Canary in the Coal Mine? Male Infertility as a Marker of Overall Health.

Male factor infertility is a common problem. Evidence is emerging regarding the spectrum of systemic disease and illness harbored by infertile men who otherwise appear healthy. In this review, we present evidence that infertile men have poor overall health and increased morbidity and mortality, increased rates of both genitourinary and non-genitourinary malignancy, and greater risks of systemic disease. The review also highlights numerous genetic conditions associated with male infertility as well as emerging translational evidence of genitourinary birth defects and their impact on male infertility. Finally, parallels to the overall health of infertile women are presented. This review highlights the importance of a comprehensive health evaluation of men who present for an infertility assessment.

A Pilot Survey of Indian Stakeholders: Parents, Doctors, and Grown-Up Patients of Disorders of Sexual Differentiation on Management Decisions and Associated Gender Dysphoria.

Background and Aims: Of late, there are many legal representations from select quarters to halt all medical interventions in children with differences of sex development (DSD). In this survey on management decisions in DSD, we distil the views of Indian stakeholders: parents, physicians, and grown-up patients with DSD on their management decisions to identify decisional satisfaction or gender dysphoria. Methods: The survey domains included the patient demographics, final diagnosis, decision on the sex of rearing, surgical interventions, opinion of the stakeholders on the preferred age of sex assignment, final sex of rearing, and agreement/disagreement about sex assignment (gender dysphoria). Results: A total of 106 responses were recorded (66% parents, 34% grown-up patients aged 12-50 years). Among parents, 65/70 (95%) preferred the sex to be assigned soon after birth. All grown-up patients preferred sex to be assigned soon after birth. Regarding decisions on surgery, 74% of physicians and 75% of the grown-up patients felt parents should be allowed to decide interventions. Among Indian parents, 90% felt they should have the right to decide surgery in the best interest of their child for a safe social upbringing. Overall, gender dysphoria among Indian DSD patients was <1% (1/103, 0.97%). Conclusions: The predominant preference and opinion of major Indian stakeholders (physicians, parents, and grown-up DSD patients) support the existing approach toward DSD management, including early sex assignment and necessary medical intervention.

Posterior Sagittal Approach for Nonanorectal Malformation: Widening Spectrum.

Background: Posterior sagittal is a very well accepted approach in the treatment of anorectal malformations. This approach provides good access and exposure through the perineum to the deep pelvic structures. It reduces risk of injury to important structures as dissection remains in midline. Aims and Objectives: To access feasibility of posterior sagittal approach for non-anorectal malformation indications and to widen the spectrum. Material and Methods: We present a series of 10 cases of non-anorectal malformations operated by this approach for 4 years. Results: Six patients included in the study were of Disorders of Sexual Differentiation with pseudovagina, three of Y duplication of the urethra, and one of cervical atresia. All patients had good results. Conclusion: Posterior sagittal approach is feasible, safe with minimal bleeding, and no postoperative incontinence. It can safely be used for non-anorectal indications.

A 10-YEAR STUDY OF CHILDREN WITH GONADAL TUMORS AND DISORDERS OF SEX DIFFERENTIATION, IN ROMANIA.

Context: Children having gonadal tumors and disorder of sex differentiation (DSD) are rare. Objective: To investigate the presentation of DSD children with malignant gonadal tumors. Methods: A retrospective study from 2010-2020, that evaluated 17 children with DSD, including 13 females, eight months to 16 years, with congenital adrenal hyperplasia, 5-alpha reductase deficiency, androgen insensitivity syndrome, Turner, Sywer, and Klinefelter syndromes. Results: Ten children had malignant gonadal tumor; nine had germ cell tumors and one person granulosa cell tumors, while seven children with non-malignant tumor had gonadoblastoma, cystadenoma (five children), and cysts. Systemic malformations, obesity, elevated tumor markers, and psychosocial issues were observed in 90%, 90%, 70%, and 50% of children with malignancy unlike 28.6%, 42.9%, 14.35%, and 57.1% children without malignancy respectively. Most (9/10) children >12 years, had psychosocial issues, unlike 0/7 children ≤12 years. From 8/17 children presenting with symptoms suggestive of tumor, 75% had malignancy, while from 9/17 children with DSD presentation, 44% had malignant tumors. Malignancy was observed in 3/10 children between eight months to age six, while 7/10 children had stage 1-2 tumors. We reported a child, identified as female, aged 13 years, with partial androgen insensivity syndrome (PAIS) 46,XY, and testicular papillary serous cystadenoma with genomic variant AR NM_000044.4:c.2750del. p.(F917Sfs*27) chromosome Xq12, never published in people with PAIS nor population databases (GnomAD). Conclusion: DSD diagnosis raises numerous challenges. People with DSD have increased risk of malignancy, especially when obesity and, systemic malformations are present; also, psychosocial issues in these children are associated with postpubertal age.

POI after chemotherapy and bone marrow transplant may mimic disorders of sexual differentiation - a case report of a patient with primary amenorrhea and 46, XY karyotype.

Cytogenetic examination may be useful in determining the reason for primary amenorrhea in phenotypically female patients. The result 46, XY usually indicates two syndromes: complete androgen insensitivity or pure gonadal dysgenesis. We report a case of a patient, who due to acute lymphoblastic leukemia in childhood was treated with total body irradiation and bone marrow transplantation. Later on the patient presented with symptoms typical for premature ovarian failure and male karyotype in peripheral lymphocytes. The cytogenetic examination for peripheral cells showed normal female karyotype. Therefore, it has been concluded that ovarian function impairment resulted rather from the gonadotoxic effect of oncological treatment than as a disorder of sexual differentiation. The survival rates of childhood cancer are very high and some of the patients will experience premature ovarian failure. It must be remembered that after bone marrow transplantation karyotype of peripheral lymphocytes may be misleading.

Feminizing Genitoplasty in a young girl with Glanzmann's thrombasthenia-management of haemostasis.

We report peri- and post-operative management of haemostasis in a 11-year old girl with Glanzmann Thrombasthenia (GT) who had feminizing genitoplasty for genital ambiguity due to Congenital Adrenal Hyperplasia (CAH-21 Hydroxylase deficiency). A blend of Glanzmann Thrombasthenia (GT) and DSD 46XX due to CAH is not reported in literature. Surgery particularly genitourinary reconstruction in patients with GT is challenging due to risk of intra and post-operative bleeding. Haemostasis can successfully be achieved with platelet transfusions, antifibrinolytic (Tranexamic acid) and judicious use of recombinant factor VIIa (rFVIIa) even in a resource limited setting.

Role of testosterone and Y chromosome genes for the masculinization of the human brain.

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. METHODS: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. RESULTS: Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern. CONCLUSION: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. © 2017 Wiley Periodicals, Inc.

Concepts and Updates in the Evaluation and Diagnosis of Common Disorders of Sexual Development.

Our understanding of disorders of sexual differentiation (DSD) has evolved from aberrations of human genital development to a broad group of complex disorders of etiological and functional significance. The unique challenge of DSD conditions is that they create a cause for significant angst and concern for both parents and physician, as they frequently lead to questions with regards to gender assignment, surgically corrective options, long-term outlook regarding gender identity, and reproductive potential. To further add to the burden, many patients who present with genital abnormalities do not have a clear explanation as to the underlying basis of their disorder. This review looks at DSD from a pediatric urology point of view with emphasis on evaluation, diagnosis, and algorithm for work-up. We also discuss novel genetic analysis techniques and their value in diagnosis. Overall, this is an all-encompassing review on a diagnostic approach to DSD, with inclusion of recent developments and controversies, which will benefit urologists and other physicians alike.

Disorders of sexual development: structured radiological reporting and practical approach.

Disorders of sexual development (DSD) comprise a complex group of conditions with varied clinical presentations, such as atypical genitalia, non-palpable testes, primary amenorrhea, or infertility. Besides being associated with other congenital anomalies, DSDs bear substantial ethical issues regarding assigning the sex of rearing to the child and future fertility options. Establishing the correct diagnosis is essential for the appropriate management of such cases. Various imaging modalities, such as ultrasonography, genitography, and MRI, when complemented with detailed clinical evaluation and karyotyping, are the key to diagnosing the condition. This article attempts to present a concise approach to various patterns of DSD, which will aid radiologists to solve these diagnostic dilemmas.

Insights into enlarged prostatic utricles and Müllerian duct system remnants associated with posterior hypospadias.

INTRODUCTION: The prostatic utricle (PU) consists of the caudal remnant of the Müllerian duct and the urogenital sinus. The term "vagina masculina" is used if other Müllerian structures are associated with the PU. This work aims to investigate the incidence, management, and follow up of enlarged PUs and Müllerian remnants in males with posterior hypospadias. PATIENTS AND METHODS: This study presents a retrospective review of cases presented with posterior hypospadias over a 5-year period. Prior to hypospadias repair, retrograde urethrograms were used to investigate enlarged PU. Subsequently, they were classified according to the Ikoma score and further assessed by karyotyping and cystoscope. Surgical excision was indicated in cases with symptomatic utricles or vagina masculina. RESULTS: Thirty patients were included in the study in the period between 2015 and 2020 (Table). All cases were asymptomatic initially. Twelve patients were diagnosed with enlarged PU; three of them had vagina masculina. One case with perineal hypospadias had a separate perineal opening for PU. Following hypospadias repair, three of the eight cases treated conservatively turned symptomatic. DISCUSSION: The incidence of enlarged PU and Müllerian remnants varied among different studies. However, it increased as the severity of hypospadias increased. Preoperative urethrogram was helpful in the diagnosis and classification of PU, but it had its limitations. Cystoscope was more advantageous in diagnosing vagina masculina. Although most cases were asymptomatic, some turned symptomatic after hypospadias repair. Some cases with perineal hypospadias had PU with a separate perineal opening. CONCLUSION: The incidence of enlarged PUs or Müllerian remnants was 40%. Although cases were asymptomatic before hypospadias surgery, some cases turned into symptomatic after hypospadias repair. In some cases, the PU or Müllerian remnants had a separate perineal opening. They can be classified as a particular form of Ikoma grade III necessitating surgical intervention.

Novel STAR Gene Variant of Congenital Lipoid Adrenal Hyperplasia With Testicular Adrenal Rests.

A mutation in the steroidogenic acute regulatory protein (STAR) gene, which encodes a protein that plays a crucial role in steroid hormone synthesis, causes a severe form of congenital adrenal hyperplasia (CAH) known as lipoid CAH (LCAH). LCAH presents with primary adrenal insufficiency (PAI) as well as atypical genitalia. Individuals with LCAH require adrenal steroid hormone supplements for survival. Masculinization in males with STAR deficiency varies from incomplete to normal virilization. Radiological examinations reveal enlarged and lipid-laden adrenals. A 10-year-old boy born of second-degree consanguinity presented with weight gain and hyperpigmentation for 1 year. He was diagnosed with PAI at age 7 months and treated with hydrocortisone and fludrocortisone. Dynamic adrenal gland testing revealed undetectable hormone reserves. Imaging detected hypoplastic adrenals and a small testis with testicular adrenal rests (TART). Genetic analysis indicated a novel homozygous pathogenic variant of STAR in exon 7, c.814C > G(pArg272Gly) associated with LCAH (OMIM No. 201710). Testing revealed that asymptomatic family members and relatives were heterozygotes for the variant. The patient was diagnosed with nonclassic LCAH with hypoplastic adrenals and TART. Adequate hormone supplementation resulted in TART regression. This genetic variation is reported for the first time.

Gender identity disorder (GID) in adolescents and adults with differences of sex development (DSD): A systematic review and meta-analysis.

Gender assignment in infants born with a difference in sexual development (DSD) remains one of the many difficult decisions faced by the multi-disciplinary treatment team as some of these children develop gender identity disorder (GID) when they become adults. In this systematic review and meta-analysis we have analyzed the prevalence of GID in adolescent and adults with DSD. The secondary outcome of this review is to help physicians in appropriate sex assignment of DSD children so that development of GID in later life can be reduced. METHODS: Pubmed/Index medicus were searched for "intersex" [All fields] OR "disorders of sexual differentiation AND "gender identity disorder OR gender dysphoria" [MeSH] for articles published between 2005 and 2020. Typical diagnoses included were congenital adrenal hyperplasia (CAH); complete androgen insensitivity syndrome (CAIS); partial androgen insensitivity syndrome (PAIS); 5 alpha reductase deficiency (5ARD); 17-hydroxysteroid dehydrogenase deficiency (17HSD); mixed gonadal dysgenesis (MGD) and complete gonadal dysgenesis (CGD). GID or gender dysphoria (a strong feeling of dissatisfaction about oneself as male or female) prevalence in DSD patients older than 12 years of age was extracted. Within each condition, GID percentage was compared between female and male rearing. RESULTS: The I2statistics for prevalence of GID in DSD showed high heterogeneity with I2 of 93% (95% C.I 90-95%) among the 20 articles included. The overall prevalence of GID among those with DSD was 15% (95% C.I 13-17%). CAH reared females had 4% GID while CAH reared males had significantly higher GID at 15% (p = 0.0056). All CAIS patients were raised as females and the prevalence of GID was 1.7%. GID prevalence was 12% in PAIS raised as females while 25% in those raised as males with no significant difference (p = 0.134). GID was significantly high in 5ARD (53%) and 17HSD (53%) reared as females with half of them virilizing at puberty forcing a gender change. Among sex chromosome DSD 22% of those reared as females had GID while none in those raised as male with no significant difference. CONCLUSIONS: GID is low in women with CAH, CAIS and CGD favoring female sex of rearing in these conditions. GID is high in women with 5ARD/17HSD favoring male sex of rearing in these conditions. GID is variable in PAIS or MGD and no recommendations on sex of rearing could be made in these conditions. Each DSD patient is unique and they warrant multi-disciplinary care and long term psycho sexual support.

Why are there no platypuses at the Olympics?: A teleological case for athletes with disorders of sexual development to compete within their sex category.

In mid-2019, the controversy regarding South African runner Caster Semenya's eligibility to participate in competitions against other female runners culminated in a Court of Arbitration for Sport judgement. Semenya possessed high endogenous testosterone levels (arguably a performance advantage), secondary to a disorder of sexual development. In this commentary, Aristotelean teleology is used to defend the existence of 'male' and 'female' as discrete categories. It is argued that once the athlete's sex is established, they should be allowed to compete in the category of their sex without obligatory medical treatment. Indeed, other athletes who possess advantageous genetic or phenotypic traits that fall outside of the human norm have been allowed to compete as humans without restraint. In both cases, if an athlete possesses the essential attributes of being a human or being male or female they should be permitted to compete in those respective categories; athletes' eligibilities should not be based upon accidental attributes.

A Case of Mixed Gonadal Dysgensis: A Diagnostic Challenge.

A 2-year-old child reared as a girl child was brought by parents with ambiguous genitalia noticed since birth. There was no history of failure to thrive or salt-losing crisis. On examination, the child had normal height and weight with normal blood pressure and no dysmorphism or Turners stigmata with external genitalia Prader Score 2. Ultrasound of the pelvis revealed hypoplastic uterus with no gonads visualized. There was no evidence of hypocortisolemia (8 am cortisol 14.08 mcg/dl) or elevated level of 17-OH-progesterone (1.1 ng/mL). Pooled follicle-stimulating hormone and luteinizing hormone levels were 2.66 mIU/ml and 0.1 mIU/ml, respectively, thyroid-stimulating hormone: 2.36 mIU/L, T4: 134.5 nmol/L, total testosterone: 2.5 ng/dl. Posthuman chorionic gonadotropin stimulation showed total testosterone levels 267 ng/dL, dihydrotestosterone: 155 pg/mL, androstenedione: 0.3 ng/mL indicating functioning testicular tissue without any evidence of 17-beta hydroxylase or 5-alpha reductase deficiency. Karyotyping revealed 45, XO genotype on two separate occasions. In view of the discrepancy between karyotype finding and ultrasound reports with the clinical and hormonal picture, fluorescence in situ hybridization cytogenetic study was carried out and showed MONOSOMY X (90% cells)/SEX ANEUPLOIDY XYY (10% cells). Laparoscopic examination showed gonad in the right ovarian fossa and left streak gonad with bilateral fallopian tubes and hypoplastic uterus. Genitoscopy showed normal vagina and cervix. Cystoscopy showed normal urethra and urinary bladder. Biopsy was taken from both gonads. A thorough histopathological examination of this specimen showed the structure of seminiferous tubules with Leydig cells in the right gonad with streak ovary on the left side. The child underwent bilateral gonadectomy and rehabilitated her to lead a life as a girl.

Is interstitial 8p23 microdeletion responsible of 46,XY gonadal dysgenesis? One case report from birth to puberty.

BACKGROUND: Chromosome 8p deletions are associated with a variety of conditions, including cardiac abnormalities, mental, behavioral problems with variable morphotype and genitourinary anomalies in boys. METHODS: We describe the follow-up over almost 15 years of a boy who initially presented with perineal hypospadias with a micropenis and cryptorchidism with 46,XY DSD. RESULTS: Imaging, pathology, and hormonal exploration suggested gonadal dysgenesis. Further genetic studies were deemed necessary during follow-up. The child's further development recommended further genetic analyses. High-resolution analysis showed an interstitial deletion on the short arm of a chromosome 8: 46,XY,del(8)(p23.1p23.1). We reviewed the literature and found 102 cases including 54 boys: 62.7% had mental problems, 50.9% a dysmorphic disorder, 55.9% cardiac anomalies, and 46.3% of the boys had genitourinary anomalies. Our patient's genital abnormalities can be explained by the haploinsufficiency of the genes, such as GATA4 (OMIM 600576) that are included in the deleted area. CONCLUSION: This case of severe 46,XY DSD raises the question of the role played by 8p23 microdeletion in gonadal dysgenesis. Clinicians are encouraged to look for this anomaly on chromosome 8 in cases of unexplained gonadal dysgenesis even when few signs suggestive of this anomaly are present.

Teleology and Defining Sex.

Disorders of sexual differentiation lead to what is often referred to as an intersex state. This state has medical, as well as some legal, recognition. Nevertheless, the question remains whether intersex persons occupy a state in between maleness and femaleness or whether they are truly men or women. To answer this question, another important conundrum needs to be first solved: what defines sex? The answer seems rather simple to most people, yet when morphology does not coincide with haplotypes, and genetics might not correlate with physiology the issue becomes more complex. This paper tackles both issues by establishing where the essence of sex is located and by superimposing that framework onto the issue of the intersex. This is achieved through giving due consideration to the biology of sexual development, as well as through the use of a teleological framework of the meaning of sex. Using a range of examples, the paper establishes that sex cannot be pinpointed to one biological variable but is rather determined by how the totality of one's biology is oriented towards biological reproduction. A brief consideration is also given to the way this situation could be comprehended from a Christian understanding of sex and suffering.

The modified Ulaanbaatar procedure: Reduced complications and enhanced cosmetic outcome for the most severe cases of hypospadias.

INTRODUCTION/OBJECTIVE: Proximal hypospadias is one of the most challenging conditions that pediatric urologists have to deal with. Many procedures have been devised over the years, but nothing has been proven to be the best option. Although there have been some attempts at correcting severe hypospadias in one procedure, most have advocated a staged approach. The classic approach - laying penile skin or a graft within a split glans followed by glanuloplasty at the second stage - by definition requires two operations on the glans. In the Ulaanbaatar procedure the distal glanular urethra is constructed at the first stage, allowing for a single glans procedure and thus potentially better cosmetic outcomes. The present study discusses experience with the Ulaanbaatar procedure for severe hypospadias. STUDY DESIGN: The study retrospectively reviewed every child who underwent both stages of this procedure at the present institution. It reviewed age, associated diagnoses, surgical technique and outcomes. SURGICAL TECHNIQUE: The first stage was analogous to a classic first-stage procedure with regard to division of the urethral plate and correction of penile curvature. However, an island flap of preputial skin was mobilized and tubularized to create the glanular urethra. No attempt was made to bridge the native meatus and this reconstructed urethra, and the remaining penile skin was placed between the two. The second stage was performed 6 months later by tubularizing the penile skin between the two meatuses. RESULTS: The series consisted of 34 boys. Mean age at surgery was 18.3 months (range 6-118). Nineteen underwent evaluation for genital ambiguity at birth (56%). Thirty (88%) received pre-operative testosterone or human chorionic gonadotropin (HCG). After urethral plate transection, persistent curvature was addressed during the first stage, with dorsal plication in 12 (35%), urethral plate transection alone in six (18%) or ventral grafting with small intestinal submucosa in 16 (47%). Twenty-three boys (67%) had the neourethra tunneled through the glans, and 11 (33%) had the glans split followed by glanuloplasty. Average time between the two stages was 7 months (range 4.0-13.9). Four patients (12%) developed urethral diverticula that required repair. One developed recurrent epididymitis related to an abnormal ejaculatory duct (no stricture) and underwent vasectomy. No patient developed a fistula. Mean length of follow-up was 15.2 months (range 0.3-55.5). DISCUSSION: This modification of the classic staged hypospadias repair may allow for better cosmetic outcome, since the majority of boys required no formal glanuloplasty. There were reduced complications, perhaps because the urethral defect acted like a controlled fistula, allowing for better tissue healing prior to final urethral reconstruction.

Reprint of "Steroid 5α-reductase 2 deficiency".

Dihydrotestosterone is a potent androgen metabolite formed from testosterone by action of 5α-reductase isoenzymes. Mutations in the type 2 isoenzyme cause a disorder of 46,XY sex development, termed 5α-reductase type 2 deficiency and that was described forty years ago. Many mutations in the encoding gene have been reported in different ethnic groups. In affected 46,XY individuals, female external genitalia are common, but Mullerian ducts regress, and the internal urogenital tract is male. Most affected males are raised as females, but virilization occurs at puberty, and male social sex develops thereafter with high frequency. Fertility can be achieved in some affected males with assisted reproduction techniques, and adults with male social sex report a more satisfactory sex life and quality of life as compared to affected individuals with female social sex.

Steroid 5α-reductase 2 deficiency.

Dihydrotestosterone is a potent androgen metabolite formed from testosterone by action of 5α-reductase isoenzymes. Mutations in the type 2 isoenzyme cause a disorder of 46,XY sex development, termed 5α-reductase type 2 deficiency and that was described forty years ago. Many mutations in the encoding gene have been reported in different ethnic groups. In affected 46,XY individuals, female external genitalia are common, but Mullerian ducts regress, and the internal urogenital tract is male. Most affected males are raised as females, but virilization occurs at puberty, and male social sex develops thereafter with high frequency. Fertility can be achieved in some affected males with assisted reproduction techniques, and adults with male social sex report a more satisfactory sex life and quality of life as compared to affected individuals with female social sex.