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InternalMed_Harrison. POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; also known as Crow-Fukase syndrome; OMIM 192240) patients usually present with a progressive sensorimotor polyneuropathy, diabetes mellitus (50%), primary gonadal failure (70%), and a plasma cell dyscrasia with sclerotic bony lesions. Associated findings can be hepatosplenomegaly, lymphadenopathy, and hyper-pigmentation. Patients often present in the fifth to sixth decade of life and have a median survival after diagnosis of less than 3 years. The syndrome is assumed to be secondary to circulating immunoglobulins, but patients have excess vascular endothelial growth factor as well as elevated levels of other inflammatory cytokines such as IL1-β, IL-6, and tumor necrosis factor α. A small series of patients have been treated with thalidomide, leading to a decrease in vascular endothelial growth factor. Hyperglycemia responds to small, subcutaneous doses of insulin. The hypogonadism is due to primary


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InternalMed_Harrison. have been treated with thalidomide, leading to a decrease in vascular endothelial growth factor. Hyperglycemia responds to small, subcutaneous doses of insulin. The hypogonadism is due to primary gonadal disease with elevated plasma levels of follicle-stimulating hormone and luteinizing hormone. Temporary resolution of the features of POEMS, including normalization of blood glucose, may occur after radiotherapy for localized plasma cell lesions of bone or after chemotherapy, thalidomide, plasmapheresis, autologous stem cell transplantation, or treatment with all-trans-retinoic acid.


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InternalMed_Harrison. Other diseases can exhibit polyendocrine deficiencies, including Kearns-Sayre syndrome, DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, progressive bilateral optic atrophy, and sensorineural deafness; also termed Wolfram’s syndrome), Down’s syndrome or trisomy 21 (OMIM 190685), Turner’s syndrome (monosomy X, 45,X), and congenital rubella.


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InternalMed_Harrison. Kearns-Sayre syndrome (OMIM 530000) is a rare mitochondrial DNA disorder characterized by myopathic abnormalities leading to ophthalmoplegia and progressive weakness in association with several endocrine abnormalities, including hypoparathyroidism, primary gonadal failure, diabetes mellitus, and hypopituitarism. Crystalline mitochondrial inclusions are found in muscle biopsy specimens, and such inclusions have also been observed in the cerebellum. Antiparathyroid antibodies have not been described; however, antibodies to the anterior pituitary gland and striated muscle have been identified, and the disease may have autoimmune components. These mitochondrial DNA mutations occur sporadically and do not appear to be associated with a familial syndrome.


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InternalMed_Harrison. Wolfram’s syndrome (OMIM 222300, chromosome 4; OMIM 598500, mitochondrial) is a rare autosomal recessive disease that is also called DIDMOAD. Neurologic and psychiatric disturbances are prominent in most patients and can cause severe disability. The disease is caused by defects in wolframin, a 100-kDa transmembrane protein that has been localized to the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant increase in intracellular calcium and may play an important role in intracellular calcium homeostasis. Wolfram’s syndrome appears to be a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Diabetes mellitus with an onset in childhood is usually the first manifestation. Diabetes mellitus and optic atrophy are present in all reported cases, but expression of the other features is variable.


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InternalMed_Harrison. Down’s syndrome, or trisomy 21 (OMIM 190685), is associated with the development of T1D, thyroiditis, and celiac disease. Patients with Turner’s syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease. It is recommended to screen patients with trisomy 21 and Turner’s syndrome for associated autoimmune diseases on a regular basis. (sex-determining region on the Y chromosome) that encodes an HMG Disorders of Sex Development box transcription factor. SRY is expressed transiently in cells destined to become Sertoli cells and serves as a pivotal switch to establish the testis John C. Achermann, J. Larry Jameson lineage. Mutation of SRY prevents testis development in 46,XY individu-


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InternalMed_Harrison. Sex development begins in utero but continues into young adulthood with the achievement of sexual maturity and reproductive capability. The major determinants of sex development can be divided into three components: chromosomal sex, gonadal sex (sex determination), and phenotypic sex (sex differentiation) (Fig. 410-1). Variations at each of these stages can result in disorders (or differences) of sex development (DSDs) (Table 410-1). In the newborn period, approximately 1 in 4000 babies require investigation because of ambiguous (atypical) genitalia. Urgent assessment is required, because some causes such as congenital adrenal hyperplasia (CAH) can be associated with life-threatening adrenal crises. Support for the parents and clear communication about the diagnosis and management options are essential. The involvement of an experienced multidisciplinary team is important for counseling, planning appropriate investigations, and discussing long-term wellbeing. DSDs can also present at


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InternalMed_Harrison. are essential. The involvement of an experienced multidisciplinary team is important for counseling, planning appropriate investigations, and discussing long-term wellbeing. DSDs can also present at other ages and to a range of health professionals. Subtler forms of gonadal dysfunction (e.g., Klinefelter’s syndrome [KS], Turner’s syndrome [TS]) often are diagnosed later in life by internists. Because these conditions are associated with a variety of psychological, reproductive, and potential medical consequences, an open dialogue must be established between the patient and health care providers to ensure continuity and attention to these issues.


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InternalMed_Harrison. Chromosomal sex, defined by a karyotype, describes the X and/or Y chromosome complement (46,XY; 46,XX) that is established at the time of fertilization. The presence of a normal Y chromosome determines that testis development will occur even in the presence of multiple X chromosomes (e.g., 47,XXY or 48,XXXY). The loss of an X chromosome impairs gonad development (45,X or 45,X/46,XY mosaicism). Fetuses with no X chromosome (45,Y) are not viable. Gonadal sex refers to the histologic and functional characteristics of gonadal tissue as testis or ovary. The embryonic gonad is bipotential and can develop (from ~42 days after conception) into either a testis or an ovary, depending on which genes are expressed (Fig. 410-2). Testis development is initiated by expression of the Y chromosome gene SRY (T, DHT, AMH/MIS)


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InternalMed_Harrison. FIGURE 410-1 Sex development can be divided into three major components: chromosomal sex, gonadal sex, and phenotypic sex. DHT, dihydrotestosterone; MIS, müllerian-inhibiting substance also known as anti-müllerian hormone, AMH; T, testosterone.


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InternalMed_Harrison. als, whereas translocation of SRY in 46,XX individuals is sufficient to induce testis development and a male phenotype. Other genes are necessary to continue testis development. SOX9 (SRY-related HMG-box gene 9) is upregulated by SRY in the developing testis but is suppressed in the ovary. WT1 (Wilms’ tumor–related gene 1) acts early in the genetic pathway and regulates the transcription of several genes, including SFI (NR5A1), DAX1 (NR0B1), and AMH (encoding müllerian-inhibiting substance [MIS]). SF1 encodes steroidogenic factor 1, a nuclear receptor that functions in cooperation with other transcription factors to regulate a large array of adrenal and gonadal genes, including SOX9 and many genes involved in steroidogenesis. SF1 mutations causing loss of function are found in ~10% of XY patients with gonadal dysgenesis and impaired androgenization. In contrast, duplication of a related gene DAX1 also impairs testis development, revealing the exquisite sensitivity of the


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InternalMed_Harrison. ~10% of XY patients with gonadal dysgenesis and impaired androgenization. In contrast, duplication of a related gene DAX1 also impairs testis development, revealing the exquisite sensitivity of the testis-determining pathway to gene dosage effects. DAX1 loss-of-function mutations cause adrenal hypoplasia, hypogonadotropic hypogonadism, and testicular dysgenesis. In addition to the genes mentioned above, studies of humans and mice indicate that at least 30 other genes are also involved in gonad development (Fig. 410-2). These genes encode an array of signaling molecules and paracrine growth factors in addition to transcription factors.


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InternalMed_Harrison. Although ovarian development once was considered a “default” process, it is now clear that specific genes are expressed during the earliest stages of ovary development. Some of these factors may repress testis development (e.g., WNT4, R-spondin-1) (Fig. 410-2). Once the ovary has formed, additional factors are required for normal follicular development (e.g., follicle-stimulating hormone [FSH] receptor, GDF9). Steroidogenesis in the ovary requires the development of follicles that contain granulosa cells and theca cells surrounding the oocytes (Chap. 412). Thus, there is relatively limited ovarian steroidogenesis until puberty.


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InternalMed_Harrison. Germ cells also develop in a sex dimorphic manner. In the developing ovary, primordial germ cells (PGCs) proliferate and enter meiosis, whereas they proliferate and then undergo mitotic arrest in the developing testis. PGC entry into meiosis is initiated by retinoic acid that activates STRA8 (stimulated by retinoic acid 8) and other genes involved in meiosis. The developing testis produces high levels of CYP26B1, an enzyme that degrades retinoic acid, preventing PGC entry into meiosis. Approximately 7 million germ cells are present in the fetal ovary in the second trimester, and 1 million remain at birth. Only 400 are ovulated during a woman’s reproductive life span (Chap. 412).


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InternalMed_Harrison. Phenotypic sex refers to the structures of the external and internal genitalia and secondary sex characteristics. The developing testis releases anti-müllerian hormone (AMH; also known as müllerianinhibiting substance [MIS]) from Sertoli cells and testosterone from Leydig cells. AMH is a member of the transforming growth factor (TGF) β family and acts through specific receptors to cause regression of the müllerian structures from 60–80 days after conception. At ~60–140 days after conception, testosterone supports the development of wolffian structures, including the epididymides, vasa deferentia, and seminal vesicles. Testosterone is the precursor for dihydrotestosterone (DHT), a potent androgen that promotes development of the external genitalia, including the penis and scrotum (65–100 days, and thereafter) (Fig. 410-3). The urogenital sinus develops into the prostate and prostatic urethra in the male and into the urethra and lower portion of the vagina in the female. The genital


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InternalMed_Harrison. days, and thereafter) (Fig. 410-3). The urogenital sinus develops into the prostate and prostatic urethra in the male and into the urethra and lower portion of the vagina in the female. The genital tubercle becomes the glans penis in the male and the clitoris in the female. The urogenital swellings form the scrotum or the labia majora, and the urethral folds fuse to form the shaft of the penis and the male urethra or the labia minora. In the female, wolffian ducts regress and the müllerian ducts form the


InternalMed_Harrison

InternalMed_Harrison. Disorders of Sex Development Sex Chromosome DSD 46,XY DSD (see Table 410-3) 46,XX DSD (see Table 410-4) 47,XXY (Klinefelter’s syndrome and Disorders of gonadal (testis) development variants) Complete or partial gonadal dysgenesis (e.g., SRY, SOX9, SF1, 45,X (Turner’s syndrome and variants) WT1, DHH, MAP3K1) 45,X/46,XY mosaicism (mixed gonadal Impaired fetal Leydig cell function (e.g., SF1/NR5A1, CXorf6/ dysgenesis) MAMLD1) 46,XX/46,XY (chimerism/mosaicism) Ovotesticular DSD Testis regression Disorders of androgen biosynthesis LH receptor (LHCGR) Smith-Lemli-Opitz syndrome Steroidogenic acute regulatory (StAR) protein Cholesterol side-chain cleavage (CYP11A1) 3β-Hydroxysteroid dehydrogenase II (HSD3B2) 17α-Hydroxylase/17,20-lyase (CYP17A1) P450 oxidoreductase (POR) Cytochrome b5 (CYB5A) 17β-Hydroxysteroid dehydrogenase III (HSD17B3) 5α-Reductase II (SRD5A2) Aldo-keto reductase 1C2 (AKR1C2)


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InternalMed_Harrison. Disorders of androgen action Androgen insensitivity syndrome Drugs and environmental modulators Syndromic associations of male genital development Persistent müllerian duct syndrome Vanishing testis syndrome Isolated hypospadias Congenital hypogonadotropic hypogonadism Cryptorchidism Environmental influences Source: Modified from IA Hughes: Arch Dis Child 91:554, 2006. Disorders of gonadal (ovary) development Gonadal dysgenesis Ovotesticular DSD Testicular DSD (e.g., SRY+, dup SOX9, RSPO1) Maternal Maternal virilizing tumors (e.g., luteomas) Androgenic drugs


InternalMed_Harrison

InternalMed_Harrison. Maternal Maternal virilizing tumors (e.g., luteomas) Androgenic drugs Syndromic associations (e.g., cloacal anomalies) Müllerian agenesis/hypoplasia (e.g., MRKH) Uterine abnormalities (e.g., MODY5) Vaginal atresia (e.g., McKusick-Kaufman) Labial adhesions fallopian tubes, uterus, and upper segment of the vagina. A female phe-firm (median length 2.5 cm [4 mL volume]; almost always <3.5 cm notype will develop in the absence of the gonad, but estrogen is needed [12 mL]) and typically seem inappropriately small for the degree of for maturation of the uterus and breast at puberty. androgenization. Biopsies are not usually necessary but typically reveal seminiferous tubule hyalinization and azoospermia. Other clinical fea- tures of KS are listed in Table 410-2. Plasma concentrations of FSH and Variations in sex chromosome number and structure can present as luteinizing hormone (LH) are increased in most adults with 47,XXY,


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InternalMed_Harrison. DSDs (e.g., 45,X/46,XY). KS (47,XXY) and TS (45,X) do not usually and plasma testosterone is decreased (50–75%), reflecting primary present with genital ambiguity but are associated with gonadal dys-gonadal failure. Estradiol is often increased, likely because of chronic function (Table 410-2). Leydig cell stimulation by LH and aromatization of androstenedione by adipose tissue; the increased ratio of estradiol-to-testosterone KLINEFELTER’S SYNDROME (47,XXY) results in gynecomastia (Chap. 411). Patients with mosaic forms of Pathophysiology The classic form of KS (47,XXY) occurs after meiotic KS have less severe clinical features, have larger testes, and sometimes nondisjunction of the sex chromosomes during gametogenesis (40% achieve spontaneous fertility. during spermatogenesis, 60% during oogenesis) (Chap. 83e). Mosaic forms of KS (46,XY/47,XXY) are thought to result from chromosomal mitotic nondisjunction within the zygote and occur in at least 10% of individuals with this


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InternalMed_Harrison. 60% during oogenesis) (Chap. 83e). Mosaic forms of KS (46,XY/47,XXY) are thought to result from chromosomal mitotic nondisjunction within the zygote and occur in at least 10% of individuals with this condition. Other chromosomal variants of KS


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InternalMed_Harrison. Growth, endocrine function, and bone mineralization should be (e.g., 48,XXYY, 48,XXXY) have been reported but are less common.


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InternalMed_Harrison. monitored, especially from adolescence. Educational and psycho-Clinical Features KS is characterized by small testes, infertility, gyne-logical support is important for many individuals with KS. Androgen comastia, tall stature/increased leg length, and hypogonadism in supplementation improves virilization, libido, energy, hypofibrinolyphenotypic males. It has an incidence of at least 1 in 1000 men, but sis, and bone mineralization in men with low testosterone levels but approximately 75% of cases are not diagnosed. Of those who are may occasionally worsen gynecomastia (Chap. 411). Gynecomastia diagnosed, only 10% are identified prepubertally, usually because of can be treated by surgical reduction if it causes concern (Chap. small genitalia or cryptorchidism. Others are diagnosed after puberty, 411). Fertility has been achieved by using in vitro fertilization in usually based on impaired androgenization and/or gynecomastia. men with oligospermia or with intracytoplasmic sperm


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InternalMed_Harrison. after puberty, 411). Fertility has been achieved by using in vitro fertilization in usually based on impaired androgenization and/or gynecomastia. men with oligospermia or with intracytoplasmic sperm injection Developmental delay, speech difficulties, and poor motor skills may (ICSI) after retrieval of spermatozoa by testicular sperm extraction be features but are variable, especially in adolescence. Later in life, techniques. In specialized centers, successful spermatozoa retrieval body habitus or infertility leads to the diagnosis. Testes are small and using this technique is possible in >50% of men with nonmosaic


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InternalMed_Harrison. WNT4 46,XX 46,XY DMRT 1,2 FIGURE 410-2 The genetic regulation of gonadal development. AMH, anti-müllerian hormone (müllerian-inhibiting substance); ATRX, α-thalassemia, mental retardation on the X; BMP2 and 15, bone morphogenic factors 2 and 15; CBX2, chromobox homologue 2; DAX1, dosage sensitive sex-reversal, adrenal hypoplasia congenita on the X chromosome, gene 1; DHH, desert hedgehog; DHT, dihydrotestosterone; DMRT 1,2, doublesex MAB3-related transcription factor 1,2; FOXL2, forkhead transcription factor L2; GATA4, GATA binding protein 4; GDF9, growth differentiation factor 9; MAMLD1, mastermind-like domain containing 1; MAP3K1, mitogen-activated protein kinase kinase kinase 1; RSPO1, R-spondin 1; SF1, steroidogenic factor 1 (also known as NR5A1); SOX9, SRY-related HMG-box gene 9; SRY, sex-determining region on the Y chromosome; WNT4, wingless-type MMTV integration site 4; WT1, Wilms’ tumor–related gene 1.


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InternalMed_Harrison. KS. Results may be better in younger men. After ICSI and embryo transfer, successful pregnancies can be achieved in ~50% of these cases. The risk of transmission of this chromosomal abnormality needs to be considered, and preimplantation screening may be desired, although this outcome is much less common than originally 2351 predicted. Long-term monitoring of men with KS is important given the increased risk of breast cancer, cardiovascular disease, metabolic syndrome, and autoimmune disorders. Because most men with KS are never diagnosed, it is important that all internists consider this diagnosis in men with these features who might be seeking medical advice for other conditions.


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InternalMed_Harrison. TURNER’S SYNDROME (GONADAL DYSGENESIS; 45,X) Pathophysiology Approximately one-half of women with TS have a 45,X karyotype, about 20% have 45,X/46,XX mosaicism, and the remainder have structural abnormalities of the X chromosome such as X fragments, isochromosomes, or rings. The clinical features of TS result from haploinsufficiency of multiple X chromosomal genes (e.g., short stature homeobox, SHOX). However, imprinted genes also may be affected when the inherited X has different parental origins.


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InternalMed_Harrison. Clinical Features TS is characterized by bilateral streak gonads, primary amenorrhea, short stature, and multiple congenital anomalies in phenotypic females. It affects ~1 in 2500 women and is diagnosed at different ages depending on the dominant clinical features (Table 410-2). Prenatally, a diagnosis of TS usually is made incidentally after chorionic villus sampling or amniocentesis for unrelated reasons such as advanced maternal age. Prenatal ultrasound findings include increased nuchal translucency. The postnatal diagnosis of TS should be considered in female neonates or infants with lymphedema, nuchal folds, low hairline, or left-sided cardiac defects and in girls with unexplained growth failure or pubertal delay. Although limited spontaneous pubertal development occurs in up to 30% of girls with TS (10%, 45,X; 30–40%, 45,X/46,XX) and ~2% reach menarche, the vast majority of women with TS develop complete ovarian insufficiency. Therefore, this diagnosis should be considered in


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InternalMed_Harrison. of girls with TS (10%, 45,X; 30–40%, 45,X/46,XX) and ~2% reach menarche, the vast majority of women with TS develop complete ovarian insufficiency. Therefore, this diagnosis should be considered in all women who present with primary or secondary amenorrhea and elevated gonadotropin levels.


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InternalMed_Harrison. The management of girls and women with TS requires a multidisciplinary approach because of the number of potentially involved organ systems. Detailed cardiac and renal evaluation should be performed at the time of diagnosis. Individuals with congenital heart Disorders of Sex Development Klinefelter’s syndrome 47,XXY or 46,XY/47,XXY Hyalinized testes Male Male Gynecomastia Small testes, azoospermia, decreased facial and axillary hair, decreased libido, tall stature and increased leg length, decreased penile length, increased risk of breast tumors, thromboembolic disease, learning difficulties, speech delay and decreased verbal IQ, obesity, diabetes mellitus, metabolic syndrome, varicose veins, hypothyroidism, systemic lupus erythematosus, epilepsy Turner’s syndrome 45,X or 45,X/46,XX Streak gonad or Female Hypoplastic female Immature female immature ovary


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InternalMed_Harrison. Turner’s syndrome 45,X or 45,X/46,XX Streak gonad or Female Hypoplastic female Immature female immature ovary Infancy: lymphedema, web neck, shield chest, low-set hairline, cardiac defects and coarctation of the aorta, urinary tract malformations, and horseshoe kidney Childhood: short stature, cubitus valgus, short neck, short fourth metacarpals, hypoplastic nails, micrognathia, scoliosis, otitis media and sensorineural hearing loss, ptosis and amblyopia, multiple nevi and keloid formation, autoimmune thyroid disease, visuospatial learning difficulties Adulthood: pubertal failure and primary amenorrhea, hypertension, obesity, dyslipidemia, impaired glucose tolerance and insulin resistance, autoimmune thyroid disease, cardiovascular disease, aortic root dilation, osteoporosis, inflammatory bowel disease, chronic hepatic dysfunction, increased risk of colon cancer, hearing loss 45,X/46,XY mosaicism 45,X/46,XY Testis or streak gonad Variable Variable Usually male


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InternalMed_Harrison. Short stature, increased risk of gonadal tumors, some Turner’s syndrome features Ovotesticular DSD (true 46,XX/46,XY Testis and ovary or ovo-Variable Variable Gynecomastia hermaphroditism) Possible increased risk of gonadal tumors Ovary Fallopian tube Uterus Vagina FemaleMaleGonad Mesonephros Mullerian duct.. Wolffian duct Urogenital sinus Epididymis Testis Vas deferens Seminal vesicle Prostate


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InternalMed_Harrison. FIGURE 410-3 Sex development. A. Internal urogenital tract. B. External genitalia. (After E Braunwald et al [eds]: Harrison’s Principles of Internal Medicine, 15th ed. New York, McGraw-Hill, 2001.) defects (CHDs) (30%) (bicuspid aortic valve, 30–50%; coarctation of to regimens may be beneficial. Girls with evidence of ovarian the aorta, 30%; aortic root dilation, 5%) require long-term follow-up insufficiency require estrogen replacement to induce breast and by an experienced cardiologist, antibiotic prophylaxis for dental or uterine development, support growth, and maintain bone miner-surgical procedures, and serial magnetic resonance imaging (MRI) alization. Most physicians now initiate low-dose estrogen therapy of aortic root dimensions, because progressive aortic root dilation is (one-tenth to one-eighth of the adult replacement dose) to induce associated with increased risk of aortic dissection. Individuals found puberty at an age-appropriate time (~12 years). Doses of estrogen to


InternalMed_Harrison

InternalMed_Harrison. to one-eighth of the adult replacement dose) to induce associated with increased risk of aortic dissection. Individuals found puberty at an age-appropriate time (~12 years). Doses of estrogen to have congenital renal and urinary tract malformations (30%) are are increased gradually to allow development over a 2to 4-year at risk for urinary tract infections, hypertension, and nephrocalci-period. Progestins are added later to regulate withdrawal bleeds. nosis. Hypertension can occur independently of cardiac and renal Some women with TS have achieved successful pregnancy after malformations and should be monitored and treated as in other ovum donation and in vitro fertilization but are high risk, and car-patients with essential hypertension. Clitoral enlargement or other diac assessment is required. Long-term follow-up of women with evidence of virilization suggests the presence of covert, translocated TS involves careful surveillance of sex hormone replacement and Y chromosomal material


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InternalMed_Harrison. Long-term follow-up of women with evidence of virilization suggests the presence of covert, translocated TS involves careful surveillance of sex hormone replacement and Y chromosomal material and is associated with increased risk of reproductive function, bone mineralization, cardiac function and gonadoblastoma. Regular assessment of thyroid function, weight, aortic root dimensions, blood pressure, weight and glucose tolerdentition, hearing, speech, vision, and educational issues should be ance, hepatic and lipid profiles, thyroid function, and hearing. This performed during childhood. Otitis media and middle-ear disease service is provided by a dedicated TS clinic in some centers. are prevalent in childhood (50–85%), and sensorineural hearing loss becomes progressively common with age (70–90%). Autoimmune hypothyroidism (15–30%) can occur in childhood but has a mean 45,X/46,XY MOSAICISM (MIXED GONADAL DYSGENESIS) age of onset in the third decade. Counseling about long-term The


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InternalMed_Harrison. age (70–90%). Autoimmune hypothyroidism (15–30%) can occur in childhood but has a mean 45,X/46,XY MOSAICISM (MIXED GONADAL DYSGENESIS) age of onset in the third decade. Counseling about long-term The phenotype of individuals with 45,X/46,XY mosaicism (sometimes growth and fertility issues should be provided. Patient support called mixed gonadal dysgenesis) can vary considerably. Some have a groups are active throughout the world and can play an invaluable predominantly female phenotype with somatic features of TS, streak role. gonads, and müllerian structures, and are managed as TS with a Y


InternalMed_Harrison

InternalMed_Harrison. Short stature can be an issue for some girls because untreated chromosome. Most 45,X/46,XY individuals have a male phenotype final height rarely exceeds 150 cm in nonmosaic 45,X TS. High-dose and testes, and the diagnosis is made incidentally after amniocenterecombinant growth hormone stimulates growth rate in children sis or during investigation of infertility. In practice, most newborns with TS and is occasionally combined with low doses of the nonaro-referred for assessment have atypical genitalia and variable somatic matizable anabolic steroid oxandrolone (up to 0.05 mg/kg per day) features. Management is complex and needs to be individualized. A in an older child (>9 years). However, final height increments are female sex-of-rearing is often assigned if uterine structures are present, often about 5–10 cm, and individualization of treatment response gonads are intraabdominal, and phallic development is incomplete. In such situations, gonadectomy usually is considered to prevent


InternalMed_Harrison

InternalMed_Harrison. often about 5–10 cm, and individualization of treatment response gonads are intraabdominal, and phallic development is incomplete. In such situations, gonadectomy usually is considered to prevent further androgen secretion at puberty and prevent risk of gonadoblastoma (up to 25%). Individuals raised as males usually require reconstructive surgery for hypospadias and removal of dysgenetic or streak gonads if the gonads cannot be brought down into the scrotum. Scrotal testes can be preserved but require regular examination for tumor development and sonography at the time of puberty. Biopsy for carcinoma in situ is recommended in adolescence, and testosterone supplementation may be required to support androgenization in puberty or if low testosterone is detected in adulthood. Height potential is usually attenuated; some children receive recombinant growth hormone using TS protocols. Screening for cardiac, renal, and other TS features should be considered, and psychological support


InternalMed_Harrison

InternalMed_Harrison. is usually attenuated; some children receive recombinant growth hormone using TS protocols. Screening for cardiac, renal, and other TS features should be considered, and psychological support offered for the family and young person.


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InternalMed_Harrison. Ovotesticular DSD (formerly called true hermaphroditism) occurs when both an ovary and a testis—or when an ovotestis—are found in one individual. Most individuals with this diagnosis have a 46,XX karyotype, especially in sub-Saharan Africa, and present with ambiguous genitalia at birth or with breast development and phallic development at puberty. A 46,XX/46,XY chimeric karyotype is less common and has a variable phenotype. Disorders of gonadal and phenotypic sex can result in underandrogenization of individuals with a 46,XY karyotype (46,XY DSD) and the excess androgenization of individuals with a 46,XX karyotype (46,XX DSD) (Table 410-1). These disorders cover a spectrum of phenotypes ranging from “46,XY phenotypic females” or “46,XX phenotypic males” to individuals with atypical genitalia. 46,XY DSD


InternalMed_Harrison

InternalMed_Harrison. 46,XY DSD Underandrogenization of the 46,XY fetus (formerly called male pseudohermaphroditism) reflects defects in androgen production or action. It can result from disorders of testis development, defects of androgen synthesis, or resistance to testosterone and DHT (Table 410-1).


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InternalMed_Harrison. Disorders of Testis Development • TesTicular dysgenesis Pure (or complete) gonadal dysgenesis (Swyer’s syndrome) is associated with streak gonads, müllerian structures (due to insufficient AMH/MIS secretion), and a complete absence of androgenization. Phenotypic females with this condition often present because of absent pubertal development and are found to have a 46,XY karyotype. Serum sex steroids, AMH/ MIS, and inhibin B are low, and LH and FSH are elevated. Patients with partial gonadal dysgenesis (dysgenetic testes) may produce enough MIS to regress the uterus and sufficient testosterone for partial androgenization, and therefore usually present in the newborn period with atypical genitalia. Gonadal dysgenesis can result from mutations or deletions of testis-promoting genes (WT1, CBX2, SF1, SRY, SOX9, MAP3K1, DHH, GATA4, ATRX, ARX, DMRT) or duplication of chromosomal loci containing “antitestis” genes (e.g., WNT4/RSPO1, DAX1) (Table 410-3). Among these, deletions or mutations of


InternalMed_Harrison

InternalMed_Harrison. SF1, SRY, SOX9, MAP3K1, DHH, GATA4, ATRX, ARX, DMRT) or duplication of chromosomal loci containing “antitestis” genes (e.g., WNT4/RSPO1, DAX1) (Table 410-3). Among these, deletions or mutations of SRY and heterozygous mutations of SF1 (NR5A1) appear to be most common but still account collectively for <25% of cases. Associated clinical features may be present, reflecting additional functional roles for these genes. For example, renal dysfunction occurs in patients with specific WT1 mutations (Denys-Drash and Frasier’s syndromes), primary adrenal failure occurs in some patients with SF1 mutations, and severe cartilage abnormalities (campomelic dysplasia) are the predominant clinical feature of SOX9 mutations. A family history of DSD, infertility, or early menopause is important because mutations in SF1/NR5A1 can be inherited from a mother in a sex-limited dominant manner (which can mimic X-linked inheritance). In some cases, a woman may later develop primary ovarian insufficiency


InternalMed_Harrison

InternalMed_Harrison. mutations in SF1/NR5A1 can be inherited from a mother in a sex-limited dominant manner (which can mimic X-linked inheritance). In some cases, a woman may later develop primary ovarian insufficiency because of the effect of SF1 on the ovary. Intraabdominal dysgenetic testes should be removed to prevent malignancy, and estrogens can be used to induce secondary sex characteristics and uterine development in 46,XY individuals raised as females, if it is felt that a female gender identity is established. Absent (vanishing) testis syndrome (bilateral anorchia) reflects regression 2353 of the testis during development. The etiology is unknown, but the absence of müllerian structures indicates adequate secretion of AMH early in utero. In most cases, androgenization of the external genitalia is either normal or slightly impaired (e.g., small penis, hypospadias). These individuals can be offered testicular prostheses and should receive androgen replacement in adolescence.


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InternalMed_Harrison. Disorders of Androgen Synthesis Defects in the pathway that regulates androgen synthesis (Fig. 410-4) cause underandrogenization of the 46,XY fetus (Table 410-1). Müllerian regression is unaffected because Sertoli cell function is preserved. Most of these conditions can present with a spectrum of genital phenotypes, ranging from female-typical external genitalia or clitoromegaly in the more severe situations to penoscrotal hypospadias or a small phallus in others. lH receptor Mutations in the LH receptor (LHCGR) cause Leydig cell hypoplasia and androgen deficiency, due to impaired actions of human chorionic gonadotropin in utero and LH late in gestation and during the neonatal period. As a result, testosterone and DHT synthesis are insufficient for complete androgenization.


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InternalMed_Harrison. SteroidoGenic enzyme patHWayS Mutations in steroidogenic acute regulatory protein (StAR) and CYP11A1 affect both adrenal and gonadal steroidogenesis (Fig. 410-4) (Chap. 406). Affected individuals (46,XY) usually have severe early-onset salt-losing adrenal failure and a female phenotype, although later-onset milder variants have been reported. Defects in 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2) also cause adrenal insufficiency in severe cases, but the accumulation of dehydroepiandrosterone (DHEA) has a mild androgenizing effect, resulting in ambiguous genitalia or hypospadias. Salt loss occurs in many but not all cases. Patients with CAH due to 17α-hydroxylase (CYP17) deficiency have variable underandrogenization and develop hypertension and hypokalemia due to the potent salt-retaining effects of corticosterone and 11-deoxycorticosterone. Patients with complete loss of 17α-hydroxylase function often present as phenotypic females who fail to enter puberty and are found to have


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InternalMed_Harrison. effects of corticosterone and 11-deoxycorticosterone. Patients with complete loss of 17α-hydroxylase function often present as phenotypic females who fail to enter puberty and are found to have inguinal testes and hypertension in adolescence. Some mutations in CYP17 selectively impair 17,20-lyase activity without altering 17α-hydroxylase activity, leading to underandrogenization without mineralocorticoid excess and hypertension. Disruption of the coenzyme, cytochrome b5 (CYB5A), can present similarly, and methemoglobinemia is usually present. Mutations in P450 oxidoreductase (POR) affect multiple steroidogenic enzymes, leading to impaired androgenization and a biochemical pattern of apparent combined 21-hydroxylase and 17α-hydroxylase deficiency, sometimes with skeletal abnormalities (Antley-Bixler craniosynostosis). Defects in 17β-hydroxysteroid dehydrogenase type 3 (HSD17β3) and 5α-reductase type 2 (SRD5A2) interfere with the synthesis of testosterone and DHT, respectively. These


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InternalMed_Harrison. craniosynostosis). Defects in 17β-hydroxysteroid dehydrogenase type 3 (HSD17β3) and 5α-reductase type 2 (SRD5A2) interfere with the synthesis of testosterone and DHT, respectively. These conditions are characterized by minimal or absent androgenization in utero, but some phallic development can occur during adolescence due to the action of other enzyme isoforms. Individuals with 5α-reductase type 2 deficiency have normal wolffian structures and usually do not develop breast tissue. At puberty, the increase in testosterone induces muscle mass and other virilizing features despite DHT deficiency. Some individuals change gender from female to male at puberty. Thus, the management of this disorder is challenging. DHT cream can improve prepubertal phallic growth in patients raised as male. Gonadectomy before adolescence and estrogen replacement at puberty can be considered in individuals raised as females who have a female gender identity. Disruption of alternative pathways to fetal DHT


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InternalMed_Harrison. before adolescence and estrogen replacement at puberty can be considered in individuals raised as females who have a female gender identity. Disruption of alternative pathways to fetal DHT production might also present with 46,XY DSD (AKR1C2/AKR1C4).


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InternalMed_Harrison. Disorders of Androgen Action • androgen insensiTiviTy syndrome Mutations in the androgen receptor cause resistance to androgen (testosterone, DHT) action or the androgen insensitivity syndrome (AIS). AIS is a spectrum of disorders that affects at least 1 in 100,000 46,XY individuals. Because the androgen receptor is X-linked, only 46,XY offspring are affected if the mother is a carrier of a mutation. XY individuals with complete AIS (formerly called testicular feminization syndrome) have a female phenotype, normal breast development Disorders of Sex Development 2354 TAblE 410-3 SElECTED gEnETiC CAuSES of 46,xy DiSoRDERS of SEx DEvEloPmEnT (DSDs)


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InternalMed_Harrison. Abbreviations: AD, autosomal dominant; AKR1C2, aldo-keto reductase family 1 member 2; AR, autosomal recessive; ARX, aristaless related homeobox, X-linked; ATRX, α-thalassemia, mental retardation on the X; CAH, congenital adrenal hyperplasia; CBX2, chromobox homologue 2; CYB5A, cytochrome b5 POR, P450 oxidoreductase; CYP11A1, P450 cholesterol side-chain cleavage; CYP17, 17α-hydroxylase and 17,20-lyase; DAX1, dosage sensitive sex-reversal, adrenal hypoplasia congenita on the X chromosome, gene 1; DHEA, dehydroepiandrosterone; DHCR7, sterol 7 δ reductase; DHH, desert hedgehog; GATA4, GATA binding protein 4; HSD17B3, 17β-hydroxysteroid dehydrogenase type 3; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; LHR, LH receptor; MAP3K1, mitogen-activated protein kinase kinase kinase 1; SF1, steroidogenic factor 1; SL, sex-limited; SOX9, SRY-related HMG-box gene 9; SRD5A2, 5α-reductase type 2; SRY, sex-related gene on the Y chromosome; StAR, steroidogenic acute regulatory protein; WAGR, Wilms’


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InternalMed_Harrison. factor 1; SL, sex-limited; SOX9, SRY-related HMG-box gene 9; SRD5A2, 5α-reductase type 2; SRY, sex-related gene on the Y chromosome; StAR, steroidogenic acute regulatory protein; WAGR, Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation; WNT4, wingless-type mouse mammary tumor virus integration site, 4; WT1, Wilms’ tumor–related gene 1.


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InternalMed_Harrison. (due to aromatization of testosterone), a short vagina but no uterus offered for girls diagnosed in childhood, because there is a low risk of (because MIS production is normal), scanty pubic and axillary hair, malignancy, and estrogen replacement is prescribed. Alternatively, the and a female gender identity and sex role behavior. Gonadotropins gonads can be left in situ until breast development is complete and and testosterone levels can be low, normal, or elevated, depending on removed because of tumor risk. Some adults with complete AIS decline the degree of androgen resistance and the contribution of estradiol gonadectomy, but should be counseled about the risk of malignancy, to feedback inhibition of the hypothalamic-pituitary-gonadal axis. especially because early detection of premalignant changes by imag-AMH/MIS levels in childhood are normal or high. Most patients ing or biomarkers is currently not possible. The use of graded dilators present with inguinal hernias (containing


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InternalMed_Harrison. changes by imag-AMH/MIS levels in childhood are normal or high. Most patients ing or biomarkers is currently not possible. The use of graded dilators present with inguinal hernias (containing testes) in childhood or with in adolescence is usually sufficient to dilate the vagina for sexual primary amenorrhea in late adolescence. Gonadectomy sometimes is intercourse.


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InternalMed_Harrison. Cholesterol StAR (Cholesterol side chain cleavage enzyme) CYP11A1 hyperplasiaCYP17, (17,20-Lyase), CYB5A (Cytochrome b5) HSD17B3 (17˜-Hydroxysteroid dehydrogenase 3) CYP21A2 (21-Hydroxylase) SRD5A2 (5°-Reductase) CYP11B1 (11-Hydroxylase) 17-Hydroxyprogesterone 11-Deoxycortisol Androstenedione Cortisol Testosterone Glucocorticoid Pathway Androgen Pathway LH (testis) ACTH (adrenal) Dihydrotestosterone and 46,XX androgenization SOX9, or defects in RSPO1 (Table 410-4). deficiency (conGenital adrenal HyperplaSia) The classic form of 21-hydroxylase deficiency (21OHD) is the most common cause of CAH (Chap. 406). It has an incidence between 1 in


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InternalMed_Harrison. deficiency (conGenital adrenal HyperplaSia) The classic form of 21-hydroxylase deficiency (21OHD) is the most common cause of CAH (Chap. 406). It has an incidence between 1 in FIGURE 410-4 Simplified overview of glucocorticoid and androgen synthesis 10,000 and 1 in 15,000 and is the most common pathways. Defects in CYP21A2 and CYP11B1 shunt steroid precursors into the androgen cause of androgenization in chromosomal 46,XX pathway and cause androgenization of the 46,XX fetus. Testosterone is synthesized in females (Table 410-4). Affected individuals are the testicular Leydig cells and converted to dihydrotestosterone peripherally. Defects in homozygous or compound heterozygous for enzymes involved in androgen synthesis result in underandrogenization of the 46,XY fetus. severe mutations in the enzyme 21-hydroxylase StAR, steroidogenic acute regulatory protein. (After E Braunwald et al [eds]: Harrison’s Principles (CYP21A2). This mutation causes a block in


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InternalMed_Harrison. Disorders of Sex Development of Internal Medicine, 15th ed. New York, McGraw-Hill, 2001.)


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InternalMed_Harrison. Partial AIS (Reifenstein’s syndrome) results from androgen receptor mutations that maintain residual function. Patients often present in infancy with penoscrotal hypospadias and small undescended testes and with gynecomastia at the time of puberty. Those individuals raised as males usually require hypospadias repair in childhood and may need breast reduction in adolescence. Some boys enter puberty spontaneously. High-dose testosterone has been given to support development if puberty does not progress, but long-term data are limited. More severely underandrogenized patients present with clitoral enlargement and labial fusion and may be raised as females. The surgical and psychosexual management of these patients is complex and requires active involvement of the parents and the patient during the appropriate stages of development. Azoospermia and male-factor infertility also have been described in association with mild loss-offunction mutations in the androgen receptor.


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OTHER DISORDERS AFFECTING 46,XY MALES

InternalMed_Harrison. OTHER DISORDERS AFFECTING 46,XY MALES


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InternalMed_Harrison. Persistent müllerian duct syndrome is the presence of a uterus in an otherwise phenotypic male. This condition can result from mutations in AMH or its receptor (AMHR2). The uterus may be removed, but only if damage to the vasa deferentia and blood supply can be avoided. Isolated hypospadias occurs in ~1 in 250 males and is usually repaired surgically. Most cases are idiopathic, although evidence of penoscrotal hypospadias, poor phallic development, and/or bilateral cryptorchidism requires investigation for an underlying DSD (e.g., partial gonadal dysgenesis, mild defect in testosterone action, or even severe adrenal glucocorticoid and mineralocorticoid synthesis, increasing 17-hydroxyprogesterone and shunting steroid precursors into the androgen synthesis pathway (Fig. 410-4). Glucocorticoid insufficiency causes a compensatory elevation of adrenocorticotropin (ACTH), resulting in adrenal hyperplasia and additional synthesis of steroid precursors proximal to the enzymatic block.


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InternalMed_Harrison. insufficiency causes a compensatory elevation of adrenocorticotropin (ACTH), resulting in adrenal hyperplasia and additional synthesis of steroid precursors proximal to the enzymatic block. Increased androgen synthesis in utero causes androgenization of the 46,XX fetus in the first trimester. Ambiguous genitalia are seen at birth, with varying degrees of clitoral enlargement and labial fusion. Excess androgen production causes gonadotropin-independent precocious puberty in males with 21-OHD.


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InternalMed_Harrison. The salt-wasting form of 21-OHD results from severe combined glucocorticoid and mineralocorticoid deficiency. A salt-wasting crisis usually manifests between 5 and 21 days of life and is a potentially life-threatening event that requires urgent fluid resuscitation and steroid treatment. Thus, a diagnosis of 21-OHD should be considered in any baby with atypical genitalia with bilateral nonpalpable gonads. Males (46,XY) with 21-OHD have no genital abnormalities at birth but are equally susceptible to adrenal insufficiency and salt-losing crises.


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InternalMed_Harrison. Females with the classic simple virilizing form of 21-OHD also present with genital ambiguity. They have impaired cortisol biosynthesis but do not develop salt loss. Patients with nonclassic 21-OHD produce normal amounts of cortisol and aldosterone but at the expense of producing excess androgens. Hirsutism (60%), oligomenorrhea (50%), and acne (30%) are the most common presenting features. This is one of the most common recessive disorders in humans, with an incidence as high as 1 in 100 to 500 in many populations and 1 in 27 in Ashkenazi Jews of Eastern European origin. 2356 TAblE 410-4 SElECTED gEnETiC CAuSES of 46,xx DiSoRDERS of SEx DEvEloPmEnT (DSDs) SRY Translocation Testis or ovotestis − Male or ambiguous SOX9 dup17q24 Unknown − Male or ambiguous RSPO1 AR Testis or ovotestis ± Male or ambiguous Palmar plantar hyperkeratosis, squamous cell skin WNT4 AR Testis or ovotestis − Male or ambiguous SERKAL syndrome (renal dysgenesis, adrenal and lung hypoplasia)


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InternalMed_Harrison. WNT4 AR Testis or ovotestis − Male or ambiguous SERKAL syndrome (renal dysgenesis, adrenal and lung hypoplasia) CAH, primary adrenal failure, mild androgenization due to ↑ DHEA CAH, phenotypic spectrum from severe salt-losing forms associated with adrenal failure to simple virilizing forms with compensated adrenal function, ↑ 17-hydroxyprogesterone Mixed features of 21-hydroxylase deficiency and 17α-hydroxylase/17,20-lyase deficiency, sometimes associated with Antley-Bixler craniosynostosis CAH, hypertension due to ↑ 11-deoxycortisol and 11-deoxycorticosterone Maternal virilization during pregnancy, absent breast development at puberty ↑ ACTH, 17-hydroxyprogesterone and cortisol; failure of dexamethasone suppression


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InternalMed_Harrison. Maternal virilization during pregnancy, absent breast development at puberty ↑ ACTH, 17-hydroxyprogesterone and cortisol; failure of dexamethasone suppression Abbreviations: ACTH, adrenocorticotropin; AR, autosomal recessive; CAH, congenital adrenal hyperplasia; CYP11B1, 11β-hydroxylase; CYP19, aromatase; CYP21A2, 21-hydroxylase; DHEA, dehydroepiandrosterone; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; POR, P450 oxidoreductase; RSPO1, R-spondin 1; SOX9, SRY-related HMG-box gene 9; SRY, sex-related gene on the Y chromosome.


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InternalMed_Harrison. Biochemical features of acute salt-wasting 21-OHD are hyponatremia, hyperkalemia, hypoglycemia, inappropriately low cortisol and aldosterone, and elevated 17-hydroxyprogesterone, ACTH, and plasma renin activity. Presymptomatic diagnosis of classic 21-OHD is now made by neonatal screening tests for increased 17-hydroxyprogesterone in many centers. In most cases, 17-hydroxyprogesterone is markedly increased. In adults, ACTH stimulation (0.25 mg of cosyntropin IV) with assays for 17-hydroxyprogesterone at 0 and 30 min can be useful for detecting nonclassic 21-OHD and heterozygotes (Chap. 406).


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InternalMed_Harrison. Acute salt-wasting crises require fluid resuscitation, IV hydrocortisone, and correction of hypoglycemia. Once the patient is stabilized, glucocorticoids must be given to correct the cortisol insufficiency and suppress ACTH stimulation, thereby preventing further virilization, rapid skeletal maturation, and the development of polycystic ovaries. Typically, hydrocortisone (10–15 mg/m2 per day in three divided doses) is used in childhood with a goal of partially suppressing 17-hydroxyprogesterone (100 to <1000 ng/dL). The aim of treatment is to use the lowest glucocorticoid dose that adequately suppresses adrenal androgen production without causing signs of glucocorticoid excess such as impaired growth and obesity. Salt-wasting conditions are treated with mineralocorticoid replacement. Infants usually need salt supplements up to the first year of life. Plasma renin activity and electrolytes are used to monitor mineralocorticoid replacement. Some patients with simple virilizing 21-OHD


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InternalMed_Harrison. usually need salt supplements up to the first year of life. Plasma renin activity and electrolytes are used to monitor mineralocorticoid replacement. Some patients with simple virilizing 21-OHD also benefit from mineralocorticoid supplements. Parents and patients should be educated about the need for increased doses of steroids during sickness, and patients should carry medic alert systems.


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InternalMed_Harrison. Steroid treatment for older adolescents and adults varies depending on lifestyle, age, and factors such as a desire to optimize fertility. Hydrocortisone remains a useful approach, but treatment with prednisolone at night may provide more complete ACTH suppression. Steroid doses should be adjusted to individual requirements because overtreatment can result in iatrogenic Cushing’s-like features, including weight gain, insulin resistance, hypertension, and osteopenia. Because it is long acting, dexamethasone given at night is useful for ACTH suppression but is often associated with more side effects, making hydrocortisone or prednisolone preferable for most patients. Androstenedione and testosterone may be useful measurements of long-term control, with less fluctuation than 17-hydroxyprogesterone. Mineralocorticoid requirements often decrease in adulthood, and doses should be reassessed and reduced to avoid hypertension in adults. In very severe cases, adrenalectomy has been advocated


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InternalMed_Harrison. Mineralocorticoid requirements often decrease in adulthood, and doses should be reassessed and reduced to avoid hypertension in adults. In very severe cases, adrenalectomy has been advocated but incurs the risks of surgery and total adrenal insufficiency.


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InternalMed_Harrison. Girls with significant genital androgenization due to classic 21-OHD usually undergo vaginal reconstruction and sometimes clitoral reduction (maintaining the glans and nerve supply), but the optimal timing of these procedures is debated, as is the need for the individual to be able to consent. There is a higher threshold for undertaking clitoral surgery in some centers because longterm sensation and ability to achieve orgasm can be affected, but the long-term results of newer techniques are not yet known. Full information about all options should be provided. If surgery is performed in infancy, surgical revision or regular vaginal dilatation may be needed in adolescence or adulthood, and long-term psychological support and psychosexual counseling may be appropriate. Women with 21-OHD frequently develop polycystic ovaries and have reduced fertility, especially when control is poor. Fecundity is achieved in 60–90% of women with good metabolic control, but ovulation induction (or even


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InternalMed_Harrison. develop polycystic ovaries and have reduced fertility, especially when control is poor. Fecundity is achieved in 60–90% of women with good metabolic control, but ovulation induction (or even adrenalectomy) may be required. Dexamethasone should be avoided in pregnancy. Men with poorly controlled 21-OHD may develop testicular adrenal rests and are at risk for reduced fertility. Prenatal treatment of 21-OHD by the administration of dexamethasone to mothers is still under evaluation. However, pending methods to diagnose the disorder early in pregnancy, both affected and nonaffected fetuses will be exposed because treatment is started ideally before 6 to 7 weeks. The longterm effects of prenatal dexamethasone exposure on fetal development are still under evaluation, and current guidelines recommend full informed consent before treatment, ideally in a protocol that allows long-term follow-up of all children treated. Newer techniques such as cell-free fetal DNA testing may potentially reduce


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InternalMed_Harrison. full informed consent before treatment, ideally in a protocol that allows long-term follow-up of all children treated. Newer techniques such as cell-free fetal DNA testing may potentially reduce treatment of nonaffected fetuses.


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InternalMed_Harrison. of treatment and support may be limited. Disorders of the Testes and male Reproductive System Shalender Bhasin, J. Larry Jameson The male reproductive system regulates sex differentiation, viriliza-tion, and the hormonal changes that accompany puberty, ultimately 411 Disorders of the Testes and Male Reproductive System The treatment of other forms of CAH includes mineralocorticoid and glucocorticoid replacement for salt-losing conditions (e.g., StAR, CYP11A1, HSD3β2), suppression of ACTH drive with glucocorticoids in disorders associated with hypertension (e.g., CYP17, CYP11B1), and appropriate sex hormone replacement in adolescence and adulthood, when necessary.


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InternalMed_Harrison. otHer cauSeS Increased androgen synthesis can also occur in CAH due to defects in POR, 11β-hydroxylase (CYP11B1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and with mutations in the genes encoding aromatase (CYP19) and the glucocorticoid receptor. Increased androgen exposure in utero can occur with maternal virilizing tumors and with ingestion of androgenic compounds. OTHER DISORDERS AFFECTING 46,XX FEMALES Congenital absence of the vagina occurs in association with müllerian agenesis or hypoplasia as part of the Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome (rarely caused by WNT4 mutations). This diagnosis should be considered in otherwise phenotypically normal females with primary amenorrhea. Associated features include renal (agenesis) and cervical spinal abnormalities.


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InternalMed_Harrison. The approach to a child or adolescent with ambiguous genita lia or another DSD requires cultural sensitivity, as the con cepts of sex and gender vary widely. Rare genetic DSDs can occur more frequently in specific populations (e.g., 5α-reductase type 2 in the Dominican Republic). Different forms of CAH also show ethnic and geographic variability. In many countries, appropriate biochemical tests may not be readily available, and access to appropriate forms leading to spermatogenesis and fertility. Under the control of the pituitary hormones—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—the Leydig cells of the testes produce testosterone and germ cells are nurtured by Sertoli cells to divide, differentiate, and mature into sperm. During embryonic development, testosterone and dihydrotestosterone (DHT) induce the wolffian duct and virilization of the external genitalia. During puberty, testosterone promotes somatic growth and the development of secondary sex


InternalMed_Harrison

InternalMed_Harrison. and dihydrotestosterone (DHT) induce the wolffian duct and virilization of the external genitalia. During puberty, testosterone promotes somatic growth and the development of secondary sex characteristics. In the adult, testosterone is necessary for spermatogenesis, stimulation of libido and normal sexual function, and maintenance of muscle and bone mass. This chapter focuses on the physiology of the testes and disorders associated with decreased androgen production, which may be caused by gonadotropin deficiency or by primary testis dysfunction. A variety of testosterone formulations now allow more physiologic androgen replacement. Infertility occurs in ~5% of men and is increasingly amenable to treatment by hormone replacement or by using sperm transfer techniques. For further discussion of sexual dysfunction, disorders of the prostate, and testicular cancer, see Chaps. 67, 115, and 116, respectively.


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InternalMed_Harrison. The fetal testis develops from the undifferentiated gonad after expression of a genetic cascade that is initiated by the SRY (sex-related gene on the Y chromosome) (Chap. 410). SRY induces differentiation of Sertoli cells, which surround germ cells and, together with peritubular 2357 myoid cells, form testis cords that will later develop into seminiferous tubules. Fetal Leydig cells and endothelial cells migrate into the gonad from the adjacent mesonephros but may also arise from interstitial cells that reside between testis cords. Leydig cells produce testosterone, which supports the growth and differentiation of wolffian duct structures that develop into the epididymis, vas deferens, and seminal vesicles. Testosterone is also converted to DHT (see below), which induces formation of the prostate and the external male genitalia, including the penis, urethra, and scrotum. Testicular descent through the inguinal canal is controlled in part by Leydig cell production of insulin-like


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InternalMed_Harrison. the prostate and the external male genitalia, including the penis, urethra, and scrotum. Testicular descent through the inguinal canal is controlled in part by Leydig cell production of insulin-like factor 3 (INSL3), which acts via a receptor termed Great (G protein–coupled receptor affecting testis descent). Sertoli cells produce müllerian-inhibiting substance (MIS), which causes regression of the müllerian structures, including the fallopian tube, uterus, and upper segment of the vagina.


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InternalMed_Harrison. Although puberty commonly refers to the maturation of the reproductive axis and the development of secondary sex characteristics, it involves a coordinated response of multiple hormonal systems including the adrenal gland and the growth hormone (GH) axis (Fig. 411-1). The development of secondary sex characteristics is initiated by adrenarche, which usually occurs between 6 and 8 years of age when the adrenal gland begins to produce greater amounts of androgens from the zona reticularis, the principal site of dehydroepiandrosterone (DHEA) production. The sex maturation process is greatly accelerated by the activation of the hypothalamic-pituitary axis and the production of gonadotropin-releasing hormone (GnRH). The GnRH pulse generator in the hypothalamus is active during fetal life and early infancy but is restrained until the early stages of puberty by a neuroendocrine brake imposed by the inhibitory actions of glutamate, γ-aminobutyric acid (GABA), and neuropeptide Y. Although the


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InternalMed_Harrison. infancy but is restrained until the early stages of puberty by a neuroendocrine brake imposed by the inhibitory actions of glutamate, γ-aminobutyric acid (GABA), and neuropeptide Y. Although the pathways that initiate reactivation of the GnRH pulse generator at the onset of puberty have been elusive, mounting evidence supports involvement of GPR54, a G protein–coupled receptor that binds an endogenous ligand, kisspeptin. Individuals with mutations of GPR54 fail to enter puberty, and experiments in primates demonstrate that infusion of the ligand is sufficient to induce premature puberty. Kisspeptin signaling plays an important role in mediating the feedback action of sex steroids on gonadotropin secretion and in regulating the tempo of sexual maturation at puberty. Leptin, a hormone produced by adipose cells, plays a permissive role in the resurgence of GnRH secretion at the onset of puberty, as leptin-deficient individuals also fail to enter puberty (Chap. 415e). The adipocyte


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InternalMed_Harrison. produced by adipose cells, plays a permissive role in the resurgence of GnRH secretion at the onset of puberty, as leptin-deficient individuals also fail to enter puberty (Chap. 415e). The adipocyte hormone leptin, gut hormone ghrelin, neuropeptide Y, and kisspeptin integrate the signals


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InternalMed_Harrison. FIGURE 411-1 Pubertal events in males. Sexual maturity ratings for genitalia and pubic hair and divided into five stages. (From WA Marshall, JM Tanner: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970.) 2358 originating in energy stores and metabolic tissues with mechanisms that control onset of puberty through regulation of GnRH secretion. Energy deficit and excess and metabolic stress are associated with disturbed reproductive maturation and timing of pubertal onset. The early stages of puberty are characterized by nocturnal surges of LH and FSH. Growth of the testes is usually the first sign of puberty, reflecting an increase in seminiferous tubule volume. Increasing levels of testosterone deepen the voice and increase muscle growth. Conversion of testosterone to DHT leads to growth of the external genitalia and pubic hair. DHT also stimulates prostate and facial hair growth and initiates recession of the temporal hairline. The growth spurt occurs


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InternalMed_Harrison. to DHT leads to growth of the external genitalia and pubic hair. DHT also stimulates prostate and facial hair growth and initiates recession of the temporal hairline. The growth spurt occurs at a testicular volume of about 10–12 mL. GH increases early in puberty and is stimulated in part by the rise in gonadal steroids. GH increases the level of insulin-like growth factor I (IGF-I), which enhances linear bone growth. The prolonged pubertal exposure to gonadal steroids (mainly estradiol) ultimately causes epiphyseal closure and limits further bone growth.


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InternalMed_Harrison. Hypothalamic GnRH regulates the production of the pituitary gonadotropins LH and FSH (Fig. 411-2). GnRH is released in discrete pulses approximately every 2 h, resulting in corresponding pulses of LH and FSH. These dynamic hormone pulses account in part for the wide variations in LH and testosterone, even within the same individual. LH acts primarily on the Leydig cell to stimulate testosterone synthesis. The regulatory control of androgen synthesis is mediated by testosterone and estrogen feedback on both the hypothalamus and the pituitary. FSH acts on the Sertoli cell to regulate spermatogenesis and the production of Sertoli products such as inhibin B, which acts to selectively suppress pituitary FSH. Despite these somewhat distinct Leydig and Sertoli cell–regulated pathways, testis function is integrated at several levels: GnRH regulates both gonadotropins; spermatogenesis requires high levels of testosterone; and numerous paracrine interactions between Leydig and Sertoli cells are


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InternalMed_Harrison. is integrated at several levels: GnRH regulates both gonadotropins; spermatogenesis requires high levels of testosterone; and numerous paracrine interactions between Leydig and Sertoli cells are necessary for normal testis function.


InternalMed_Harrison

THE LEYDIG CELL: ANDROGEN SYNTHESIS

InternalMed_Harrison. THE LEYDIG CELL: ANDROGEN SYNTHESIS


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InternalMed_Harrison. LH binds to its seven-transmembrane, G protein–coupled receptor to activate the cyclic AMP pathway. Stimulation of the LH receptor induces steroid acute regulatory (StAR) protein, along with several steroidogenic enzymes involved in androgen synthesis. LH receptor mutations cause Leydig cell hypoplasia or agenesis, underscoring the importance of this pathway for Leydig cell development and function. The rate-limiting process in testosterone synthesis is the delivery of cholesterol by the StAR protein to the inner mitochondrial membrane. Peripheral benzodiazepine receptor, a mitochondrial cholesterol-binding protein, is also an acute regulator of Leydig cell steroidogenesis. The five major enzymatic steps involved in testosterone synthesis are summarized in Fig. 411-3. After cholesterol transport into the mitochondrion, the formation of pregnenolone by CYP11A1 (side chain cleavage enzyme) is a limiting enzymatic step. The 17α-hydroxylase and the 17,20-lyase reactions are catalyzed by a


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InternalMed_Harrison. into the mitochondrion, the formation of pregnenolone by CYP11A1 (side chain cleavage enzyme) is a limiting enzymatic step. The 17α-hydroxylase and the 17,20-lyase reactions are catalyzed by a single enzyme, CYP17; posttranslational modification (phosphorylation) of this enzyme and the presence of specific enzyme cofactors confer 17,20-lyase activity selectively in the testis and zona reticularis of the adrenal gland. Testosterone can be converted to the more potent DHT by 5α-reductase, or it can be aromatized to estradiol by CYP19 (aromatase). Two isoforms of steroid 5α-reductase, SRD5A1 and SRD5A2, have been described; all known kindreds with 5α-reductase deficiency have had mutations in SRD5A2, the predominant form in the prostate and the skin.


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InternalMed_Harrison. Testosterone Transport and Metabolism In males, 95% of circulating testosterone is derived from testicular production (3–10 mg/d). Direct secretion of testosterone by the adrenal and the peripheral conversion of androstenedione to testosterone collectively account for another 0.5 mg/d of testosterone. Only a small amount of DHT (70 μg/d) is secreted directly by the testis; most circulating DHT is derived from peripheral conversion of testosterone. Most of the daily production of estradiol (~45 μg/d) in men is derived from aromatase-mediated peripheral conversion of testosterone and androstenedione.


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InternalMed_Harrison. +––++HypothalamusGonadotrope (LH, FSH) GnRH-producing neuron Tunica albuginea Seminiferous tubules Seminiferous tubules Interstitial Leydig cells (testosterone) AnteriorpituitaryVas deferens Testosterone Inhibin B E2 DHT LH FSH LH FSH Epididymis Sertoli cell (Inhibin B) Spermatid Spermatogonium FIGURE 411-2 Human pituitary gonadotropin axis, structure of testis, and seminiferous tubule. E2, 17β-estradiol; DHT, dihydrotes-tosterone; FSH, follicle-stimulating hormones; GnRH, gonadotropin-releasing; LH, luteinizing hormone.


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InternalMed_Harrison. Circulating testosterone is bound to two plasma proteins: sex hormone–binding globulin (SHBG) and albumin (Fig. 411-4). SHBG binds testosterone with much greater affinity than albumin. Only 0.5–3% of testosterone is unbound. According to the “free hormone” hypothesis, only the unbound fraction is biologically active; however, albumin-bound hormone dissociates readily in the capillaries and may be bioavailable. SHBG-bound testosterone also may be internalized through endocytic pits by binding to a protein called megalin. SHBG concentrations are decreased by androgens, obesity, diabetes mellitus, insulin, and nephrotic syndrome. Conversely, estrogen administration, hyperthyroidism, many chronic inflammatory illnesses, infections such as HIV or hepatitis B and C, and aging are associated with high SHBG concentrations. Testosterone is metabolized predominantly in the liver, although some degradation occurs in peripheral tissues, particularly the (17,20-Lyase)


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InternalMed_Harrison. Testosterone is metabolized predominantly in the liver, although some degradation occurs in peripheral tissues, particularly the (17,20-Lyase) FIGURE 411-3 The biochemical pathway in the conversion of 27-carbon sterol cholesterol to androgens and estrogens. • External genitalia• Prostate growth• Acne• Facial/body hair• Scalp hair loss• Hypothalamic/ pituitary feedback• Bone resorption• Epiphyseal closure• Gynecomastia• Some vascular and behavioral effectsAlbumin(50-70%)Estradiol• Wolffian duct• Bone formation• Muscle mass• SpermatogenesisSHBG(30-45%)Unbound(0.5-3.0%)TestosteroneExcretion(90%)Dihydrotestosterone(DHT)Aromatase(0.3%)5˜-Reductase(6-8%)Testosterone (5 mg/d) FIGURE 411-4 Androgen metabolism and actions. SHBG, sex hormone–binding globulin.


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InternalMed_Harrison. FIGURE 411-4 Androgen metabolism and actions. SHBG, sex hormone–binding globulin. prostate and the skin. In the liver, testosterone is converted by 2359 a series of enzymatic steps that involve 5αand 5β-reductases, 3αand 3β-hydroxysteroid dehydrogenases, and 17β-hydroxysteroid dehydrogenase into androsterone, etiocholanolone, DHT, and 3-α-androstanediol. These compounds undergo glucuronidation or sulfation before being excreted by the kidneys.


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InternalMed_Harrison. Mechanism of Androgen Action Testosterone exerts some of its biologic effects by binding to androgen receptor, either directly or after its conversion to DHT by the steroid 5-α reductase. Testosterone’s effects on the skeletal muscle, erythropoiesis, and bone in men do not require its obligatory conversion to DHT. However, the conversion of testosterone to DHT is necessary for the masculinization of the urogenital sinus and genital tubercle. Aromatization of testosterone to estradiol mediates additional effects of testosterone on the bone resorption, epiphyseal closure, sexual desire, vascular endothelium, and fat. DHT can also be converted in some tissues by 3-keto reductase/3β-hydroxysteroid dehydrogenase enzymes to 5α-androstane-3β,17β-diol, which is a high-affinity ligand and agonist of estrogen receptor β.


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InternalMed_Harrison. The androgen receptor (AR) is structurally related to the nuclear receptors for estrogen, glucocorticoids, and progesterone (Chap. 400e). The AR is encoded by a gene on the long arm of the X chromosome and has a molecular mass of about 110 kDa. A polymorphic region in the amino terminus of the receptor, which contains a variable number of glutamine repeats, modifies the transcriptional activity of the receptor. The AR protein is distributed in both the cytoplasm and the nucleus. The ligand binding to the AR induces con formational changes that allow the recruitment and assembly of tissue-specific cofactors and causes it to translocate into the nucleus, where it binds to DNA or other transcription factors already bound to DNA. Thus, the AR is a ligand-regulated transcription factor that regulates the expression of androgen-dependent genes in a tissue-specific manner. Some androgen effects may be mediated by nongenomic AR signal transduction pathways. Testosterone binds to AR with half


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InternalMed_Harrison. the expression of androgen-dependent genes in a tissue-specific manner. Some androgen effects may be mediated by nongenomic AR signal transduction pathways. Testosterone binds to AR with half the affinity of DHT. The DHT-AR complex also has greater thermostability and a slower dissociation rate than the testosterone-AR complex. However, the molecular basis for selective testosterone versus DHT actions remains incompletely explained.


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InternalMed_Harrison. THE SEMINIFEROUS TUBULES: SPERMATOGENESIS


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InternalMed_Harrison. The seminiferous tubules are convoluted, closed loops with both ends emptying into the rete testis, a network of progressively larger efferent ducts that ultimately form the epididymis (Fig. 411-2). The seminiferous tubules total about 600 m in length and comprise about two-thirds of testis volume. The walls of the tubules are formed by polarized Sertoli cells that are apposed to peritubular myoid cells. Tight junctions between Sertoli cells create a blood-testis barrier. Germ cells compose the majority of the seminiferous epithelium (~60%) and are intimately embedded within the cytoplasmic extensions of the Sertoli cells, which function as “nurse cells.” Germ cells progress through characteristic stages of mitotic and meiotic divisions. A pool of type A spermatogonia serve as stem cells capable of self-renewal. Primary spermatocytes are derived from type B spermatogonia and undergo meiosis before progressing to spermatids that undergo spermiogenesis (a differentiation process


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InternalMed_Harrison. cells capable of self-renewal. Primary spermatocytes are derived from type B spermatogonia and undergo meiosis before progressing to spermatids that undergo spermiogenesis (a differentiation process involving chromatin condensation, acquisition of an acrosome, elongation of cytoplasm, and formation of a tail) and are released from Sertoli cells as mature spermatozoa. The complete differentiation process into mature sperm requires 74 days. Peristaltic-type action by peritubular myoid cells transports sperm into the efferent ducts. The spermatozoa spend an additional 21 days in the epididymis, where they undergo further maturation and capacitation. The normal adult testes produce >100 million sperm per day.


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InternalMed_Harrison. Naturally occurring mutations in the FSHβ gene and in the FSH receptor confirm an important, but not essential, role for this pathway in spermatogenesis. Females with these mutations are hypogonadal and infertile because ovarian follicles do not mature; males exhibit variable degrees of reduced spermatogenesis, presumably because of impaired Sertoli cell function. Because Sertoli cells produce inhibin B, an inhibitor of FSH, seminiferous tubule damage (e.g., by radiation)


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InternalMed_Harrison. Disorders of the Testes and Male Reproductive System 2360 causes a selective increase of FSH. Testosterone reaches very high concentrations locally in the testis and is essential for spermatogenesis. The cooperative actions of FSH and testosterone are important in the progression of meiosis and spermiation. FSH and testosterone regulate germ cell survival via the intrinsic and the extrinsic apoptotic mechanisms. FSH may also play an important role in supporting spermatogonia. Gonadotropin-regulated testicular RNA helicase (GRTH/ DDX25), a testis-specific gonadotropin/androgen-regulated RNA helicase, is present in germ cells and Leydig cells and may be an important factor in the paracrine regulation of germ cell development. Several cytokines and growth factors are also involved in the regulation of spermatogenesis by paracrine and autocrine mechanisms. A number of knockout mouse models exhibit impaired germ cell development or spermatogenesis, presaging possible mutations associated


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InternalMed_Harrison. of spermatogenesis by paracrine and autocrine mechanisms. A number of knockout mouse models exhibit impaired germ cell development or spermatogenesis, presaging possible mutations associated with male infertility. The human Y chromosome contains a small pseudoautosomal region that can recombine with homologous regions of the X chromosome. Most of the Y chromosome does not recombine with the X chromosome and is referred to as the male-specific region of the Y (MSY). The MSY contains 156 transcription units that encode for 26 proteins, including nine families of Y-specific multicopy genes; many of these Y-specific genes are also testis-specific and necessary for spermatogenesis. Microdeletions of several Y chromosome azoospermia factor (AZF) genes (e.g., RNA-binding motif, RBM; deleted in azoospermia, DAZ) are associated with oligospermia or azoospermia.


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InternalMed_Harrison. Treatment options for male factor infertility have expanded greatly in recent years. Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins (see below). Assisted reproductive technologies such as the in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15–20 × 106/mL and normal motility). Moderate male factor infertility (10–15 × 106/mL and 20–40% motility) should begin with intrauterine insemination alone or in combination with treatment of the female partner with clomiphene or gonadotropins, but it may require IVF with or without ICSI. For men with a severe defect (sperm count of <10 × 106/mL, 10% motility), IVF with ICSI or donor


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InternalMed_Harrison. of the female partner with clomiphene or gonadotropins, but it may require IVF with or without ICSI. For men with a severe defect (sperm count of <10 × 106/mL, 10% motility), IVF with ICSI or donor sperm should be used.


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InternalMed_Harrison. The history should focus on developmental stages such as puberty and growth spurts, as well as androgen-dependent events such as early morning erections, frequency and intensity of sexual thoughts, and frequency of masturbation or intercourse. Although libido and the overall frequency of sexual acts are decreased in androgen-deficient men, young hypogonadal men may achieve erections in response to visual erotic stimuli. Men with acquired androgen deficiency often report decreased energy and increased irritability.


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InternalMed_Harrison. The physical examination should focus on secondary sex characteristics such as hair growth, gynecomastia, testicular volume, prostate, and height and body proportions. Eunuchoid proportions are defined as an arm span >2 cm greater than height and suggest that androgen deficiency occurred before epiphyseal fusion. Hair growth in the face, axilla, chest, and pubic regions is androgen-dependent; however, changes may not be noticeable unless androgen deficiency is severe and prolonged. Ethnicity also influences the intensity of hair growth (Chap. 68). Testicular volume is best assessed by using a Prader orchidometer. Testes range from 3.5 to 5.5 cm in length, which corresponds to a volume of 12–25 mL. Advanced age does not influence testicular size, although the consistency becomes less firm. Asian men generally have smaller testes than Western Europeans, independent of differences in body size. Because of its possible role in infertility, the presence of varicocele should be sought by


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InternalMed_Harrison. Asian men generally have smaller testes than Western Europeans, independent of differences in body size. Because of its possible role in infertility, the presence of varicocele should be sought by palpation while the patient is standing; it is more common on the left side. Patients with Klinefelter’s syndrome have markedly reduced testicular volumes (1–2 mL). In congenital hypogonadotropic hypogonadism, testicular volumes provide a good index for the degree of gonadotropin deficiency and the likelihood of response to therapy.


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InternalMed_Harrison. LH and FSH are measured using two-site immunoradiometric, immunofluorometric, or chemiluminescent assays, which have very low cross-reactivity with other pituitary glycoprotein hormones and human chorionic gonadotropin (hCG) and have sufficient sensitivity to measure the low levels present in patients with hypogonadotropic hypogonadism. In men with a low testosterone level, an LH level can distinguish primary (high LH) versus secondary (low or inappropriately normal LH) hypogonadism. An elevated LH level indicates a primary defect at the testicular level, whereas a low or inappropriately normal LH level suggests a defect at the hypothalamic-pituitary level. LH pulses occur about every 1–3 h in normal men. Thus, gonadotropin levels fluctuate, and samples should be pooled or repeated when results are equivocal. FSH is less pulsatile than LH because it has a longer half-life. Selective increase in FSH suggests damage to the seminiferous tubules. Inhibin B, a Sertoli cell product that


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InternalMed_Harrison. results are equivocal. FSH is less pulsatile than LH because it has a longer half-life. Selective increase in FSH suggests damage to the seminiferous tubules. Inhibin B, a Sertoli cell product that suppresses FSH, is reduced with seminiferous tubule damage. Inhibin B is a dimer with α-βB subunits and is measured by two-site immunoassays.


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InternalMed_Harrison. GnRH Stimulation Testing The GnRH test is performed by measuring LH and FSH concentrations at baseline and at 30 and 60 min after intravenous administration of 100 μg of GnRH. A minimally acceptable response is a twofold LH increase and a 50% FSH increase. In the prepubertal period or with severe GnRH deficiency, the gonadotrope may not respond to a single bolus of GnRH because it has not been primed by endogenous hypothalamic GnRH; in these patients, GnRH responsiveness may be restored by chronic, pulsatile GnRH administration. With the availability of sensitive and specific LH assays, GnRH stimulation testing is used rarely except to evaluate gonadotrope function in patients who have undergone pituitary surgery or have a space-occupying lesion in the hypothalamic-pituitary region.


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InternalMed_Harrison. TESTOSTERONE ASSAYS Total Testosterone Total testosterone includes both unbound and protein-bound testosterone and is measured by radioimmunoassays, immunometric assays, or liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS involves extraction of serum by organic solvents, separation of testosterone from other steroids by high-performance liquid chromatography and mass spectrometry, and quantitation of unique testosterone fragments by mass spectrometry. LC-MS/MS provides accurate and sensitive measurements of testosterone levels even in the low range and is emerging as the method of choice for testosterone measurement. Laboratories that have been certified by the Centers for Disease Control and Prevention (CDC) Hormone Standardization Program for Testosterone (HoST) can ensure that testosterone measurements are accurate and calibrated to an international standard. A single fasting morning sample provides a good approximation of the average testosterone concentration


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InternalMed_Harrison. ensure that testosterone measurements are accurate and calibrated to an international standard. A single fasting morning sample provides a good approximation of the average testosterone concentration with the realization that testosterone levels fluctuate in response to pulsatile LH. Testosterone is generally lower in the late afternoon and is reduced by acute illness. The testosterone concentration in healthy young men ranges from 300 to 1000 ng/dL in most laboratories, and efforts are under way to generate harmonized population-based reference ranges that can be applied to all CDC-certified laboratories. Alterations in SHBG levels due to aging, obesity, diabetes mellitus, hyperthyroidism, some types of medications, or chronic illness or on a congenital basis can affect total testosterone levels. Heritable factors contribute substantially to the population-level variation in testosterone levels, and genome-wide association studies have revealed polymorphisms in the SHBG gene as


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InternalMed_Harrison. levels. Heritable factors contribute substantially to the population-level variation in testosterone levels, and genome-wide association studies have revealed polymorphisms in the SHBG gene as important contributors to variation in testosterone levels.


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InternalMed_Harrison. Measurement of Unbound Testosterone Levels Most circulating testosterone is bound to SHBG and to albumin; only 0.5–3% of circulating testosterone is unbound, or “free.” The unbound testosterone concentration can be measured by equilibrium dialysis or calculated from total testosterone, SHBG, and albumin concentrations. Recent research has shown that testosterone binding to SHBG is a multistep process that involves complex homoallostery within the SHBG dimer; a novel allosteric model of testosterone binding to SHBG dimers provides good estimates of free testosterone concentrations. The previous law of mass action equations based on linear models of testosterone binding to SHBG have been shown to be erroneous. Tracer analogue methods are relatively inexpensive and convenient, but they are inaccurate. Bioavailable testosterone refers to unbound testosterone plus testosterone that is loosely bound to albumin; it can be determined by the ammonium sulfate precipitation method.


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InternalMed_Harrison. hCG Stimulation Test The hCG stimulation test is performed by administering a single injection of 1500–4000 IU of hCG intramuscularly and measuring testosterone levels at baseline and 24, 48, 72, and 120 h after hCG injection. An alternative regimen involves three injections of 1500 units of hCG on successive days and measuring testosterone levels 24 h after the last dose. An acceptable response to hCG is a doubling of the testosterone concentration in adult men. In prepubertal boys, an increase in testosterone to >150 ng/dL indicates the presence of testicular tissue. No response may indicate an absence of testicular tissue or marked impairment of Leydig cell function. Measurement of MIS, a Sertoli cell product, is also used to detect the presence of testes in prepubertal boys with cryptorchidism.


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InternalMed_Harrison. Semen analysis is the most important step in the evaluation of male infertility. Samples are collected by masturbation following a period of abstinence for 2–3 days. Semen volumes and sperm concentrations vary considerably among fertile men, and several samples may be needed before concluding that the results are abnormal. Analysis should be performed within an hour of collection. Using semen samples from over 4500 men in 14 countries, whose partners had a time-to-pregnancy of less than 12 months, the World Health Organization (WHO) has generated the following one-sided reference limits for semen parameters: semen volume, 1.5 mL; total sperm number, 39 million per ejaculate; sperm concentration, 15 million/mL; vitality, 58% live; progressive motility, 32%; total (progressive + nonprogressive) motility, 40%; morphologically normal forms, 4.0%. Some men with low sperm counts are nevertheless fertile. A variety of tests for sperm function can be performed in specialized laboratories, but


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InternalMed_Harrison. motility, 40%; morphologically normal forms, 4.0%. Some men with low sperm counts are nevertheless fertile. A variety of tests for sperm function can be performed in specialized laboratories, but these add relatively little to the treatment options.


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InternalMed_Harrison. Testicular biopsy is useful in some patients with oligospermia or azoospermia as an aid in diagnosis and indication for the feasibility of treatment. Using local anesthesia, fine-needle aspiration biopsy is performed to aspirate tissue for histology. Alternatively, open biopsies can be performed under local or general anesthesia when more tissue is required. A normal biopsy in an azoospermic man with a normal FSH level suggests obstruction of the vas deferens, which may be correctable surgically. Biopsies are also used to harvest sperm for ICSI and to classify disorders such as hypospermatogenesis (all stages present but in reduced numbers), germ cell arrest (usually at primary spermatocyte stage), and Sertoli cell–only syndrome (absent germ cells) or hyalinization (sclerosis with absent cellular elements). See Chap. 410.


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InternalMed_Harrison. See Chap. 410. The onset and tempo of puberty varies greatly in the general population and is affected by genetic and environmental factors. Although some of the variance in the timing of puberty is explained by heritable factors, the genes involved remain unknown. Puberty in boys before age 9 is considered precocious. Isosexual precocity refers to premature sexual development consistent with phenotypic sex and includes features such as the development of facial hair and phallic growth. Isosexual precocity is divided into gonadotropindependent and gonadotropin-independent causes of androgen excess (Table 411-1). Heterosexual precocity refers to the premature development of estrogenic features in boys, such as breast development.


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InternalMed_Harrison. Gonadotropin-Dependent Precocious Puberty This disorder, called central precocious puberty (CPP), is less common in boys than in girls. It is caused by premature activation of the GnRH pulse generator, sometimes because of central nervous system (CNS) lesions such as hypothalamic hamartomas, but it is often idiopathic. CPP is characterized by gonadotropin levels that are inappropriately elevated for age. Because pituitary priming has occurred, GnRH elicits LH and FSH responses typical of those seen in puberty or in adults. Magnetic resonance imaging (MRI) should be performed to exclude a mass, structural defect, infection, or inflammatory process. Mutations in MKRN3, an imprinted gene encoding makorin ring-finger protein 3, which is expressed only from the paternally inherited allele, have been associated with CPP.


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InternalMed_Harrison. Gonadotropin-Independent Precocious Puberty In gonadotropinindependent precocious puberty, androgens from the testis or the adrenal are increased, but gonadotropins are low. This group of disorders includes hCG-secreting tumors; congenital adrenal hyperplasia; sex steroid–producing tumors of the testis, adrenal, and ovary; accidental or deliberate exogenous sex steroid administration; hypothyroidism; and activating mutations of the LH receptor or Gsα subunit. CAuSES of PRECoCiouS oR DElAyED PubERTy in boyS I. Precocious puberty A. Gonadotropin-dependent 1. 2. 3. B. Gonadotropin-independent 1. 2. 3. 4. 5. II. A. Constitutional delay of growth and puberty B. 1. 2. 3. C. CNS tumors and their treatment (radiotherapy and surgery) D. Hypothalamic-pituitary causes of pubertal failure (low gonadotropins) 1. 2. a. b. E. Gonadal causes of pubertal failure (elevated gonadotropins) 1. 2. 3. 4. 5. F. Androgen insensitivity


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InternalMed_Harrison. D. Hypothalamic-pituitary causes of pubertal failure (low gonadotropins) 1. 2. a. b. E. Gonadal causes of pubertal failure (elevated gonadotropins) 1. 2. 3. 4. 5. F. Androgen insensitivity Abbreviations: CNS, central nervous system; GnRH, gonadotropin-releasing hormone; hCG, human chronic gonadotropin; LH, luteinizing hormone.


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InternalMed_Harrison. 2. 3. 4. 5. F. Androgen insensitivity Abbreviations: CNS, central nervous system; GnRH, gonadotropin-releasing hormone; hCG, human chronic gonadotropin; LH, luteinizing hormone. Disorders of the Testes and Male Reproductive System 2362 familial male-limited precociouS puBerty Also called testotoxicosis, familial male-limited precocious puberty is an autosomal dominant disorder caused by activating mutations in the LH receptor, leading to constitutive stimulation of the cyclic AMP pathway and testosterone production. Clinical features include premature androgenization in boys, growth acceleration in early childhood, and advanced bone age followed by premature epiphyseal fusion. Testosterone is elevated, and LH is suppressed. Treatment options include inhibitors of testosterone synthesis (e.g., ketoconazole), AR antagonists (e.g., flutamide and bicalutamide), and aromatase inhibitors (e.g., anastrazole).


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InternalMed_Harrison. mccune-alBriGHt Syndrome This is a sporadic disorder caused by somatic (postzygotic) activating mutations in the Gsα subunit that links G protein–coupled receptors to intracellular signaling pathways (Chap. 426e). The mutations impair the guanosine triphosphatase activity of the Gsα protein, leading to constitutive activation of adenylyl cyclase. Like activating LH receptor mutations, this stimulates testosterone production and causes gonadotropin-independent precocious puberty. In addition to sexual precocity, affected individuals may have autonomy in the adrenals, pituitary, and thyroid glands. Café au lait spots are characteristic skin lesions that reflect the onset of the somatic mutations in melanocytes during embryonic development. Polyostotic fibrous dysplasia is caused by activation of the parathyroid hormone receptor pathway in bone. Treatment is similar to that in patients with activating LH receptor mutations. Bisphosphonates have been used to treat bone lesions.


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InternalMed_Harrison. conGenital adrenal HyperplaSia Boys with congenital adrenal hyperplasia (CAH) who are not well controlled with glucocorticoid suppression of adrenocorticotropic hormone (ACTH) can develop premature virilization because of excessive androgen production by the adrenal gland (Chaps. 406 and 410). LH is low, and the testes are small. Adrenal rests may develop within the testis of poorly controlled patients with CAH because of chronic ACTH stimulation; adrenal rests do not require surgical removal and regress with effective glucocorticoid therapy. Some children with CAH may develop gonadotropin-dependent precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis, elevated gonadotropins, and testicular growth.


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InternalMed_Harrison. Heterosexual Sexual Precocity Breast enlargement in prepubertal boys can result from familial aromatase excess, estrogen-producing tumors in the adrenal gland, Sertoli cell tumors in the testis, marijuana smoking, or exogenous estrogens or androgens. Occasionally, germ cell tumors that secrete hCG can be associated with breast enlargement due to excessive stimulation of estrogen production (see “Gynecomastia,” below). APPROACH TO THE PATIENT:


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InternalMed_Harrison. After verification of precocious development, serum LH and FSH levels should be measured to determine whether gonadotropins are increased in relation to chronologic age (gonadotropin-dependent) or whether sex steroid secretion is occurring independent of LH and FSH (gonadotropin-independent). In children with gonadotropindependent precocious puberty, CNS lesions should be excluded by history, neurologic examination, and MRI scan of the head. If organic causes are not found, one is left with the diagnosis of idiopathic central precocity. Patients with high testosterone but suppressed LH concentrations have gonadotropin-independent sexual precocity; in these patients, DHEA sulfate (DHEAS) and 17α-hydroxyprogesterone should be measured. High levels of testosterone and 17α-hydroxyprogesterone suggest the possibility of CAH due to 21α-hydroxylase or 11β-hydroxylase deficiency. If testosterone and DHEAS are elevated, adrenal tumors should be excluded by obtaining a computed tomography (CT)


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InternalMed_Harrison. suggest the possibility of CAH due to 21α-hydroxylase or 11β-hydroxylase deficiency. If testosterone and DHEAS are elevated, adrenal tumors should be excluded by obtaining a computed tomography (CT) scan of the adrenal glands. Patients with elevated testosterone but without increased 17α-hydroxyprogesterone or DHEAS should undergo careful evaluation of the testis by palpation and ultrasound to exclude a Leydig cell neoplasm. Activating mutations of the LH receptor should be considered in children with gonadotropinindependent precocious puberty in whom CAH, androgen abuse, and adrenal and testicular neoplasms have been excluded.


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InternalMed_Harrison. In patients with a known cause (e.g., a CNS lesion or a testicular tumor), therapy should be directed toward the underlying disorder. In patients with idiopathic CPP, long-acting GnRH analogues can be used to suppress gonadotropins and decrease testosterone, halt early pubertal development, delay accelerated bone maturation, prevent early epiphyseal closure, promote final height gain, and mitigate the psychosocial consequences of early pubertal development without causing osteoporosis. The treatment is most effective for increasing final adult height if it is initiated before age 6. Puberty resumes after discontinuation of the GnRH analogue. Counseling is an important aspect of the overall treatment strategy.