Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 287

Growth hormone therapy should begin as soon as height falls below the 5th percentile for age, usually between 2 and 5 years of age. 538 Early diagnosis and treatment with growth hormone can increase lean body mass 539 and help patients to achieve a normal adult height. 540–542 Combined treatment with growth hormone and low doses of oxandrolone (an anabolic steroid) can help to maximize growth for older girls between 9 and 12 years of age when diagnosis is delayed. 543,544 Estrogen therapy decreases height velocity and gain in height and therefore generally is not recommended before age 13 or 14 years. 543,545,546 Estrogen treatment should begin at a low dose (0.25–0.5 mg micronized estradiol or its equiva lent) and increase gradually at 3–6-month intervals until reaching the final dose (2.0 mg micronized estradiol or its equivalent); the goal is to complete sexual maturation over a period of 2–3 years. Transdermal options may offer a superior metabolic profile benefit. Once treatment with estrogen begins, linear growth will continue for no longer than another 18–36 months. Treatment with a cyclic proges tin (e.g., medroxyprogesterone acetate, 5 mg daily for 12–14 days of each month) should begin after the first episode of menstrual bleeding or after 12–24 months of treatment. 534 Treatment with oral contraceptives offers a convenient alter native for longer-term management. Recent reconsideration regarding oral estrogens due to the first-pass effect from the liver has made transdermal estrogens a potentially more preferred option. A meta-analysis showed improved whole body bone mineral density, fasting glucose, and total cho lesterol with transdermal estrogen. The lowest commercially available patches deliver 14–25 μ g/day. These can be cut into smaller pieces to deliver 3–7 μ g daily, which is recommended at the start of puberty or 11–12 years of age. The dose is then escalated in 6-month intervals up to a 100- μ g daily dose fol lowing 2–3 years or therapy. 547 Oocyte donation offers the possibility of pregnancy to patients with Turner syndrome, but the cardiovascular demands of pregnancy pose unique and potentially seri ous risks that must be carefully considered. The risk of death during pregnancy is increased as much as 100-fold, primarily due to complications of aortic dissection or rup ture. Risk is greatest for those with preexisting abnormalities such as a bicuspid aortic valve or a dilated aortic root, but even those without such findings remain at risk. Consequently, Turner syndrome generally should be regarded as a rela tive contraindication to pregnancy. Those expressing serious interest in oocyte donation must receive thorough evalua tion and counseling, and those having any significant cardiac abnormality should be strongly discouraged. 548 47,XXY (Klinefelter Syndrome and Variants) Klinefelter syndrome is the most common congenital cause of hypogonadism in males, affecting approximately 1 in 1,000 male births. 549,550 The most common karyotype associ ated with the disorder is 47,XXY, but additional X chromo somes (e.g., 48,XXXY) and mosaics (e.g., 46,XY/47,XXY)

also have been described. 551 Klinefelter syndrome results from nondisjunction of the sex chromosomes of either parent during meiosis; mosaics likely result from mitotic nondisjunction. The phenotype of men with Klinefelter syndrome varies with the number of extra X chromosomes. 551 The gonads are almost always small and firm and sperm production usu ally is severely decreased. Serum testosterone concentra tions generally are low, causing decreased virilization, and gonadotropin levels are elevated. 552 The body habitus exhib its long arms and legs, due both to a long bone abnormal ity and the influence of testosterone deficiency, and a short trunk. Affected patients also commonly exhibit a variety of psychosocial problems unrelated to hypogonadism. 553–555 The prevalence of pulmonary disease, breast 556 and medias tinal cancers, 557 varicose veins, and diabetes is increased in patients with Klinefelter syndrome. 558 Their mortality from breast cancer is higher than in the general population, and that from prostate cancer is lower. 559 Diagnosis of Klinefelter syndrome is made by karyo type. Hypogonadism can be treated effectively with testos terone. Fertility is possible via ICSI, even when there are no sperms in the ejaculate. In a substantial number of azoosper mic men with Klinefelter syndrome, sperms can be obtained via testicular sperm extraction (TESE). However, the preva lence of sex chromosome hyperploidy and autosomal aneu ploidies is increased in sperms obtained from men with Klinefelter syndrome, compared to normal men, and those chromosomal errors might in some cases be transmitted to their offspring unless preimplantation or prenatal testing is performed. 560 45,X/46,XY (Mixed Gonadal Dysgenesis) Mixed gonadal dysgenesis is a term used to describe asym metrical gonadal dysgenesis, where one gonad can be identi fied as a testis and the other is a streak or absent altogether. The most common karyotype associated with the condition is 45,X/46,XY. The dysgenetic testis typically contains imma ture seminiferous tubules lined by immature Sertoli cells and primitive germ cells. Rarely, the gonad contains primitive sex cord-like structures, with or without germ cells, within an ovary-like stroma. 561

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The phenotype in mixed gonadal dysgenesis can vary widely, probably reflecting the relative proportions of 45,X and 46,XY cells in the gonadal ridge. Typically, the genitalia are ambiguous, but also can be female or male. Müllerian and wolffian duct development correspond with the char acter of the ipsilateral gonad. 562,563 In prepubertal children, basal serum testosterone and gonadotropin concentrations are normal and the testosterone response to exogenous hCG stimulation is highly variable. After puberty, patients exhibit varying degrees of virilization, depending on the level of tes tosterone production, and serum gonadotropin concentra tions are elevated. 563 As might be expected, the incidence of gonadal tumors is relatively high (25%). Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.