External Genital Abnormalities Research Articles

Spotting the Culprit: A Rare Case of Hematometra in a Menstruating Female with Fraser Syndrome

Background: Fraser syndrome is a rare autosomal disorder that is associated with multiple genetic abnormalities. Discussed here is one abnormality associated with the genital tract.
 Case Description: A 19-year-old female with Fraser syndrome presented to the pediatric emergency department for abdominal distention and pain for two days, noted to have hematometra on CT guided imaging. Decision was made to proceed with total abdominal hysterectomy bilateral salpingoophorectomy.
 Conclusion: This case highlights the rarity of Fraser syndrome with associated hematometra secondary to both internal and external genital abnormalities post-menarche. Hematometra should be a differential diagnosis in patients with syndromes that are associated with genital abnormalities as failure to drain the retained blood and tissue products, can act as a foci for infection.

Application of fluorescence in situ hybridization combined with chromosomal karyotyping analysis in children with disorders of sex development due to sex chromosome abnormalities

To retrospectively analyze sex chromosomal abnormalities and clinical manifestations of children with disorders of sex development (DSD). A total of 14 857 children with clinical features of DSD including short stature, cryptorchidism, hypospadia, buried penis and developmental delay were recruited from Zhengzhou Children's Hospital from January 2013 to March 2022. Fluorescence in situ hybridization (FISH) and chromosomal karyotyping were carried out for such children. In total 423 children were found to harbor sex chromosome abnormalities, which has yielded a detection rate of 2.85%. There were 327 cases (77.30%) with Turner syndrome and a 45,X karyotype or its mosaicism. Among these, 325 were females with short stature as the main clinical manifestation, 2 were males with short stature, cryptorchidism and hypospadia as the main manifestations. Sixty-two children (14.66%) had a 47,XXY karyotype or its mosaicism, and showed characteristics of Klinefelter syndrome (KS) including cryptorchidism, buried penis and hypospadia. Nineteen cases (4.49%) had sex chromosome mosaicisms (XO/XY), which included 11 females with short stature, 8 males with hypospadia, and 6 cases with cryptorchidism, buried penis, testicular torsion and hypospadia. The remainder 15 cases (3.55%) included 9 children with a XYY karyotype or mosaicisms, with main clinical manifestations including cryptorchidisms and hypospadia, 4 children with a 47,XXX karyotype and clinical manifestations including short stature and labial adhesion, 1 child with a 46,XX/46,XY karyotype and clinical manifestations including micropenis, hypospadia, syndactyly and polydactyly, and 1 case with XXXX syndrome and clinical manifestations including growth retardation. Among children with DSD due to sex chromosomal abnormalities, sex chromosome characteristics consistent with Turner syndrome was most common, among which mosaicism (XO/XX) was the commonest. In terms of clinical manifestations, the females mainly featured short stature, while males mainly featured external genital abnormalities. Early diagnosis and treatment are particularly important for improving the quality of life in such children.

Predictive value of ultrasound in prenatal diagnosis of hypospadias: hints for accurate diagnosis.

This study aims to assess the diagnostic accuracy of targeted ultrasound examination in prenatal diagnosis of hypospadias and to evaluate the predictive values ofdefined ultrasonographic findings of hypospadias. The cases diagnosed with hypospadias in our fetal medicine center were identified on an electronic database. The ultrasound reports, images and hospital records were reviewed retrospectively. The predictive value of prenatal ultrasound diagnosis and the predictive values of each sonographic finding were assessed according to the postnatal clinical examinations. Thirty-nine cases were diagnosed with hypospadias on ultrasound during the 6 years. Nine fetuses with missing postnatal examination records were excluded. Twentytwo of the remaining fetuses had their prenatal diagnosis of hypospadias confirmed in postnatal examinations, indicating a 73.3 % positive predictive value. Normal external genitalia was detected in postnatal examinations of three fetuses. Five fetuses were diagnosed with other external genital abnormalities, including micropenis (n=2), clitoromegaly (n=2), and buried penis with bifid scrotum (n=1) in postnatal examinations. The positive predictive value of prenatal ultrasound for any external genital abnormality was 90 %. Although the positive predictive value of ultrasound for genital anomalies is satisfying, it is slightly lower for the specific diagnosis of hypospadias. This reflects overlapping ultrasound findings of different external genitalia anomalies. Standardized, systematic evaluation of the internal and external genital organs, karyotyping and genetic sex determination are essential to achieve a precise prenatal diagnosis of hypospadias.

A case of Potter sequence with WT1 mutation.

Wilms tumor 1 (WT1) is the causative gene of Denys-Drash syndrome and Frasier syndrome, and in most cases, kidney failure develops after birth. We report an unusual case of Potter sequence due to fetal nephropathy and kidney failure with a WT1 mutation. The neonate was born at 37weeks of gestation, and had no distinctive facial appearance or anomalies of the extremities. The external genitalia were ambiguous. Presence of a penile-like structure or hypertrophic clitoris was noted, and the urethra opened at the base of the penis or clitoris. On ultrasonographic examination, the kidney sizes were small. No kidney cysts were noted, but the kidney parenchymal luminosity was increased. Although the neonate received mechanical ventilation because of severe retractive breathing after birth, he died of poor oxygenation due to air leak syndrome at 60h after birth. The congenital anomalies of the kidney and urinary tract (CAKUT) gene panel revealed a heterozygous missense mutation in WT1 [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)]. In WT1, missense mutations are associated with earlier onset of nephropathy than nonsense or splicing mutations. However, severe cases of fetal onset and early neonatal death with WT1 mutations are rare, and only one severe case with the same missense mutation in WT1 has been reported. Therefore, WT1 mutation may be suspected in Potter sequence patients with external genital abnormalities, and the WT1 missense mutation in our case [NM_024426.6:exon9:c.1400G > A, p.(Arg467Gln)] may indicate a severe case with fetal onset of nephropathy and kidney failure.

Small atrophic testis in infant: Should it be excised? or preserved?

We have struggled to decide whether the unilateral atrophic testis without external genital abnormalities, which we call a “small atrophic testis (SAT)”, should be preserved or removed, because no definitive reviews of surgical outcomes have yet been reported. The aim of this study was to clarify the outcomes of our surgical management and to outline our surgical strategy for SATs. 5 cases in SAT were evaluated. Outcomes of surgery including bilateral testicular size were analyzed retrospectively. Retrospective studies of SAT cases with surgical intervention showed that the amount of affected testicular tissue has an impact on the pathogenesis of compensatory contralateral testicular hypertrophy (CCTH), but other factors may also be associated with the development of CCTH. We assume that one should remove an SAT that is very small at surgery or displays progression of atrophy on follow-up ultrasonography even after fixation because there may be a risk of seminomas developing from atrophic testes.

Three cases of 3β-hydroxysteroid dehydrogenase deficiency: Clinical analysis.

3β-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations. In order to improve the understanding and diagnosis of the disease, we analyzed and summarized the clinical characteristics, genetic variants and treatment for 3 children with 3β-HSD deficiency in this study. A summary of the clinical data, hormone levels (17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, testosterone, dehydroepiandrosterone, androstenedione, renin, and aldosterone), therapeutic drugs, and gene sequencing results from 3 3β-HSD deficiency patients was created. The 3 patients developed external genital abnormalities and adrenal insufficiency in infancy. Steroid hormone levels were consistent with 3β-hydroxysteroid dehydrogenase deficiency. Gene sequencing for the 3 patients detected complex heterozygous mutations in the HSD3B2 gene, which confirmed the diagnosis of 3β-HSD deficiency type II. Among the mutation types, c.154_162delinsTCCTGTT and c.674T>A have not been reported in the literature. The 3 children were treated with glucocorticoid and mineralocorticoid replacement, which controlled the adrenal insufficiency satisfactorily. In 2 male patients, external genital dysplasia manifested as hypospadias and small penis. After long-acting testosterone intramuscular injection to increase the penis size, the hypospadias were repaired. Mild masculinization in the female patient resulted in skin pigmentation and clitoral hypertrophy; however, no surgical intervention was required. The main clinical manifestations of 3β-HSD deficiency were adrenal insufficiency and sex hormone synthesis dysfunction. There was a strong phenotype correlation between the observed clinical manifestations in conjunction with steroid hormone levels and HSD3B2 mutations. The novel mutations c.154_162delinsTCCTGTT and c.674T>A were classified as pathogenic variants. Adrenal cortical function control was satisfactory after hormone replacement therapy, and hypospadias and small penis were attenuated using testosterone replacement therapy during mini-puberty for optimal surgical outcome.

External genital abnormalities in male primary school children: importance of structured school health survey

Background: Abnormalities of external genitalia are often under diagnosed in early childhood because of lack of awareness of parents about the anatomy of external genitalia and social inhibitions. These abnormalities, if left untreated, may lead to psychological, social, and sexual complication. Structured school health survey and awareness among parents can identify these abnormalities at early stage to avoid further complications later. Study was aimed at spreading awareness among parents of young children and school administration about importance of structured screening programme for detecting external genital abnormalities among the young boys to avoid various related complications later.Methods: It was a cross-sectional study covering 586 male primary school children of class I to V aged 6-12 yrs of two Schools in a capital city in northern state of India. All participants were physically examined for external genital anomalies by a trained medical officer. Data collected were analysed using standard statistical software, Statistical Programme for Social Sciences (SPSS) 15.0.Results: Abnormalities were detected in 84 (14.33%) children. Phimosis was commonest abnormality (7.5%), followed by Inguinal Hernia, Un-descended Testes, Hypospadias, Varicocele and Hydrocele. Children of parents having higher educational level were found having lesser prevalence of abnormalities.Conclusions: Diagnosis and management of abnormalities of external genitals of children is delayed due to lack of awareness among parents. Careful screening of these abnormalities at pre-school and school age, increased public awareness and early referral of children is very important to avoid the risk of having urogenital complications during adulthood.

Study of Primary Amenorrhea with etiology in out door patient of Rupganj Upazilla Health Complex

Background : Amenorrhea means without menstruation. Primary Amenorrhea is the absence of menstruation by 16 years of age in the presence of normal secondary sexual characteristics or by 14 years of age if secondary sexual characteristics have not developed.Objectives : To explore the prevalence of Primary Amenorrhea with etiology in outdoor patient with limited investigation sourcesMethods : This was a cross sectional study conducted at Rupganj Upazila Health Complex (UHC) from January 2014 to June 2016. During this period total 2500 patients attended at Gynae out patient department (OPD). Among them 45 patients was sorted out with Primary amenorrhea. History and physical examination was done for presence or absence of secondary sexual characteristics, external genital abnormalities. Investigations were ultrasonogram (USG), Hormonal test were Follicle stimulating Hormone (FSH), Lutilizing hormones (LH), Serum Prolactin, Thyroid Stimulating Hormone. Karyotyping done. Data were analysed by using SPSS version 20.Result : In our study prevalence of Primary Amenorrhea was 1.8%. Among them infantile uterus was 17.78%, imperforated hymen was 13.33%. Turner mosaic 11.4%, mullarian agenesis 6.66%, gonadal agenesis-4.45%. hypothyroid 8.89%, hyperprolactenemia-8.89%, and 11.11% patients were with positive progesterone challenge test without anatomical and hormonal abnormalities.Conclusion : Considering the study result, Infantile uterus was the most prevalent etiological factor of amenorrhoea followed by imperforated hymen and Turner mosaic.Northern International Medical College Journal Vol.9(2) Jan 2018: 300-303

E relation between isolated micropenis in childhood with CAG and GGN repeat polymorphisms in the androgen receptor gene

Background/aim: In micropenis cases accompanied by external genital abnormalities such as hypospadias and cryptorchidism, infertility and spermatogenic failures have been reported to correlate with androgen receptor ( AR ) gene CAG and GGN repeat polymorphisms. While there is one study on isolated micropenis and CAG repeats, no study related to GGN repeats has been reported. We investigated the relation between CAG and GGN repeats in the AR gene with development of penis length in boys with isolated micropenis. Materials and methods: A total of 24 Turkish boys with isolated micropenis (<–2.5 SD) and 64 healthy controls who had normal basal serum gonadotropin levels were examined. Genotyping was performed by DNA sequencing of the patients and controls. Results: The distribution of CAG and GGN repeat lengths in our patients and controls was within the normal range and did not significantly differ between the patients and the controls. Conclusion: CAG repeat length in the AR constitutes one of multiple genetic factors relevant to the development of isolated micropenis, and the expansion of this repeat can be detected as a likely modifying factor. Moreover, the interactions of other genes that may be involved in the etiology of isolated micropenis with CAG and GGN repeats have to be taken into consideration.

High Prenatal Exposure to Bisphenol A Reduces Anogenital Distance in Healthy Male Newborns.

Objective:To estimate the relationship between cord blood bisphenol A (BPA) levels and anogenital measurements in healthy newborns.Methods:Pregnancy and birth history, together with body mass and length data, anogenital measurements, penile measurements and cord blood samples were obtained from healthy newborns. Cord blood concentration of BPA was analyzed by sandwich enzyme-linked immunosorbent assays kit.Results:Among 130 healthy newborns (72 boys, 58 girls), mean anopenile distance was 45.2±6 mm and anoscrotal distance was 21.9±5.4 mm in boys; mean anoclitoral distance was 33.8±6.6 mm and mean anofourchette distance was 12.2±4.9 mm in girls. Mean cord blood BPA level was 4.75±2.18 ng/mL. 90th percentile value for cord blood BPA was 8.26 ng/mL and the analysis showed a statistically significant correlation between anoscrotal distance and cord blood BPA levels above the 90th percentile (p=0.047) in boys. The changes in anogenital distance in girls were not statistically significant.Conclusion:We showed a significant association between high cord blood BPA levels and shortened anoscrotal distance in male newborns. However, this result should be interpreted with caution since there were no significant external genital abnormalities in our study group.

External Genital Abnormalities and Inguinal Hernia among Males of Children Nurseries, North West of Iran

Background Abnormalities of external genitalia in male children nurseries and inguinal hernia are the most common congenital disorders in children. We aimed to determine prevalence rate of inguinal hernia and other genital among children nurseries, in Shahrood-Iran. Materials and Methods In this descriptive cross-sectional study, we examined 920 children nurseries boys. Physical examination of children was performed in presence of a parent in a warm room in supine and upright position with and without Valsalva maneuver. A written consent was obtained from parents before examination. Past medical history and history of surgery on inguinal and genital area was taken. Examination was performed 2 interns who were trained about genital system examination. Results A total of 920 children nurseries boys aged 3 to 6 years were examined which were detected in 88 children and prevalence rate of these abnormalities were 9.6%. The prevalence of abnormalities in the children under study were as follows: Inguinal hernia (5.1%), cryptorchidism (2.1%), Hydrocele (1.5%), hypospadias (0.4%), Varicocele (0.1%), micropenis (0.4%). Conclusion Regarding to relatively high prevalence rate of these abnormalities and low level of people knowledge, seem screening systems for diagnosis and appropriate treatment of these abnormalities to be necessary.

Evaluation of the neonates with anomalies of the external genitalia in our hospital

Evaluation of the neonates with anomalies of the external genitalia in our hospital Objective: To determine the prevalance of external genital abnormalities among neonates in our hospital. Material and Method: A total 3437 neonates delivered at Sisli Hamidiye Etfal Hospital between January 2010- December 2010 were examined at birth for external genital abnormalities. The presence of cliteromegali, inguinal / labial mass, hypospadias, micropenis, and undescended testicles and ambigus genitalia were examined. Results: The study identified 20 (6/1000) neonates with external genital abnormalities. All of them were examined within 3 days of life. Morphological abnormalities comprised: undescended testes (cryptorchidsm)(12/20), isolate hypospadias (5/20), cliteromegali (1/20), epispadias (1/20) and ambiguous genitale (1/20). The incidence of hypospadias and cryptorchidism were found 0.34%, 0.23%, respectively. Prematurity occured in 4/20 cases. Congenital adrenal hyperplasia were detected in two cases. Conclusions: External genital anomalies are among the most common congenital anomalies. Proper early diagnosis and management of genital abnormalities are of great importance to minimize medical, psychological and social complications. Our result reinforce the importance of a careful examination of genital morphology in neonatal period towards the recognition of minor defects that can be clinical features of a disorder of sex devolpoment.

Determining external genital abnormalities with a pre-circumcision examination in previously undiagnosed male school children.

We investigated whether children getting ready for circumcision under local anesthesia had any additional genital region abnormalities not detected before the circumcision. We performed circumcision under local anesthesia for children with normal physical examination findings, and together with corrective surgery for those with other genital anomalies among the children aged 6 years old and over presenting at the pediatric surgery department of our hospital during the school break. Circumcision was planned under local anesthesia in a total of 1,695 cases aged between 6 and 17 years during the June to September 2010 and 2011 periods. We found an external genital anomaly in the pre-circumcision physical examination in 58 patients (3.4%), with a mean age of 7.87 ± 1.49 years. These patients were operated on with corrective surgery while 1,637 children underwent circumcision under local anesthesia. The most common anomaly was inguinal hernia seen in 14 (24.1%), followed by hypospadias in 11 (18.9%), hydrocele in 9 (15.9%) and undescended testis in 8 (13.8%). In countries where circumcision is traditional, an intervention room within the hospital to perform circumcision under local anesthesia can enable many children to be circumcised under hospital conditions and previously undetected genital abnormalities to be found with a pre-circumcision genital region examination.

Prevalence of External Genital Abnormalities among Secondary School Pupils in Ekiti State, Nigeria

BACKGROUND/OBJECTIVE OF THE STUDY: There is paucity of information on the prevalence of external genital abnormalities in Nigeria particularly in Ekiti State. This study was designed to determine the prevalence of external genital abnormalities among primary school pupils in Ekiti State. Patients and Methods: This was a descriptive, cross sectional study that used multistage sampling to select pupils in Primary schools in the three senatorial district of Ekiti state. Pupils from ages two to sixteen years were examined by trained physicians for external genital abnormalities. Results: A total of 1200 pupils were examined, out of which 372 [31%] pupils had external genital abnormalities. M: F =1. There were 31 [2.58%] pupils with congenital external genital abnormalities out of 1200 pupils. All were males, with a prevalence of 5.18% among the boys. The prevalence of congenital external abnormalities by senatorial district was 3.43%, 1.07%, and 10.63% for Ekiti Central, North and South respectively. Right testicular volume was significantly greater than the left testis [t=3.426, P-value=0.001]. A high prevalence [56.15%] of Female Genital Cutting [FGC] was noted with the highest prevalence in Ekiti South senatorial district. Conclusion: Prevalence of Congenital external genital abnormalities is still low in this environment but the prevalence of FGC is quite high. Hydrocele, micro testis and high rising testes are the commonest congenital defects.

Analysis of clinical and genetic characteristics of 20 cases of children with Silver Russell syndrome

To improve the accuracy of the diagnosis of the disease on the basis of the clinical features and genetic characteristics of patients with Silver Russell syndrome (SRS). Patients diagnosed with SRS by Price criteria in 2006 to 2011 were reviewed for their clinical manifestations, physical signs, laboratory examinations and treatments. Twenty cases with SRS were 0.08-12.17 yr old. Fifteen were male and 5 were female. The clinical characteristics included more than 80% of cases had postnatal growth retardation 100% (20/20), craniofacial dysmorphism 100% (20/20), small for gestation age 95% (19/20), asymmetry and thinning of the face and/or limbs 90% (18/20), fifth finger clinodactyly 80% (16/20), BMI < -2 SDS 80% (16/20). Their height was obviously lagging behind in the bone age. HD SDS/average of bone retardation was 3.08. The two patients with the chief complaint of external genital abnormalities would have aggressive surgical treatment and they did not use the growth hormone (GH) treatment. Only six patients had used the GH treatment. GH treatment at a dose of 0.1 IU/(kg·d) used in 2 cases achieved a growth velocity (GV) 8 - 11 cm/yr but in another 2 cases < 5 cm/yr. In genetic study, 6 patients were found to have 11p15 low methylation, 1 had low and high methylation, 1 had duplication, no relation between clinical and methylation of 11p15 was found. There were great variations of clinical features in SRS characterized by small for gestation age and/or postnatal growth retardation, craniofacial dysmorphism, asymmetry of the face and/or limbs or ultrafine limbs, fifth finger clinodactyly. Severely low BMI was seen and height was obviously lagging behind in the bone age. The findings of laboratory tests and imaging of SRS were not specific. Some of SRS had 11p15 imprinting defects. The treatment of SRS is mainly symptomatic.

Türkiye’de Okul Çağındaki Erkek Çocuklarda Dış Genital Anomaliler: Epidemiyolojik Değerlendirme

Objective: Our aim is to determine the prevalence of undiagnosed external genital abnomalities in school-age boys in our region. Material and Methods: Five thousand sixty-one Turkish primary school boys between the ages of 7 and 13 years (mean age 10.9 years) were examined regarding to external genital abnormalities. Physical examinations were performed in standing position initially and then in supine position when necessary. All boys were questioned closely regarding symptoms (such as scrotal pain) and awareness of any abnormality. Results: Abnormalities of the external genitalia were found in 243 (4.80%) of the boys. Of these, 75 (1.48%) had varicocele, 73 (1.44%) had undescended testis, 40 (0.79%) had indirect inguinal hernia, 29 (0.57%) had hydrocele and 23 (0.45%) had hypospadias. Other rarely diagnosed abnormalities were poliorchidism, paratesticular mass and penile curvature. Of the boys with varicocele, 14.6% had grade I, 77.3% had grade II and 8% had grade III disease according to Dubin and Amelar's grading system. Fifty percent of undescended testes were right-sided and the others were either left-sided or bilateral. Conclusion: High prevalence of external genital abnormalities in our region is remarkable. Poor primary healthcare and socio-economic factors might have been contributed to this issue.

Aphalangia possibly linked to unintended use of finasteride during early pregnancy

Aphalangia possibly linked to unintended use of finasteride during early pregnancy

SIMPLIFIED MONS PLASTY: A NEW TECHNIQUE TO IMPROVE COSMESIS IN FEMALES WITH THE EXSTROPHY-EPISPADIAS COMPLEX

Long-term data suggest that a significant number of women with the exstrophy-epispadias complex (EEC) report dissatisfaction with the cosmetic appearance of the genitalia. We developed a new technique of mons plasty in an attempt to improve the overall cosmetic appearance of the external genitalia in females with EEC. Nine consecutive females with a mean age of 6.4 years (range 2 days to 12.2 years) previously diagnosed with EEC underwent simplified mons plasty concomitantly with various other urological reconstructive procedures. Briefly, a simplified mons plasty was performed by approximating the bifid hemiclitoris and subsequently incising the lateral sulci between the labia majora and minora, which allowed the superomedial rotation of the labia majora and underlying peripubic adipose tissue, thus, recreating the mons. There were no perioperative complications. With a mean followup of 6 months (range 4 to 12) all patients had improved cosmesis with respect to a more prominent mons, more appropriately situated labia and adequately recessed introitus. Simplified mons plasty improves cosmesis in females with external genital abnormalities secondary to EEC. Although our followup is admittedly short, we believe that this technique should be considered in the armamentarium of the reconstructive surgeon during the operative treatment of this complex group of patients.

External genital abnormalities in male schoolchildren: an epidemiological study

External genital abnormalities represent the most common congenital anomalies. Proper, not delayed diagnosis and treatment of certain abnormalities (undescended testis, hypospadia, varicocele) is of great importance for future fertility potential of children. An epidemiological study, that consisted of an urological checkup, was performed among school-aged boys in two elementary schools. Prevalence of external genital, and inguinal region was examined. A total of 1229 elementary school boys were examined. The incidence of external genital abnomalities was 27.8%. Certain anomalies were already surgically treated in 7.8% of boys. Phimosis wasfound in 66 patients (5,5%), which represents 26.6% of all abnomalities. In this study the incidence of undescended testis was 2.0%. Although it is similar to literature data, the fact that undescended testis was found in 25 boys older than 7 years (two of them 15 years old!) suggests that the primary health care is not satisfactory. The incidence of inguinal hernia and hydrocele varies according to different authors from 0.8-4.4% to 13.44%. In this study the incidence was 2.4%. Varicocele represents a developmental anomaly and the incidence is increasing with age. It is rare in boys up to 10 years of age, but the incidence of varicocele in boys aged 15 years (15.8%) reaches the level of incidence in adults (19.82%). The incidence of phimosis in this study was 5.5%. High incidence of external genital abnormalities in school aged boys suggests a need for further education of physicians in primary health care services as well as of parents.

Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta).

In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring was performed during the course of gestation to monitor viability, growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (i.v.) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least 60-750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities were observed in either male or female fetuses of mothers given iv doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the i.v. formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5 alpha R isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5 alpha R inhibitors administered during pregnancy.