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“Approved” on the meeting of methodical board Department of Obstetrics and Gynaecology with the Course of Infantile and Juvenile Gynaecology dated “__”_________ 20__, minutes № __ Deputy Chief, DMS ___________ professor O.A.Andriiets Methodological Instructions №4 to organize independent student’s work on the topic: “Abnormalities of sexual development of girls. Classification, clinical picture, diagnostics and principles of treatment” Subject: Infantile Gynaecology Year: VI Faculty: Medical Number of hours: 2 and Juvenile Methodical instructions compiled by: assistant lecturer Rak L.M. Chernivtsi - 2008 I. Topic: Abnormalities of sexual development of girls. Classification, clinical picture, diagnostics and principles of treatment II. Class duration – 4 hours. III. Educational objectives: The student must know: 1. Special methods of examination in girls with abnormalities of sexual development. 2. Deontology of communication with patients with such pathology in juvenile age. 3. Estimate data of general clinical, special, hormonal, roentgenological, medical and genetic examination of girls with abnormalities of sexual development. The student must be able to: Examine of a patient with abnormalities of sexual development. Make diagnostics and treatment. Interpret data of clinical and laboratorial and instrumental examination. IV. Advice to the student. Disorders of Puberty Delayed Puberty o Delay of puberty can be caused by anatomic abnormalities, chromosomal disorders, neoplastic growths, or nutritional deficiencies. o Commonly presents as a physical delay in maturation combined with amenorrhea. o Causes of delayed puberty can be classified, based on the level of follicle stimulating hormone (FSH) present, as outlined in Table 30.5. o Hypergonadotropic Hypogonadism (High FSH) A sufficient amount of gonadotropins are present, but the end organs are not responsive and therefore do not produce sex steroids. Gonadal dysgenesis Present as phenotypic female with persistent prepubertal development. Usually lack breast development. May have some secondary sex characteristics and spontaneous menstruation. Most often associated with primary amenorrhea. Table 30.5 An Overview of Causes of Delayed Puberty FSH Differential Level Diagnosis High >30 mIU/mL Gonadal dysgenesis syndromes: Turner's syndrome, Sweyer's syndrome Primary ovarian failure Low <10 mIU/mL Constitutional delay Intracranial neoplasms Isolated gonadotropin deficiencies Hormone deficiencies Kallmann syndrome Prader-Labhart-Willi syndrome Laurence-Moon-Biedl syndrome Chronic disease and malnutrition Normal Anatomic deformities result in normal development with primary amenorrhea. Imperforate hymen Transverse vaginal septum MГјllerian agenesis o Turner syndrome (45, X) is most commonly associated with gonadal dysgenesis. Occurs in 1 in 2,000 to 2,500 born girls and is present in approximately 6% of all spontaneous abortions (3). Sweyer syndrome(46, XY) is also associated with gonadal dysgenesis, but patients often have a normal-totall stature. Most often related to a mutation or structural abnormality of the Y chromosome. Must remove gonads. Primary ovarian failure Ovaries develop but do not contain oocytes; may be associated with chemotherapy, radiation, galactosemia, gonadotropin resistance, autoimmune ovarian failure, or ovarian failure secondary to previous infection. Treatment involves administration of exogenous estrogen and progesterone to avoid osteoporosis and to facilitate development of secondary sexual characteristics. Hypogonadotrophic Hypogonadism (Low FSH) An insufficient level of gonadotropins is present to permit follicular development and therefore sex steroids are not produced. Chronic disease of malnutrition: Conditions including states of malnutrition, including starvation, anorexia nervosa, cystic fibrosis, Crohn's disease, diabetes mellitus, inflammatory o disease, and hypothyroidism, are thought to lead to a disruption of gonadotropin-releasing hormone GnRH production, therefore resulting in pubertal delay (4). Constitutional delay: A delay in the (GnRH) pulse generator postpones the normal physiologic events of puberty. Intracranial neoplasms: Both craniopharyngiomas and pituitary adenomas may cause delayed puberty. Visual symptoms are often associated with these tumors, as is short stature and diabetes insipidus. Diagnosis is by CT or MRI of the head. Treatment includes either surgical excision or radiotherapy. Isolated gonadotropin deficiencies: often secondary to abnormalities in genes encoding proteins related to GnRH, FSH, or leutinizing hormone (LH) (3). Hormone deficiencies: Any aberration of growth hormone or thyroid hormone levels will affect puberty. Therefore, these levels should be investigated and treated appropriately. In addition, hyperprolactinemia can cause a decrease in levels of FSH and LH and thus delay puberty. Kallmann syndrome: A sporadic or X-linked syndrome with a classic triad of anosmia, hypogonadism, and color blindness. The hypothalamus cannot secrete GnRH due to dysfunction in the arcuate nucleus. Few or no secondary sexual characteristics are present. Prader-Labhart-Willi syndrome: an autosomal dominant condition associated with extreme obesity, emotional instability, and delayed puberty secondary to hypothalamic dysfunction (4). Laurence-Moon syndrome: a rare autosomal disorder associated with retinitis pigmentosa, hypogonadism, and spastic paraplegia (4). Bardet-Biedl syndrome: a rare autosomal recessive disorder associated with retinitis pigmentosa, hypogonadism, and postaxial polydactyly (4). Eugonadism (Normal FSH) In cases of eugonadism, the hypothalamic-pituitary-gonadal axis remains intact, and delay of puberty presents with primary amenorrhea related to anatomic abnormalities in the genitourinary tract, androgen insensitivity, or inappropriate positive feedback mechanisms. Anatomic abnormalities of the genitourinary tract resulting in primary amenorrhea: Imperforate hymen: may be evident in a neonate and may regress as the girl enters childhood. After menarche, the imperforate hymen may become evident when accumulating menstrual blood forms a hematocolpos and may present as an abdominal mass. Surgical intervention is required to incise the hymen and allow stored debris to escape. Transverse vaginal septum: due to failure of canalization of mГјllerian tubules and the sinovaginal bulb, leaving a membrane present. May be associated with urinary tract abnormalities as well. If the membrane is thin, it can be incised and dilated. If it is thick, surgical excision with a split thickness skin graft may be required. MГјllerian agenesis: failure of the mГјllerian tract to develop results in a blind vaginal pouch without uterus or fallopian tubes present. Ovaries are present and function normally and, therefore, puberty progresses as usual with primary amenorrhea as a presenting complaint. This must be distinguished from androgen insensitivity, as described later. One-third of these patients have associated urinary tract anomalies, and 12% have skeletal anomalies. A neovagina can be created by progressive dilation or surgery. Vaginal atresia: The lower vagina is replaced by fibrous tissue; differentiated from mГјllerian agenesis by the presence of normal uterus and fallopian tubes. Androgen insensitivity: discussed later under male feminization. Karyotype XY males present as phenotypic females with a blind vaginal pouch secondary to an insensitivity of circulating androgens. Other causes of primary amenorrhea with eugonadism include anovulation, androgen producing adrenal disease, and polycystic ovarian syndrome. Precocious Puberty o Precocious puberty is a rare condition that occurs in only 1 of 10,000 girls (5). o Defined as evidence of secondary sexual characteristics, including breast or pubic hair development at an age more than 2.5 standard deviations below the mean (5). o According to a recent study, such findings should be investigated in African American girls under age 6 and Caucasian girls under age 7 (6). o Characteristic accelerated growth velocity in combination with rapid bone growth and maturation can result in short adult stature (7). o Common causes of precocious puberty can be divided into GnRHdependent disorders, or true or central precocious puberty, versus GnRH-independent disorders, or pseudoprecocious puberty. o o Central Precocious Puberty Most commonly idiopathic; secondary sexual characteristics progress in normal sequence but more rapidly than in normal puberty, and may fluctuate between progression and regression. Related to premature development of the hypothalamicpituitary axis and is therefore GnRH-dependent, but the initiating cause is unknown (5). May be transmitted in an autosomal recessive fashion, so check family history. Often ovarian follicular cysts are present due to elevated levels of LH and FSH (5). Other causes of central precocious puberty involve central nervous system disease: Disease often involves areas surrounding the hypothalamus; mass effect, radiation, or ectopic GnRH secreting cells are thought to cause premature activation of pulsatile secretion of GnRH from the hypothalamus. Diagnosis by CT or MRI of the head; history may be significant for headache, mental status changes, mental retardation, dysmorphic syndromes, along with the premature development of secondary sexual characteristics. Treatment should be directed at the underlying cause; the location of many of such tumors makes resection difficult, and, as a result, chemotherapy or radiation may be involved. GnRH agonist administration can result in a short burst of gonadotropin release followed by down-regulation and desensitization resulting in an overall decrease in the level of circulating gonadotropins. Follow estradiol levels to make appropriate dose adjustments (8). Pseudoprecocious Puberty Premature development of secondary sexual characteristics occurs by a GnRH-independent mechanism. Differential diagnosis includes estrogen-secreting tumors, benign follicular ovarian cysts, McCune-Albright syndrome, Peutz-Jeghers syndrome, adrenal disorders, and primary hypothyroidism. Estrogen secreting ovarian tumors Granulosa cell tumors (60%): usually >8 cm in size; 80% are palpable on abdominal examination; others include arrhenoblastomas, thecomas, lipid cell tumors, teratomas, or choriocarcinomas. Diagnose by sonography, manage surgically with adjuvant chemotherapy, if indicated, and follow by estradiol levels. Benign follicular ovarian cysts Most common form of estrogen-secreting masses in children May require a diagnostic laparoscopy versus exploratory laparotomy to differentiate from a malignant tumor. Removal of the cyst may be therapeutic. McCune-Albright syndrome Triad: cafГ© au lait spots, polyostotic fibrous dysplasia, and cysts of skull and long bones; precocious puberty is present in 40% (9). Sexual precocity results from recurrent follicular cyst. Removal of cyst is not helpful. Aromatase inhibitors (i.e., testolactone) may help symptoms. Evaluate with serial pelvic sonograms to detect the presence of gonadal tumors. Peutz-Jeghers syndrome Commonly characterized by mucocutaneous pigmentation and GI polyposis Also associated with rare sex cord tumors, including epithelial tumors of the ovary, dysgerminomas, or Sertoli-Leydig cell tumors, whose estrogen secretion may result in feminization and incomplete sexual precocity Girls with Peutz-Jeghers syndrome should be screened with serial pelvic sonograms. Adrenal disorders Some adrenal adenomas have been noted to secrete estrogen alone and may therefore give rise to sexual precocity. Primary hypothyroidism Characterized by premature breast development and galactorrhea without an associated growth spurt Key points in evaluation and management of precocious puberty Perform a detailed evaluation with Tanner staging. Laboratory data should include LH, FSH, estradiol, progesterone, 17-hydroxyprogesterone, DHEA, DHEAS, TSH, T4, hCG (5). A GnRH stimulation test would provide a definitive diagnosis of central precocious puberty (5). Obtain an x-ray to determine bone age. Head CT or MRI can rule out an intracranial mass. Abdominal/pelvic ultrasound can be used to evaluate the ovaries (5). Goals for management include maximizing adult height and delaying maturation until a normal age of puberty. Treat the intracranial, ovarian, or adrenal pathology if present and attempt to reduce associated emotional problems (8). Male Feminization o Genetic males (XY) undergo feminization related to androgen insensitivity. o Complete androgen insensitivity, or “testicular feminization” (10). Transmitted in a maternal X-linked recessive fashion Pathophysiology: Androgen presence is unable to induce the Wolffian duct to mature and, as a result, seminal vesicles, vas deferens, and epididymis do not form. AntimГјllerian hormone is present so mГјllerian duct formation remains inhibited such that uterus, cervix, and fallopian tubes do not form either. The resulting phenotype is female, with a vagina derived from the urogenital sinus that ends in a blind pouch, and testes that often descend through the inguinal canal. Clinical presentation: primary amenorrhea, Tanner stage V breast development, scant axillary and pubic hair Management: gonadectomy is recommended secondary to an increased incidence of malignancy; exogenous estrogen therapy is also recommended. o Incomplete androgen insensitivity (10) Less common with presentation ranging from near complete masculinization to near complete failure or virilization. As minimal sensitivity to androgens is present, the Wolffian duct system develops to some extent, although spermatogenesis usually remains absent. Physical exam may include a range of clitoromegaly or ambiguous genitalia. Sex assignment depends on the degree of masculinization present; if a male sex assignment is made, caution should be taken because gynecomastia may occur during puberty, if androgen receptor presence is inadequate. o 5-alpha reductase deficiency is a condition in genotypic males (XY) who are phenotypically female in the prepubertal state and become phenotypic men at puberty. No breast development is present, which distinguishes this condition from androgen insensitivity. Normal testicular function is present. Female Virilization o o o o Genetic females (XX) are exposed to increased androgen levels that lead to inappropriate virilization, most often an indicator of organic disease in girls. Virilizing congenital adrenal hyperplasia (CAH): most commonly associated with deficiency of 21-hydroxylase, an autosomal recessive disorder. Many present as the newborn girl with ambiguous genitalia and possible associated salt-wasting due to mineralocorticoid deficiency. Virilization may also be delayed until later childhood, related to androgen excess at that time (11). Cushing's disease: may result from an adrenal carcinoma and may manifest as growth failure, with or without virilization, obesity, striae, or moon facies. Ovarian tumors: arrhenoblastoma is the most common virilizing ovarian tumor. Others include lipoid cell tumor and gonadoblastoma. VIII. Premature Thelarche Definition: bilateral breast development without other signs of sexual maturation in girls before age 8 (12). Commonly occurs by age 2 and is rare after age 4. The etiology behind premature thelarche is unclear, but an exogenous estrogen source must be excluded. Not known to be associated with central nervous system pathology and is not known to be a familial condition. The mechanism is thought to be related to a temporary activation of the hypothalamic-pituitary-gonadal axis with increased FSH secretion (12). Upon finding during physical examination, precocious puberty must be ruled out: o Document the appearance of the vaginal mucosa, breast size, and presence or absence of a pelvic mass on pelvic/rectal examination. o Determine bone age with radiographic imaging; should be within normal range in premature thelarche and advanced in precocious puberty. o Pelvic sonography should demonstrate a normal prepubertal uterus. o Plasma estrogen levels may be mildly elevated, but dramatic elevations suggest another etiology. Stimulated responses of LH and FSH may be obtained and are both generally elevated in precocious puberty, whereas only stimulated FSH is elevated in premature thelarche (12). Also, review recently used medications and topical creams as application of topical conjugated estrogens (Premarin) for longer than 2 to 3 weeks, which may result in breast changes. Prognosis: In idiopathic cases, a regression in breast enlargement often occurs after a few months but may persist for several years. In approximately 50% of patients, breast development can last 3 to 5 years. V. Self-assessment tasks: 1. What is premature development? 2. Methods of diagnostics of premature sexual development. 3. Make a plan to treat the patient with premature sexual development. 4. What is sexual development delay? Clinical picture. 5. Methods of diagnostics and treatment of syndrome of sexual development delay. VI. Literature. 1. American Academy of Pediatrics Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice Parameter: The diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103;4:843–852. 2. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:227–231. 3. Reiter EO, Lee PA. Adolescent endocrinology: delayed puberty. Adolesc Med 2002;13 (1):101–118. 4. Larsen PR. Williams Textbook of Endocrinology, 10th Ed. Elsevier, 2003:1171–1202. 5. Stenchever MA. Comprehensive Gynecology, 4th Ed. Mosby, 2001:280–288. 6. Kaplowitz PB. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implication for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999;104 (4 Pt 1):936–941. 7. Antoniazzi F, Zamboni G. Central precocious puberty: current treatment options. Paediatr Drugs 2004;6 (4):211–231. 8. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:380–382. 9. Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003;143 (1):60–66. 10. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:340–342. 11. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:277–287. 12. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:605–608.