample since the early 1900s, by approximately 2.2%/year (Table 1A). This study appears to be the first to find a strong, highly significant correlation between younger ages at menarche and at the onset of various mood or anxiety disorders even when menarche preceded illness onset by many years. The significant correlations also held when women were divided in age classes (< 20, 20–39, and 40 years) for illness onset. This association appears to accord with findings reviewed above (Introduction) that an early menarche was associated with earlier or greater psychopathology of various types. However, associations with depression have been somewhat inconsistent and studies involving bipolar or anxiety disorders have been rare. We also confirmed previous reports of increased risk of mood disorders emerging close to the age at menarche [50,53,54]. Such perimenarchal risk within two years of a first mensis was especially high in BD-I subjects, in whom it was 2.50-times (8.52%/3.41%) more likely than
with MDD (Table 3). We also confirmed reports that menarche occurred earlier among women with fewer ( 2) or no siblings [55]. In addition, risks for suicidal ideation or behavior, substance abuse, and unemployment all were associated with earlier menarche. Such tendencies suggest relatively unfavorable functional or adaptational status, which also may be associated with earlier or more severe affective illnesses. A new finding was of younger menarche among women with more dense family histories of psychiatric illnesses (% of first-degree relatives affected; Table 1A). This association, and the strong association of early menarche with early onset of mood or anxiety disorders – further indication of earlier menarche – is associated with a greater or earlier risk of psychopathology, and suggests operation of familial or genetic factors. Moreover, the presence of a higher rate of unemployment in women with early age at menarche is probably explained as the more likely presence of psychopathological difficulties in association with early onset of menstruation. It is unlikley that age at menarche itself would be influenced by occupational level which usually occurs at later ages. However, we did not find correlations with some other factors previously reported to be associated with younger menarche age, including season of birth (menarche age reportedly lowest in summer) [54], being earlier in birth-order among siblings [56,57], having greater body weight or BMI [58,59], presence of attentionhyperactivity disorder [34,60], and cyclothymic or depressive temperament type [35]. Moreover, in the present subjects, age at menarche was not associated with other social or reproductive factors, including marital status, age at marriage, or number of children. Age at menopause also has been related inconsistently with age at menarche [44,60,61], as has socioeconomic status [59,62,63], but we found no relationship of either factor with menarche age. In addition, we found no significant association of menarche age with several clinical factors including type of firstlifetime illness episode (specifically, manic versus depressive), and annual episode counts or proportion of time in depression, mania, or any psychiatric illness. It is important to emphasize that as a predictor of age of onset of mood disorders, menarche age was highly statistically significant, but probably of limited clinical value, based on Bayesian characteristics. Such limitations probably reflect the relatively narrowly determined age at menarche, even in the present clinical sample. Mechanisms involved in the relationship of ages at menarche and at the onset of mood disorders are not clear. Before puberty, the prevalence of depression is reportedly similar in boys and girls, but after that age, a sharp increase of depression in girls has been noted [64,65]. Depressive episodes in females are likely to be influenced by gonadal steroids — so-called ‘reproductive depressions’ [66] — which increase after menarche [67]. Too, early menarche has been associated with higher circulating concentrations of estrogen around the onset of puberty as well as in early adulthood [68]. A plausible relationship between depressive symptoms and circulating concentrations of estrogens is supported by findings that major cerebral neurotransmitter systems are
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responsive to gonadal hormones, including ability to modulate gene transcription and the synthesis of various enzymes and receptor proteins involved in neurotransmission [69]. In particular, fluctuations in estrogens may contribute to mood oscillations and neurotransmission mediated by serotonin, including by decreasing expression of serotonin receptors [69,70]. In addition, hormonal changes occurring around menarche may tend to dysregulate mood through the hypothalamic–pituitary–adrenal axis, at a time of heightened vulnerability to external stressors [65]. How early menarche might influence the onset of mood disorders later in adult life (Table 2) is less clear. 5. Limitations Recollection of age at menarche is likely to vary and to be less reliable in older women. However, variance in such recollection should be similarly distributed across the investigated diagnostic groups, whose current ages were similar. 6. Conclusions Age at menarche among affectively ill women in Sardinia, as elsewhere, has declined over the past century and was strongly associated with age at onset of major affective and anxiety disorders across the age range. Younger menarche also was associated with factors suggestive of less-adaptive functioning, including suicidal behavior, substance abuse, and unemployment. Though early menarche was very strongly associated with earlier illness-onset, especially of mood disorders, the association had limited power as a potential clinical predictive measure, though with best Bayesian performance in MDD and BD-I. Nevertheless, the strong association of earlier menarche with earlier illnessonset throughout life suggests that biological mechanisms, including those related to reproductive endocrinology, may play a role in determining the timing of onset of mood and anxiety disorders. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments Supported in part by a research award from the Aretaeus Foundation of Rome (to LT), a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychiatric Research Fund (to RJB). References [1] Hosokawa M, Imazeki S, Mizunuma H, Kubota T, Hayashi K. Secular trends in age at menarche and time to establish regular menstrual cycling in Japanese women born between 1930 and 1985. BMC Womens Health 2012;12:19. [2] Silva CML da, Gigante DP, Minten GC. Premenstrual symptoms and syndrome according to age at menarche in a 1982 birth cohort in southern Brazil. Cad Saude Publica 2008;24:835–44. [3] De Sanctis V, Bernasconi S, Bianchin L, Bona G, Bozzola M, Buzi F, et al. Onset of menstrual cycle and menses features among secondary school girls in Italy: a questionnaire study on 3,783 students. Indian J Endocrinol Metab 2014; 18(Suppl. 1):S84–92. [4] Rigon F, De Sanctis V, Bernasconi S, Bianchin L, Bona G, Bozzola M, et al. Menstrual pattern and menstrual disorders among adolescents: an update of the Italian data. Ital J Pediatr 2012;38:38. [5] Lalys L, Pineau J-C. Age at menarche in a group of French schoolgirls. Pediatr Int 2014;56:601–4. [6] Anderson SE, Dallal GE, Must A. Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart. Pediatrics 2003;111:844–50. [7] Cabrera SM, Bright GM, Frane JW, Blethen SL, Lee PA. Age of thelarche and menarche in contemporary US females: a cross-sectional analysis. J Pediatr Endocrinol Metab 2014;27:47–51.
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