When testes make no testosterone: Identifying a rare cause of 46, XY female phenotype in adulthood Gardner DG, Shoback D. Greenspan's Basic & Clinical Endocrinology, 10e; 2017 Sira Korpaisarn, MD Endocrinology Fellow Section of Endocrinology, Diabetes, Nutrition and Weight Management Boston University School of Medicine
DISCLOSURE NONE
Objective Understand clinical and diagnostic approach in female 46, XY disorders of sex development
Case A 21-year-old female presented with primary amenorrhea Minimal breast development, normal female appearing axillary and pubic hair and a normal growth history Adrenarche age 14-15 (pubic hair, legs and underarm hair growth) Deepening of her voice in her mid-teens No hair loss, acne, electrolyte or BP abnormalities Physical Examination Height of 5 2 Tanner 2 breast development, a short vaginal pouch and clitoromegaly with a clitoral width of 1.5 centimeters
Case PMH None Meds None Family history No history of endocrine or chromosomal abnormalities, inherited disorders, infertility, or consanguinity. Social history Never been sexually active Originally from Cape Verde
Case Transvaginal ultrasound Bilateral inguinal gonads without the presence of internal female structures Karyotype 46, XY (+SRY)
Impression Primary amenorrhea External female genitalia Absence of internal female organs Minimal breast development Virilization in adolescent Inguinal testes 46, XY (+SRY) Female phenotype 46, XY disorders of sex development
Disorders of Sex Development (DSD) Discrepancy between one s chromosomal, gonadal and phenotypic sex Gene dependent SRY (sex-determining region of the Y chromosome) Hormone dependent Kasper D, et al. Harrison's Principles of Internal Medicine, 19e; 2015
Normal Male Sex Differentiation 46, XY +SRY Gonad Testes T T Sertoli cells Leydig cells AMH T DHT epididymis vas deferens seminal vesicle Kasper D, et al. Harrison's Principles of Internal Medicine, 19e; 2015 Gardner DG, Shoback D. Greenspan's Basic & Clinical Endocrinology, 10e; 2017 Prostate Penis
Normal Female Sex Differentiation 46, XX No SRY Gonad Ovary O O No AMH No T Uterus fallopian tubes upper vagina Kasper D, et al. Harrison's Principles of Internal Medicine, 19e; 2015 Gardner DG, Shoback D. Greenspan's Basic & Clinical Endocrinology, 10e; 2017 lower end of the vagina
DDx for Female 46, XY DSD Disorders of testis development - Gonadal dysgenesis - Testicular regression syndrome Disorders of androgen synthesis - 17-beta-hydroxysteroid dehydrogenase type 3 deficiency - 5-alpha-reductase type 2 deficiency - LH receptor defects - CAH - 17-alpha-hydroxylase deficiency - 17,20 lyase deficiency - 3-beta-hydroxysteroid Disorders dehydrogenase of androgen type 2 response deficiency - Low AMH - Persistent Müllerian duct structures
Steroidogenesis Pathway DHT CYP17A1 3-beta-HSD def def 17,20 17-beta-hydroxysteroid 5-alpha-reductase 17-hydroxypregnenolone/ DOC, corticosterone lyase def type 17OHP 2 17OH-steroids, 17OHP/androstenedione cortisol ratio deficiency dehydrogenase cortisol and aldosterone type 3 def aldosterone androgens and estrogens T/A T/DHT androgens <0.8 No androgens (>20) and estrogens HTN, HypoK and estrogens HTN, Hypotension androgens HypoK Hoffman BL, et al. Williams Gynecology, 3e; 2016
DDx for Female 46, XY DSD Disorders of testis development - Gonadal dysgenesis - Testicular regression syndrome Disorders of androgen synthesis - 17-beta-hydroxysteroid dehydrogenase type 3 def - 5-alpha-reductase type 2 def - LH receptor defects - CAH - 17-alpha-hydroxylase def - 17,20 lyase def - 3-beta-hydroxysteroid dehydrogenase type 2 def Disorders of androgen response - Androgen insensitivity syndrome (complete vs partial) - Low AMH - Persistent Müllerian duct structures - Androstenedione to T defect - Low T/A (<0.8) - T to DHT defect - high T/DHT (>20) - Low T, low DHT, high LH - HTN, hypok, alkalosis - High 17-OHP/A - Adrenal insuff. - High 17-OHpregnenolone/17-OHP - High T, high LH
Biochemistry Studies Male Reference Range: Androstenedione (A) 50-220 ng/dl 1210 A.M. testosterone (T) 250-1100 ng/dl 296 Dihydrotestosterone 5-46 ng/dl 26 estradiol <39 pg/ml 38 T/A >0.8 0.24 LH 0.6-12.1 miu/ml 15.4 FSH 1.0-12.0 miu/ml 13.5 DHEA-S 85-690 mcg/dl 538 11-deoxycortisol <107 ng/dl 29 Deoxycorticosterone <15 ng/dl <16 Male Reference Range: Cosyntropin stimulation 17-hydroxyprogesterone < 307 ng/dl 162 187 17-hydroxypregnenolone < 905 ng/dl 98 639
Back to the patient 46, XY, +SRY External female genitalia Absence of internal female organs No T Müllerian duct regression AMH Low T/A 17-beta-hydroxysteroid dehydrogenase type 3 deficiency
Steroidogenesis Pathway 17-beta-hydroxysteroid dehydrogenase type 3 def T/A <0.8 androgens Hoffman BL, et al. Williams Gynecology, 3e; 2016
T/A ratio in 17-β-HSD3 deficiency 17-β-HSD3 def Control AIS In 17-β-HSD3 def. : mean T/A =0.4 (SD =0.2) T/A <0.8 suggests 17-β-HSD3 def Boehmer AM, et al.j Clin Endocrinol Metab. 1999; 84: 4713-4721.
Genetic Analysis Homozygous intronic mutation c.277+4a>7 near exon 3 of the HSD17B3 gene on chromosome 9q22 This variant has been reported to be cause for 46 XY, DSD (Boehmer et al. 1999. J Clin Endocrinol Metab. 84(12):4713-21).
46 XY, DSD 1 in 20,000 births Most of female 46, XY DSD are due to - androgen insensitivity syndromes (AIS) - 1-5 in 100,000 births - X-linked recessive - gonadal dysgenesis - 1 in 80,000 births Enzyme deficiencies comprising the remainder of the cases Lee PA, et al. Horm Res Paediatr. 2016;85:158-80. Berglund A, et al. J Clin Endocrinol Metab. 2016; 12: 4532-4540.
17-beta-hydroxysteroid dehydrogenase type 3 deficiency 1 in 200-300 to 1 in 147,000 live births Autosomal recessive Mutations in the HSD17B3 gene located on chromosome 9q22.32 Boehmer AM, er al.j Clin Endocrinol Metab. 1999; 84: 4713-4721. Castro CC, et al. Arq Bras Endocrinol Metab. 2012;56: 533-9.
AIS vs 17-β-HSD3 def AIS 17-β-HSD3 def 46, XY Female+blind vaginal pouch Woffian duct present Mellerian duct absent X-linked recessive High T AR gene 46, XY Female+blind vaginal pouch Woffian duct present Mellerian duct absent Autosomal recessive Low T/A HSD17B3 gene
Management Gender assignment Gonadectomy (28% risk germ cell tumors) - Prophylactic bilateral orchiectomy bilateral seminiferous tubules without spermatogenesis and unremarkable vas deferens, epididymis and spermatic cords Hormone replacement therapy - estrogen Genetic counseling Psychological support
Summary 17- -HSD deficiency is a rare and suspected underdiagnosed cause of 46, XY DSD High androstenedione concentration compared to testosterone and subsequent low T/A ratio Clinical similarities with AIS Autosomal recessive; genetic counseling differs
Acknowledgements Boston University Medical Center, Section of Endocrinology, Diabetes, Nutrition and Weight Management Catherine A. Sullivan, MD Joshua D. Safer, MD
Clinical Manifestations Female appearing external genital Minimal virilization Blind vaginal pouch Inguinal testes, and hypoplastic or absent prostate No internal female structures Virilization in puberty -peripheral conversion of A to T by extra gonadal 17- -HSD enzymes or partial activity of 17- -HSD3
17-beta-hydroxysteroid dehydrogenase type 3 deficiency Kasper D, et al. Harrison's Principles of Internal Medicine, 19e;
17-beta-hydroxysteroid dehydrogenase type 3 deficiency 46, XY +SRY Gonad Testes T T Sertoli cells Leydig cells AMH T DHT epididymis vas deferens seminal vesicle Kasper D, et al. Harrison's Principles of Internal Medicine, 19e; 2015 Gardner DG, Shoback D. Greenspan's Basic & Clinical Endocrinology, 10e; 2017 External female genitalia