Anogenital distance in children born of mothers with polycystic ovary syndrome: the Odense Child Cohort

Abstract

STUDY QUESTION Are higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)? SUMMARY ANSWER AGD was similar in 3-month-old children born of mothers with PCOS compared to controls. WHAT IS KNOWN ALREADY AGD is considered a marker of prenatal androgenization. STUDY DESIGN, SIZE, DURATION Maternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (<35 days) before conception and no signs of androgen excess (hirsutism and/or acne). MAIN RESULTS AND THE ROLE OF CHANCE AGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P < 0.001). In women with PCOS, maternal testosterone was an independent positive predictor of offspring AGDas and AGDap in boys. Maternal testosterone levels did not predict AGD in girls born of mothers with PCOS or in boys or girls born of women in the control group. LIMITATIONS, REASONS FOR CAUTION The diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS Our finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain. STUDY FUNDING/COMPETING INTEREST(S) Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported.

Endometriosis and polycystic ovary syndrome are diametric disorders

“…Women with PCOS have significantly longer AGDs than unaffected controls (Table 1 ), supporting the hypothesis that PCOS involves elevated prenatal exposure to testosterone (Filippou & Homburg, 2017 ). Daughters of mothers with PCOS also demonstrate evidence of longer AGDs than daughters of unaffected women (Barrett et al, 2018 ; Perlman et al, 2020 , but see Glintborg et al, 2019 ), in association with high serum testosterone in affected mothers during gestation. Clinical characteristics of PCOS, including elevated serum testosterone and increased ovarian follicle count, are also positively associated with AGD in nonclinical samples of female college students (Mendiola et al, 2012 ; Mira‐Escolano et al, 2014 ).…”

Anogenital Distance and Gynaecological Diseases: A Narrative Review

“…Data derived from different study groups and the potential role of androgen in the pathophysiology of the disease has strong foundations. However, a recent Danish study (43) did not find an association between higher maternal testosterone levels and longer AGD in the offspring, questioning the impact of prenatal hormonal exposure on AGD length.…”

Maternal polycystic ovary syndrome and attention deficit hyperactivity disorder in offspring at 3 years of age: Odense Child Cohort

“…Further, 74 women were pregnant more than once within the inclusion period, and only the first pregnancy was included in the data set. Maternal age, pre-pregnancy body mass index (BMI), and parity were collected Health Foundation (Helsefonden), The National Board of Social Services, and Lundbeckfonden (F-61171- [19][20][21][22][23][24][25][26][27].…”

“…18 We previously reported comparable AGD length in women with PCOS compared with controls; however, maternal testosterone was an independent positive predictor of offspring AGD in boys. 19 These findings suggested that boys could be more susceptible to maternal testosterone exposure than girls. 19 To our knowledge, associations between offspring AGD and risk of ADHD have not been investigated in human studies.…”

“…19 These findings suggested that boys could be more susceptible to maternal testosterone exposure than girls. 19 To our knowledge, associations between offspring AGD and risk of ADHD have not been investigated in human studies.…”