Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study.
Do teenage girls with a history of menstrual irregularity and/or elevated androgen levels in adolescence exhibit an increased risk of polycystic ovary syndrome (PCOS) and/or infertility later on in adulthood?
Our results suggest that menstrual irregularity and/or elevated androgen levels at 16 years are still associated with symptoms of PCOS at 26 years as well as infertility problems at 26 years but not with decreased pregnancy or delivery rates at 26 years.
Hyperandrogenaemia is associated with menstrual irregularity, hirsutism, acne and potentially higher risk for PCOS, but there are few follow-up studies investigating whether adolescent hyperandrogenaemia and/or menstrual irregularity are an early sign of PCOS.
A prospective population-based cohort study was conducted using two postal questionnaires targeting girls in the Northern Finland Birth Cohort 1986 (NFBC1986, n = 4567). The NFBC1986 comprises all expected births from the year 1986 in the two northernmost provinces of Finland. Collection of the database was performed at the age of 16 and 26. The 16-year and 26-year questionnaires included one question about the regularity and length of the menstrual cycle. The 26-year questionnaire also included questions about symptoms of PCOS, reproduction and infertility problems.
The response rates for the questionnaires were 80% (n = 3669) at 16 years and 50% (n = 2270) at 26 years. At 15-16 years, of 2448 girls, 709 (29%) girls reported menstrual irregularity (symptomatic girls) and 1739 (71%) had regular periods (non-symptomatic girls). After combining data from the two questionnaires a total of 2033 girls were included in the analyses. The χ(2) and Student's t-test was used to compare reproductive outcome and prevalence of clinical hyperandrogenaemia, PCOS and infertility at 26 years between the study groups. Univariate and multivariate logistic regression models were employed to estimate the association of menstrual irregularity at 16 years with clinical hyperandrogenaemia, PCOS and infertility at 26 years.
At follow-up, the proportion of symptomatic girls who had conceived at least once (68.0 versus 67.9%) and had delivered at least one child (25.7 versus 28.1%) was similar to the non-symptomatic women and the groups had similar miscarriage rates (11.6 versus 12.1%). Logistic regression analyses indicated that menstrual irregularity at 16 years was associated with an increased risk of menstrual irregularity [adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.00-1.88, P = 0.050], PCOS (adjusted OR 2.91, 95% CI 1.74-4.84, P < 0.001) and infertility problems (adjusted OR 2.07, 95% CI 1.16-3.76, P = 0.013) at 26 years. At 26 years, women with PCOS (P = 0.013), hirsutism (P = 0.001) and acne (P < 0.001) exhibited significantly higher values of free androgen index (FAI) at 16 years than control women. There was a significant linear trend in the higher FAI quartiles at 16 years towards higher prevalence of PCOS (P = 0.005), hirsutism (P < 0.001) and acne (P < 0.001) at 26 years. Only 10.5% of the girls with menstrual irregularity at 16 years had PCOS at 26 years.
The diagnosis of menstrual irregularity was based on a self-reported questionnaire, thus introducing a risk of information bias in reporting the symptoms. Moreover, ovarian ultrasonography was not available to aid the diagnosis of PCOS and there was no clinical evaluation of hyperandrogenism. The relatively low rate of participation to the questionnaire at 26 years may also have biased the results.
Our findings confirm that menstrual irregularity and/or elevated androgen levels are already present in adolescence in women with PCOS and infertility in later life, which strengthens the importance of early identification of menstrual irregularity.
This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, the Sigrid Juselius Foundation, University Hospital Oulu and University of Oulu, the European Commission and the Medical Research Council, UK, Welcome Trust (089549/Z/09/Z). None of the authors have any conflict of interest.
West S
，Lashen H
，Bloigu A
，Franks S
，Puukka K
，Ruokonen A
，Järvelin MR
，Tapanainen JS
，Morin-Papunen L
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BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.
What is the association between childhood and adolescent BMI and reproductive capacity in women?
Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS).
Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited.
A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years.
Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period.
BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS.
Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported.
This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions.
NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose.
N/A.
Laru J
，Nedelec R
，Koivuaho E
，Ojaniemi M
，Järvelin MR
，Tapanainen JS
，Franks S
，Tolvanen M
，Piltonen TT
，Sebert S
，Morin-Papunen L
... -
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Anti-Müllerian hormone: correlation with testosterone and oligo- or amenorrhoea in female adolescence in a population-based cohort study.
Can serum anti-Müllerian hormone (AMH) levels measured in female adolescents predict polycystic ovary syndrome (PCOS)-associated features in adolescence and early adulthood?
AMH levels associated well with PCOS-associated features (such as testosterone levels and oligoamenorrhoea) in adolescence, but was not an ideal marker to predict PCOS-associated features in early adulthood.
Several studies have reported that there is a strong correlation between antral follicle count and serum AMH levels and that women with PCOS/PCO have significantly higher serum AMH levels than women with normal ovaries. Other studies have reported an association between AMH serum levels and hyperandrogenism in adolescence, but none has prospectively assessed AMH as a risk predictor for developing features of PCOS during adulthood.
A subset of 400 girls was selected from the prospective population-based Northern Finland Birth Cohort 1986 (n = 4567 at age 16 and n = 4503 at age 26). The population has been followed from 1986 to the present.
At age 16, 400 girls (100 from each testosterone quartile: 50 with oligo- or amenorrhoea and 50 with a normal menstrual cycle) were selected at random from the cohort for AMH measurement. Metabolic parameters were also assessed at age 16 in all participants. Postal questionnaires enquired about oligo- or amenorrhoea, hirsutism, contraceptive use and reproductive health at ages 16 and 26.
There was a significant correlation between AMH and testosterone at age 16 (r = 0.36, P < 0.001). AMH levels at age 16 were significantly higher among girls with oligo- or amenorrhoea compared with girls with normal menstrual cycles (35.9 pmol/l [95% CI: 33.2;38.6] versus 27.7 pmol/l [95% CI: 25.0;30.4], P < 0.001). AMH at age 16 was higher in girls who developed hirsutism at age 26 compared with the non-hirsute group (31.4 pmol/l [95% CI 27.1;36.5] versus 25.8 pmol/l [95% CI 23.3;28.6], P = 0.036). AMH at age 16 was also higher in women with PCOS at age 26 compared with the non-PCOS subjects (38.1 pmol/l [95% CI 29.1;48.4] versus 30.2 pmol/l [95% CI 27.9;32.4], P = 0.044). The sensitivity and specificity of the AMH (cut-off 22.5 pmol/l) for predicting PCOS at age 26 was 85.7 and 37.5%, respectively. The addition of testosterone did not significantly improve the accuracy of the test. There was no significant correlation between AMH levels and metabolic indices at age 16.
AMH is related to oligo- or amenorrhoea in adolescence, but it is not a good marker for metabolic factors. The relatively low rate of participation in the questionnaire at age 26 may also have affected the results. AMH was measured in a subset of the whole cohort. AMH measurement is lacking international standardization and therefore the concentrations and cut-off points are method dependent.
Using a high enough cut-off value of AMH to predict which adolescents are likely to develop PCOS in adulthood could help to manage the condition from an early age due to a good sensitivity. However, because of its low specificity, it is not an ideal diagnostic marker, and its routine use in clinical practice cannot, at present, be recommended.
The study was funded by a grant from Wellcome Trust (089549/Z/09/Z) to H.L., S.F. and M.-R.J. Study funding was also received from Oulu University Hospital Research Funds, Sigrid Juselius Foundation and the Academy of Finland. None of the authors have any competing interest to declare.
Pinola P
，Morin-Papunen LC
，Bloigu A
，Puukka K
，Ruokonen A
，Järvelin MR
，Franks S
，Tapanainen JS
，Lashen H
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