G. S. Conway

HETEROGENEITY OF THE POLYCYSTIC OVARY SYNDROME: CLINICAL, ENDOCRINE AND ULTRASOUND FEATURES IN 556 PATIENTS

This paper reports an analysis of the clinical, endocrine and ultrasound data within a population of 556 patients with ultrasound‐diagnosed polycystic ovaries. Compared with those not so affected, hirsutism was associated with a higher mean serum testosterone concentration, infertility was associated with higher mean gonadotrophin concentrations, obesity was associated with a higher mean serum testosterone concentration, hyperprolactinaemia was associated with a lower mean serum testosterone concentration and smaller ovaries, alopecia was associated with lower mean serum LH and testosterone concentrations, and acanthosis nigricans was associated with obesity and a raised mean serum testosterone concentration. The heterogeneity illustrates the limitations in the use of specific clinical or endocrine criteria as requirements for the diagnosis of the polycystic ovary syndrome.

Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients.

Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. Objective: Our objective was to establish the health status of adults with CAH. Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years. Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

Studies of FRAXA and FRAXE in women with premature ovarian failure.

Recent reports suggest that women with FRAXA premutations have an increased likelihood of having premature ovarian failure (POF). We screened 147 women with idiopathic POF for the number of trinucleotide repeats at the FRAXA and FRAXE loci. We found six women with FRAXA premutations, including four familial and two sporadic cases, but no women with FRAXA full mutations. At the FRAXE locus there were no pre- or full mutations but there was an excess of small alleles with fewer than 11 repeats, including at least one small deletion at or near the triplet. The association of FRAXA premutations with POF confirms that premutation alleles can affect ovarian development or function or both.

Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21‐hydroxylase deficiency.

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow

To investigate whether changes in circulating serum vascular endothelial growth factor (VEGF) concentrations during the menstrual cycle are associated with changes in blood flow within the ovaries and uterus.

Genotype‐phenotype analysis in late onset 21‐hydroxylase deficiency in comparison to the classical forms

To establish the type and frequency of mutations causing late onset 21‐hydroxylase deficiency and associated clinical and biochemical phenotypes and to compare these findings to those from heterozygotes and homozygotes for classical 21‐hydroxylase deficiency.

Frequency of a polymorphism in the regulatory region of the 17α-hydroxylase-17,20-lyase (CYP17) gene in hyperandrogenic states

OBJECTIVE Dysregulation of 17α‐hydroxylase (CYP17) has been proposed as a cause of hyperandrogenism. We have determined the prevalence of a polymorphic allele in the CYP17 gene in sporadic patients with polycystic ovaries (PCOS) compared to a reference population, and to a group of hyperandrogenic individuals, to assess its significance to androgen production.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015)

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Genotype-Phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort

CONTEXT In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.