Antenatal factors in the development of disorders of sex development

Cox, Kathryn Joan (2018) Antenatal factors in the development of disorders of sex development. MD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.
Printed Thesis Information:


Disorders of sex development (DSD) are a diverse group of conditions in which there is variation from the typical chromosomal, gonadal, or anatomical developmental pathway. While much has been learnt about the genetic aetiology of many of these disorders, a significant proportion of cases remain without a definitive diagnosis. This thesis consists of a series of studies designed to look at different aspects of DSD in order to identify causes and develop better ways to assess and research these conditions in the future.
Chapter 1 is an extensive literature review of normal sex development, models to describe the sex phenotype, steroidogenesis, steroid hormone structure and physiological role, classification of DSD, clinical uses of progestogens and determinants of foetal growth. An understanding of these diverse subjects is essential to consider the topics investigated.
Chapter 2 presents the rationale for, and specific aims of, this thesis.
Chapter 3 describes a study using the I-DSD registry, the largest international register of cases of DSD, to identify associated conditions co-occurring in DSD. 649 cases with documented consent were identified and analysed from the registry, with further information obtained from the reporting clinician where necessary. Associated conditions were reported in 168 cases (26%), overall, and when considered according to karyotype were reported in 112 cases of 46,XY DSD (24%), 27 cases of 46,XX DSD (22%), 19 cases of 45,X/46,XY (45%), and 6 cases of 45,X (75%). In 46,XY DSD, which represents the largest group of cases in the Registry, small for gestational age (SGA), cardiac and CNS anomalies were the most commonly reported associated conditions. This study strengthens the recognised association between SGA and non-specific 46,XY DSD. Additionally, the data indicate a possible association between genetically confirmed AIS and skeletal and renal anomalies. These results provide new research targets for cases in which the aetiology of DSD remains unclear. They also highlight the need for multi-disciplinary teams for management of these patients.
Chapter 4 documents a clinical study investigating the association between hypospadias, one of the mildest conditions on the spectrum of DSD, and the measurement of anogenital distance (AGD). 88 boys had AGD measured under general anaesthetic during hypospadias surgery, alongside assessment of severity of hypospadias. Medical notes were reviewed for further information including birth weight, gestation and the presence of additional genital anomalies, as described by the external masculinisation score (EMS). Median AGD was found to be shorter in boys with severe hypospadias (63mm), than those with mild hypospadias (75mm) (p<0.001). Additionally these boys were more likely to have lower birth weight SDS (-0.61) than boys with mild hypospadias (-0.42) (p= 0.013). This study is the first to show a link between severity of hypospadias, additional genital anomalies, and degree of AGD shortening. This supports the hypothesis that severe forms of hypospadias may be linked to inadequate androgen exposure in utero. Results also show that boys with more severe hypospadias have a lower birthweight, reinforcing the link between 46,XY DSD and SGA.
Chapter 5 describes the use of a rat model to investigate the developmental effects of exposure to the progestogen medroxyprogesterone acetate (MPA) during the male programming window. It has been previously suggested that antenatal exposure to progestogens may be associated with DSD. In this study Sprague Dawley dams were injected with 75mg/kg or 150mg/kg of subcutaneous MPA on gestational days 14.5 to 18.5. Results showed that MPA exposure was associated with a shorter than normal AGD in male rats, and a longer AGD in female rats. Offspring of both sexes had reduced birth weight when exposed to MPA (control weight 5.99g, MPA 75mg/kg 4.58g, MPA 150mg/kg 4.72g). There was no evidence of an effect on internal reproductive structures, including testis weight.
Chapter 6 describes studies using small vessel myography to investigate vascular function in the pregnant dams exposed to MPA in the previous studies. Low birth weight can be the result of altered vascular remodelling during pregnancy, leading to impaired placental function. It has previously been suggested that impaired placental function may be responsible for the combination of intra-uterine growth restriction and DSD. Uterine artery segments from animals exposed to MPA 150mg/kg demonstrated greater vessel wall thickness, and a trend towards an increase in internal and external diameter, with increased distensibility at higher pressures when compared to control segments. Wire myography showed that vasoconstriction in response to noradrenaline and NG-nitro-L-arginine methyl ester (L-NAME) was reduced following MPA exposure. These studies do not explain the causes of reduced growth in MPA exposed offspring. The responses seen are the opposite of those seen in animals with pre-eclampsia and hypertension, and may demonstrate the protective effect of progestogens in pregnancies complicated by these conditions.
Chapter 7 draws together the findings of all the studies in this thesis, to reach overall conclusions. The common theme of an association between DSD and impaired foetal growth from all three branches of this work in discussed. The potential for further investigations in pursuing this work to strengthen conclusions and inform future practice is considered.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Disorder of sex development, difference of sex development, DSD, intersex, hypospadias, anogenital distance, progestogen, progesterone, intrauterine growth restriction, uterine artery, vascular remodelling.
Subjects: R Medicine > RG Gynecology and obstetrics
R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Supervisor's Name: Ahmed, Professor S. Faisal and Welsh, Dr. Michelle
Date of Award: 2018
Embargo Date: 22 May 2021
Depositing User: Dr Kathryn J Cox
Unique ID: glathesis:2018-9134
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 May 2018 13:26
Last Modified: 14 Jun 2018 07:19

Actions (login required)

View Item View Item


Downloads per month over past year