Marlene Inacio

Male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency. Diagnosis, psychological evaluation, and management

Sixteen subjects (from 10 Brazilian families) with male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency have been evaluated in 1 clinic. The diagnoses were made on the basis of normal plasma testosterone values, normal or low plasma dihydrotestosterone levels and high testosterone/dihydrotestosterone ratios in the basal state in postpubertal subjects or after treatment with either human chorionic gonadotropin or testosterone in prepubertal subjects. The analysis of the ratios of etiocholanolone to androsterone in urine confirmed the diagnosis in all subjects who were tested, and the molecular basis of the underlying mutations was established in 9 of the families. Fourteen of the individuals were evaluated by the same psychologist. All subjects but 1 were given a female sex assignment at birth. Three of the subjects (1 the sibling of an individual who has undergone female to male social behavior) maintain a female social sex; they have been gonadectomized and treated with exogenous estrogens. Ten of 13 subjects of postpubertal age underwent a change of social sex from female to male, had surgical correction of the hypospadias, and were treated with high-dose testosterone esters by parenteral injection and subsequently with dihydrotestosterone cream. These regimens brought serum dihydrotestosterone levels to the normal male range (or above) but resulted only in limited growth of the prostate and penis and, in some, increase in body and facial hair and enhancement of libido and sexual performance. Treatment of the prepubertal boys with testosterone and/or dihydrotestosterone resulted in a doubling of penis size.

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management.

Ten male pseudohermaphrodites with 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency were evaluated in 1 clinic with an average follow-up of 10.1 years. The diagnoses were made by demonstrating low to normal serum testosterone levels, high androstenedione levels, and high ratios of serum androstenedione to testosterone in the basal state or after treatment with human chorionic gonadotropin. The molecular features of the underlying mutations were identified in all 7 families. Two additional males in the same families are believed to be affected on the basis of history obtained from family members. All of the 46,XY individuals in these families were registered at birth and raised as females (despite the presence of ambiguous genitalia in all or most), and all virilized after the time of expected puberty due to a rise in serum testosterone to or toward the normal male range. The age at diagnosis varied from 4 to 37 years. Ten individuals were studied by the same psychologist, and change of gender role (social sex) from female to male occurred in 3 subjects and in the 2 presumed affected subjects not studied. The individual with the highest serum testosterone level maintained female sexual identity, and in 2 families some of the affected males changed gender role and others did not. Thus, while androgen action plays a role in the process, additional undefined psychological, social, and/or biologic factors must be determinants of gender identity/role behavior. Management of the 7 individuals who chose to maintain female sex roles included castration, clitoroplasty, vaginal enlargement procedures when appropriate, treatment of hirsutism, cricoid cartilage reduction, and estrogen replacement. Three of the 7 are married (2 twice), 1 is involved in a long-term heterosexual relationship, 1 is engaged to be married, and the other 2 are not married and not believed to be sexually active. The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy. One of these men is divorced, and the other 2 (aged 29 and 35 years) are unmarried. The diagnosis in 8 of these subjects was made after the time of expected puberty; it is unclear whether the functional and social outcomes would have been different if the diagnosis had been made and therapy begun earlier in life.

Management of ambiguous genitalia in pseudohermaphrodites: new perspectives on vaginal dilation.

OBJECTIVE To evaluate vaginal size and sexual activity after different techniques of feminization of external genitalia in patients with pseudohermaphroditism. DESIGN Retrospective clinical study. SETTING Pseudohermaphrodite patients seen at our institution. PATIENT(S) Three female and 20 male pseudohermaphrodites raised as females. INTERVENTION(S) Bilateral orchidectomy, feminization of external genitalia (clitoridectomy or clitoroplasty, urogenital sinus enlargement), and/or neovaginoplasty or vaginal dilation with acrylic molds. MAIN OUTCOME MEASURE(S) Psychological evaluation, vaginal size, and quality of intercourse. RESULT(S) All patients referred sexual drive to men. Fifty percent of the patients who were submitted to neovaginoplasty referred pain or bleeding during sexual intercourse. On the other hand, 87% of the patients who were submitted to vaginal dilation with acrylic molds, after genitoplasty or not, referred satisfactory sexual intercourse. All patients who were submitted to clitoroplasty referred orgasm and 29% of the patients submitted to clitoridectomy referred no orgasm. Of three patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, two became pregnant and delivered normal children through cesarian section. CONCLUSION(S) In pseudohermaphrodites with female social sex, surgical correction of external genitalia performed in childhood and vaginal dilation with acrylic molds performed when they wished to start having sexual intercourse resulted in best outcome.

Long-Term Surgical Outcome of Masculinizing Genitoplasty in Large Cohort of Patients With Disorders of Sex Development

PURPOSE We evaluated the results of masculinizing genitoplasty in a large cohort of patients with disorders of sex development treated at a single public tertiary center. MATERIALS AND METHODS We evaluated 52 patients with 46,XY and 7 with 46,XX disorders of sex development with proximal hypospadias and genital ambiguity reared as males who had undergone surgery between 1965 and 2008. Mean +/- SD followup was 14.1 +/- 9.2 years and median age at last examination was 22 years, with 38 patients having reached adulthood. Morphological result and urinary stream were evaluated by a physician. Urinary and sexual symptoms, and satisfaction with surgical results were assessed by questionnaire. RESULTS Mean penile length at diagnosis was compared between 46,XY patients and showed that those with 5alpha-reductase 2 deficiency had the shortest penile length (-5.4 +/- 1.2 SD). At the last clinical evaluation following surgical and hormonal treatment mean +/- SD penile length in 38 adults was 7.5 +/- 2.1 cm (range 4 to 12), corresponding to -4.3 +/- 1.3 SD (-6.5 to -1.5). All but 2 patients had penile length less than -2 SD. At that time mean penile length remained shorter in patients with 5alpha-reductase 2 deficiency (-5.4 +/- 1 SD) compared to those with testosterone production deficiency or indeterminate disorders of sex development (p <0.05). There was no statistical difference between mean penile length before and after treatment in all etiological groups (p >0.05). Morphological results were good in 43% of patients, fair in 54% and poor in 3%. The most common complications were urethral fistula (51%) and urethral stenosis (22%). Dribbling after voiding was the most frequent urinary symptom. Satisfaction with surgical results was reported by 89% of patients. Among adults 87% were sexually active, with 64% reporting normal sexual activity. CONCLUSIONS Most patients with 46,XY disorders of sex development were satisfied with long-term results of masculinizing genitoplasty, although specific complaints about small penile length, sexual activity and urinary symptoms were frequent. New surgical approaches should be developed to ensure full satisfaction in adulthood among patients with disorders of sex development.

DSD Due to 5 alpha-Reductase 2 Deficiency - from Diagnosis to Long Term Outcome

Most of the patients with 5α-RD 2 deficiency are reared in the female social sex due to their severely undervirilized external genitalia but ~60% who have not been submitted to orchiectomy in childhood undergo male social sex change at puberty. In our cohort of 30 cases from 18 families, all subjects were registered in the female social sex except for two children-one who had an affected uncle and the other who was diagnosed before being registered. The majority of the patients were satisfied with the long-term results of their treatment and surprisingly, penile length was not associated with satisfactory or unsatisfactory sexual activity. Steroid 5α-RD2 deficiency should be included in the differential diagnosis of all newborns with 46,XY DSD with normal testosterone production before gender assignment or any surgical intervention because these patients should be considered males at birth.

Quality of life of patients with 46,XX and 46,XY disorders of sex development

Disorders of sex development (DSD) result from abnormalities in the complex process of sex determination and differentiation. An important consideration to guide the assignment of social sex in newborns with ambiguous genitalia is the quality of life (QoL) of these patients in adulthood. The rarity of most DSD conditions makes it difficult to conduct a long‐term follow‐up of affected patients through adulthood. This review of papers on the QoL of DSD patients evaluated in developing and developed countries by qualitative and quantitative instruments revealed a large spectrum of QoL, ranging from very poor to similar to, or even better than, the normal population. A more adequate QoL was found in patients from tertiary centres, indicating that the medical care of DSD patients should be multidisciplinary and carried out by specialized teams.

Long-Term Followup of a Large Cohort of Patients with Ovotesticular Disorder of Sex Development

PURPOSE We present the followup of a large cohort of patients with ovotesticular disorder of sex development treated at a single tertiary center. MATERIALS AND METHODS We reviewed the records of 20 patients with ovotesticular disorder of sex development. We retrospectively evaluated clinical and surgical characteristics. A prospective study was also performed, including evaluation of surgical results, gonadal function, sexual activity and voiding symptoms of these patients during adulthood. RESULTS All patients had ambiguous genitalia, including 18 with a 46,XX karyotype and 2 with a 46,XX/46,XY karyotype. Gender assignment at birth was male in 13 patients and female in 7. Three females were later reassigned to the male gender. Bilateral gonadectomy was performed in 10 patients. Testicular tissue was preserved in 8 males and ovarian tissue was preserved in 2 females. Average followup was 25 years (range 4 to 46). Puberty started spontaneously in 14 patients between ages 11 and 14 years. Seven patients showed spontaneous puberty after conservative gonadal surgery and 4 required hormonal replacement during adulthood. The most frequent complications in males were urethral fistula in 6 and late urethral stenosis in 3. Two patients with urethral stenosis had symptoms 10 years postoperatively. One female presented with temporary dyspareunia. In adulthood 8 males and 2 females reported sexual activity. All male patients reported orgasm and 2 reported ejaculation. CONCLUSIONS Male gender assignment was more prevalent. Long-term followup revealed adequate pubertal development and sexual activity. Complications involving the urethra developed frequently in male patients.

Quality of life in a large cohort of adult Brazilian patients with 46,XX and 46,XY disorders of sex development from a single tertiary centre

Few studies have focused on the quality of life (QoL) of patients with disorders of sex development (DSD). Our aim was to evaluate QoL in DSD patients with defined diagnoses followed until adulthood in a single tertiary centre.

46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency

17β-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17β-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17β-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5α-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17β-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the previously reported cases of 17β-HSD3 deficiency adding our own cases.

Successful Live Birth in a Woman With 17α-Hydroxylase Deficiency Through IVF Frozen-Thawed Embryo Transfer

CONTEXT Congenital adrenal hyperplasia (CAH) due to 17α-hydroxylase deficiency in 46,XX patients is characterized by primary amenorrhea, absent or incomplete sexual maturation, infertility, low serum levels of estradiol, and elevated progesterone (P). There were no previous reports of singleton live births from such women. OBJECTIVE To describe the first successful singleton live birth in a female with CAH due to 17α-hydroxylase deficiency. CASE DESCRIPTION A 26-year-old Brazilian woman with CAH associated with 17α-hydroxylase deficiency due to the compound heterozygote mutation (p.W406R/P428L) in the CYP17A1 gene expressed the desire to conceive. In vitro fertilization (IVF) was recommended due to the complexity of the disorder. The first attempt of treatment failed despite the production of viable embryos. At the second IVF attempt, all viable embryos were frozen due to inadequate endometrial development associated with prematurely elevated serum P during ovarian stimulation. Subsequently, a long-acting GnRH agonist and oral dexamethasone were used to lower ovarian and adrenal P overproduction. Once serum levels of P were < 1 ng/mL, endometrial preparation with estradiol valerate and frozen-thawed embryo transfer were performed, resulting in a singleton pregnancy. Estradiol supplementation was completely suspended by 14 weeks of gestation. She delivered at 30 weeks and 4 days due to acute fetal distress. The puerperium was uneventful; the newborn was discharged in good conditions 5 weeks after birth. CONCLUSION A successful live birth was achieved in a woman with 17-hydroxylase deficiency through IVF, cryopreservation of all embryos, and frozen-thawed embryo transfer after adequate endometrial preparation.