Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center.

OBJECTIVE: To study the clinical characteristics and genetic basis of complete androgen insensitivity syndrome (CAIS) in patients from the People's Republic of China. CAIS patients with 46 XY karyotype produce male levels of androgens but present with female external genitalia and secondary sex characteristics. The majority of affected individuals have androgen receptor (AR) gene mutations. This case series explored clinical and molecular characteristics of CAIS patients from the People's Republic of China. DESIGN: Genomic DNA from peripheral blood of clinically diagnosed CAIS patients was sequenced for mutation in the androgen receptor (AR) gene and steroid 5α-reductase type 2 gene (SRD5A2). SETTING: Participants were recruited from Peking Union Medical College Hospital when they came in for consultation. PATIENTS: Thirty patients from unrelated families were recruited. INTERVENTIONS: Data from medical documents recording diagnosis and treatment of these patients were retrospectively collected. MAIN OUTCOME MEASURES: Patient genotypes were determined by sequencing the AR and SRD5A2 genes. Their clinical characteristics were summarized based on symptoms, hormone profiles, operative findings, and pathological results. RESULTS: Twenty-one patients diagnosed with CAIS had mutations in AR exons. Analysis of AR exons revealed the presence of seven novel mutations (c.58C>T, c.645_652delGGGGGCTC, c.910G>T, c.1078C>T, c.1786T>A, c.2230G>T, and c.2522G>C); of these mutations, 47.6% (10/21) were located in the ligand-binding domain. Gonadal insufficiency was found in one case of CAIS. Among the remaining nine patients, three had SRD5A2 mutations and therefore a steroid 5α-reductase deficiency. No AR or SRD5A2 mutations were detected in the other six patients. CONCLUSION: This study broadens the spectrum of known AR gene mutations responsible for CAIS, and implies that there can be more complex underlying causes of CAIS.

Long-term consequences of androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is one of the most common sexual developmental disorders. According to the grade of the remaining androgen receptor (AR) function, AIS is classified as complete (CAIS), partial (PAIS) or mild (MAIS). In CAIS, the prevalence of germ cell tumours is increased compared with the general population. Although patients with CAIS used to undergo gonadectomy before puberty, nowadays a gonadectomy is recommended after spontaneous puberty, and up to 15% of patients retain their gonads. Nevertheless, the risk of germ cell tumour increases gradually after puberty. Annual follow-up with ultrasound or magnetic resonance imaging (MRI) is recommended. Unfortunately, these imaging methods are not sensitive enough for the diagnosis of an in situ germ cell tumour. In PAIS, the risk of germ cell tumour is higher than in CAIS; therefore, an early gonadectomy or an orchidopexy is indicated. Optimal hormone replacement therapy (HRT) is necessary for long-term health. The risks of osteopenia and of regimen osteoporosis are higher, ESPECIALLY in patients with early gonadectomy. Infertility is the rule in CAIS and PAIS. A few mutations do not affect fertility detrimentally, and these are responsible for MAIS. In PAIS leading to a predominantly male phenotype or ambiguous genitalia, multiple surgical procedures for gynaecomastia and/or hypospadias are required. Some small studies have found a higher risk of obesity, hyperlipidaemia and impaired insulin sensitivity. Psychological support is essential, as the prevalence of psychiatric disorders is increased. In conclusion, the diagnosis of AIS has long-term consequences for which shared decision-making (physicians, patients, parents) is appropriate.

Etiology and management of primary amenorrhoea: A study of 102 cases at tertiary centre.

OBJECTIVE: To determine the prevalence of etiologic causes of primary amenorrhea in Indian population. MATERIALS AND METHODS: A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo-sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype. RESULTS: The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis. CONCLUSIONS: The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea.

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

STUDY QUESTION: What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? SUMMARY ANSWER: No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). WHAT IS KNOWN ALREADY: Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. STUDY DESIGN, SIZE, DURATION: This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. MAIN RESULTS AND ROLE OF CHANCE: The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A limited number of cases were included. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

Update on the Pathophysiology and Risk Factors for the Development of Malignant Testicular Germ Cell Tumors in Complete Androgen Insensitivity Syndrome.

Prophylactic gonadectomy in young adult women with complete androgen insensitivity syndrome (CAIS) to avoid development of an invasive testicular germ cell tumor (TGCT) is currently advised in most centers. However, women with CAIS increasingly question the need of this procedure. In order to provide optimal counseling and follow-up of these women, insight in the mechanisms underlying TGCT development in androgen insensitivity syndrome (AIS), data regarding the incidence of TGCT in AIS adults specifically, and an overview of existing and novel screening tools for in situ and invasive neoplastic lesions are crucial. The current knowledge regarding these topics is revised in this paper.

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis.

BACKGROUND: Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. OBJECTIVE AND HYPOTHESES: To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy. METHOD: Data were collected from the Cambridge DSD database on patients with CAIS (n = 225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry. RESULTS: Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n = 62; postpuberty, n = 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table. DISCUSSION: In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres. CONCLUSION: The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development.

CONTEXT: The prevalence of phenotypic females with a 46,XY karyotype is low, thus current knowledge about age and clinical presentation at diagnosis is sparse even for the most frequent conditions, androgen insensitivity syndrome (AIS), and gonadal dysgenesis. OBJECTIVE: To estimate incidence, prevalence, age at diagnosis, and clinical presentation at diagnosis in 46,XY females. DESIGN AND SETTING: A nationwide study covering all known females with a 46,XY karyotype in Denmark since 1960. The diagnosis of 46,XY disorder of sex development (DSD) was determined by medical record evaluation, data from the Danish National Patient Registry, and genetic testing, if available. PATIENTS: A total of 166 females registered as 46,XY females in the Danish Cytogenetic Central Registry were identified. RESULTS: A total of 124 females were classified as having 46,XY DSD, 78 with AIS and 25 with gonadal dysgenesis, whereas the remaining subjects had a variety of different diagnoses. The prevalence of 46,XY females was 6.4 per 100 000 live born females, and for AIS and gonadal dysgenesis, it was 4.1 and 1.5 per 100 000, respectively. Median age at diagnosis was 7.5 years (95% confidence interval, 4.0-13.5; range, 0-34 y) in AIS and 17.0 years (95% confidence interval, 15.5-19.0; range, 0-28 y) in gonadal dysgenesis (P = .001). Clinical presentation was dependent on cause of DSD. CONCLUSIONS: The first estimate on prevalence of 46,XY females is 6.4 per 100 000 live born females. The presentation of AIS and gonadal dysgenesis is distinctly different, with AIS being diagnosed during childhood and gonadal dysgenesis during pubertal years. The presenting phenotype is dependent on the cause of 46,XY DSD.

Meta-analysis of Androgen Insensitivity in Preoperative Hormone Therapy in Hypospadias.

OBJECTIVE: To define androgen insensitivity prevalence in hypospadias patients treated with preoperative hormone therapy. MATERIALS AND METHODS: We searched databases that were published in English and Chinese up to September 10, 2014 for our studies. Eligibility criteria were pre-established. Title, abstract, and full-text screenings were conducted by 2 authors independently. Discrepancies were resolved by consensus. Quality assessment of included studies was completed. Meta-analysis was done when appropriate using R, version 3.1.1 for Windows. Heterogeneity among individual studies was tested using the Cochran chi-square Q test and quantified by calculating the I(2) index. RESULTS: Thirteen of 1278 publications met inclusion criteria and were incorporated into this study. Of 306 patients with preoperative hormone therapy, 25 displayed androgen resistance. Meta-analysis demonstrated that the random-effects model generates a pooled estimate of 7.14% (95% confidence interval [CI], 3.16%-15.31%), whereas the fixed-effect model provides an estimate of 14.61% (95% CI, 10.00%-20.85%). Heterogeneity among included studies was found above medium (I(2) = 67.1% [95% CI, 41.2%-81.6%]; P = .0003]. After exclusion of the heterogeneity, both random-effects and fixed-effect models produce a consistent pooled estimate of 6.95% (95% CI, 0%-47.8%). CONCLUSION: We have defined that the prevalence of androgen resistance in hypospadias is 7.14% (95% CI, 3.16%-15.31%). To distinguish isolated hypospadias from patients with androgen insensitivity syndrome, we recommend that androgen-resistant patients should be specifically targeted by molecularly focused diagnosis. Management strategies should include identification of mutations in the androgen receptor gene, timely surgery to repair hypospadias, and long-term follow-up of sexual function and fertility later in life.

Androgen insensitivity syndrome: ten years of our experience.

Abnormalities of secondary sexual differentiation manifest in varying degrees depending upon the severity of the underlying cause. Primary amenorrhea in phenotypic females is caused by several different factors, including hormonal imbalance, nutritional deficiency and sex differentiation abnormalities. Androgen insensitivity syndrome (AIS) accounts for a large proportion of such cases in phenotypic females but genetically male individuals. Over the past 10 years, we have collected data related to androgen insensitivity from more than 150 cases. The research identified several important but neglected facts about this syndrome; including the identification of mutations in 39% of the cases and the establishment of the cause of pathogenesis in 60% of them. The most intriguing facts were uncovered in relation to late presentation of the AIS cases, little awareness among patients and family members, no consensus on the age of performing gonadectomy, and reluctance of the patients to undergo recommended surgery. These issues need immediate attention to improve healthcare and management of AIS cases. This article summarizes our observations about AIS with an aim to spread awareness among patients and clinicians.

Lower urinary tract symptoms after feminizing genitoplasty.

OBJECTIVE: To investigate the prevalence of lower urinary tract symptoms (LUTS) in a Finnish cohort of patients who had undergone feminizing genitoplasty in childhood. PATIENTS AND METHODS: Information on LUTS was assessed using the Danish Prostatic Symptom Score questionnaire: 24 out of 45 females (53%) returned the questionnaire; 16 patients with prenatal androgen exposure (congenital adrenal hyperplasia = CAH group) and eight with androgen insensitivity (AIS group). RESULTS: Urge urinary incontinence was reported by 13% of the patients in both the CAH and AIS groups and by 15% of the controls. Stress urinary incontinence was reported by 31% of the patients in the CAH group, 13% of the patients in the AIS group and 22% of the controls. Distressing voiding symptoms were reported by 19% of the patients in the CAH group, 13% of the patients in the AIS group and 28% of the controls, and of these straining and incomplete emptying were the most prevalent. CONCLUSIONS: LUTS are as common in female DSD patients with feminizing genitoplasty as they are in controls. Some degree of distressing incontinence occurred in 13%-25% of the young female patients and the controls.

Androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a disorder caused by a mutation of the gene encoding the androgen receptor (AR; Xq11-q12). The prevalence of AIS has been estimated to be one case in every 20,000 to 64,000 newborn males for the complete syndrome (CAIS), and the prevalence is unknown for the partial syndrome (PAIS). The symptoms range from phenotypically normal males with impaired spermatogenesis to phenotypically normal women with primary amenorrhea. Various forms of ambiguous genitalia have been observed at birth. The diagnosis is confirmed by determining the exact mutation in the AR gene. PAIS individuals require precise diagnosis as early as possible so that the sex can be assigned, treatment can be recommended, and they can receive proper genetic counseling. After birth, differential diagnosis should be performed using other forms of abnormal sexual differentiation of primary amenorrhea. The treatment of AIS is based on reinforcement sexual identity, gonadectomy planning, and hormone replacement therapy. The prognosis for CAIS is good if the testicular tissue is removed at the appropriate time. For PAIS, the prognosis depends on the ambiguity of the genitalia and physical and psychosocial adjustment to the assigned sex.

Disorders of sex development among Sudanese children: 5-year experience of a pediatric endocrinology clinic.

BACKGROUND: The birth of a child with disorders of sex development (DSDs) is considered a medical and psychosocial emergency. Management of these cases requires facilities and a multidisciplinary team. In developing countries, this is made difficult by the lack of facilities in addition to sociocultural and religious factors that can affect management. This is the first experience to be published from Sudan. OBJECTIVE: The aim of this study was to see the prevalence, etiological factors, management, and problems faced in handling these cases. METHODS: This is a retrospective descriptive study reviewing the records of all cases referred to a pediatric endocrinology clinic over a 5-year period. Cases were managed by a multidisciplinary team. RESULTS: One hundred fifty-six cases were seen, of which 122 were included in the study. A total of 79 (64.8%) were born at home, whereas 59 (52.2%) of the cases were not observed at birth by health-care providers. The average cost of investigating a case was $250-300. The investigations showed that 69 had XX DSD and 45 had XY DSD. The most common cause of XX DSD was congenital adrenal hyperplasia and that of XY DSD was androgen insensitivity syndrome. Twenty-three (19%) needed sex reassignment. There was a preference for the male sex. CONCLUSION: DSDs are not uncommon in Sudan. Because of lack of awareness and sociocultural reasons cases are referred late. Investigating these cases is expensive and has to be supported, and more multidisciplinary teams have to be trained to make services accessible and affordable.

Androgen insensitivity syndrome: risk of malignancy and timing of surgery in a paediatric and adolescent population.

BACKGROUND: Management of female phenotype XY disorders poses a series of problems for the treating clinician. Even after a series of investigations and imaging modalities, there are lingering doubts about the exact nature of the disease and the correct management option. Optimal timing and necessity for removal of their testes have been a debated issue by physicians. There is a generally accepted opinion among physicians that the risk of malignancy in androgen insensitivity syndrome (AIS) is considerably lower than with other intersex disorders and occurs at a later age. OBJECTIVE: The highlight of this presentation is to reinforce the value of laparoscopic gonadectomy in management of AIS in correlation with data suggesting higher risk of malignancy. PATIENTS AND METHODS: A retrospective review of 11 phenotypic females with XY karyotype was carried out. The patients were evaluated by a diagnostic protocol which included clinical, hormonal, sonographic and cytogenetic examinations. Patients/parents were counselled by the team concerning the different treatment modalities and contrary to the assigned gender, laparoscopy was offered to them. Uneventful bilateral gonadectomy was performed in all the patients and gonads submitted for histopathological examination. RESULTS: A total of 11 patients (mean age, 10.4 ± 4.1 years), including six with complete AIS and five with partial AIS (PAIS) were reviewed. In two patients with PAIS (18.1%), histopathology revealed malignancy (bilateral seminoma and gonadoblastoma) and in an additional patient, a benign hamartoma was found. Literature evidence suggests that AIS female phenotype patients retaining their testes through puberty have a 5% chance for developing malignant tumours. Reviewing our results in correlation with literature, we found that PAIS patients may harbour a higher risk of malignancy. CONCLUSIONS: In complementation to hormonal tests and cytogenetic techniques, laparoscopic gonadectomy is required to complete the diagnostic work up for AIS as it also adds a final therapeutic approach with low risk and huge benefit. Since laparoscopy is now a well-tolerated and widely accepted gold standard, it should be included in routine management for patients with AIS. Risk of malignancy in PAIS should be investigated in larger cohort of these patients.

Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations.

OBJECTIVE: To confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic analysis and to determine the prevalence of exon 1 mutations in the androgen receptor (AR) transactivation defects of a large series of CAIS patients. DESIGN: International retrospective study. SETTING: University Hospital of Montpellier, Department of Hormonology. PATIENT(S): 105 patients with normal female external genitalia, bilateral intra-abdominal or inguinal testis, normal breast development, absent or sparse pubic hair, normal or high endogenous testosterone production, hypoplastic or absent wolffian structures, and 46,XY karyotype. INTERVENTION(S): Sequencing of the AR gene. MAIN OUTCOME MEASURE(S): Prevalence of AR exon 1 mutations. RESULT(S): Over a 10-year period (1997 to 2007), we identified 78 AR gene mutations in 105 patients with CAIS; 21 of them were located in exon 1, and 13 of these were new mutations. We report 13 new mutations in the AR gene. All but one were stop codons, and the last was a splicing abnormality. CONCLUSION(S): The finding that 27% of the mutations in our cohort were localized in exon 1 versus 15% in previous works justifies the sequencing of this exon in patients with CAIS.

[The androgen receptor gene polymorphism and clinical picture of androgen deficiency syndrome during aging male of men's population in Wroclaw]. / Polimorfizm genu receptora androgenowego a obraz kliniczny zespolu niedoboru androgenów w procesie starzenia sie populacji mezczyzn wroclawskich.

INTRODUCTION: One of the changes observed in the ageing process is the progressive reduction in androgen levels, which may be associated with the development of the clinical syndrome of androgen deficiency. The androgen receptor gene polymorphism may also contribute to the development of the above syndrome of clinical manifestations. To assess the relationship between CAG androgen receptor gene polymorphism and the development of manifestations of androgen deficiency syndrome in men aged 45 to 65. MATERIAL AND METHODS: A total of 268 men aged 45-65, randomly selected from the population of Wroclaw, Poland, were included in the study. The subjects completed the Heinemann questionnaire, followed by blood sampling for determination of the CAG androgen receptor gene polymorphism by polymerase chain reaction (PCR). The PCR reaction products for all the subjects were separated by capillary electrophoresis (ABI PRISM 310) and the number of CAG repeats was determined using the previously constructed standard curve: (CAG) n = 0.5*M[bp]-101. RESULTS: The minimum number of CAG repeats was 52 with the mean of 24. Based on the total score in the Heinemann questionnaire in all of the study subjects we found no or slight manifestations of androgen deficiency syndrome in 68 (25%) subjects, mild manifestations consistent with the andropause syndrome in 93 (35%) subjects, moderate manifestations in 88 (33%) subjects and severe manifestations in 19 (7%) subjects. The numbers of subjects with specific severities of androgen deficiency manifestations across the specific subscales were as follows: a) Psychological manifestations subscale: 111 subjects with no or very mild manifestations, 117 with mild manifestations, 33 with moderate manifestations and 7 with severe manifestations; b) Somatic manifestations subscale: 17 subjects with no or very mild manifestations, 72 with mild manifestations, 120 with moderate manifestations and as many as 59 with severe manifestations; c) Sexual dysfunction subscale: 26 subjects with no or very mild manifestations, 45 with mild manifestations, 80 with moderate manifestations and 117 with severe manifestations. In all the study men (n = 268) we found 76 with a low (< 21) and 119 with a high (> 23) number of CAG repeats. CONCLUSIONS: 1. In the entire study group (n = 268) we found a positive correlation between the number of CAG repeats and the severity of psychological manifestations. We also found that in men with a higher number of CAG repeats (> 23 repeats) the somatic and psychological manifestations associated with signs of androgen deficiency are more common during the ageing period and that these patients score higher on the overall Heinemann scale. 2. We found no correlation between the number of CAG repeats in men divided into 4 subgroups with respect to their scores (hence the severity) on the overall Heinemann scale and its three subscales (psychological, somatic and sexual dysfunction subscales) and their scores.