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Gynecology_Novak. genetic female so that genitoplasty was not needed in the majority of cases (87,88). The majority of studies proved that this management scheme is effective for both mother and the child. Maternal complications, including hypertension, massive weight gain, and overt Cushing syndrome, were noted in about 1% of pregnancies in which the mothers are given low doses of dexamethasone. All maternal complications disappear after delivery. The long-term effects of this treatment strategy on the physical and neurodevelopmental health of the offspring remains unclear. A recent systematic review concluded that dexamethasone seems to reduce virilization without significant adverse maternal or fetal effects, though the available data allow merely weak inferences to be made (89). Despite the risks and the nonuniformity of beneficial outcome to affected female fetuses, many parents may choose prenatal medical treatment because of the psychological impact of ambiguous genitalia.


Gynecology_Novak

Gynecology_Novak. Girls with ambiguous genitalia may require reconstructive surgery, including clitoral recession and vaginoplasty. Timing of such surgery is debated, but the girl must be of appropriate size to ensure the surgery is as simple as possible.


Gynecology_Novak

Gynecology_Novak. The most common cause of heterosexual development at the expected age of puberty is PCOS (Fig. 29.21). Because the syndrome is heterogeneous and poorly defined, clinical difficulties result in diagnosis and management (90). For the sake of simplicity, PCOS may be defined as LH-dependent hyperandrogenism (91). The Rotterdam criteria are commonly used to identify individuals with PCOS and require the presence of at least two of the following: oligoor anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries, with exclusion of other etiologies (CAH, androgen-secreting tumors, Cushing syndrome) (92). Polycystic ovaries ultrasonically are defined as the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL). Most clinical manifestations arise as a consequence of the hyperandrogenism and often include hirsutism beginning at or near puberty and irregular menses from the age of menarche because


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Gynecology_Novak. (>10 mL). Most clinical manifestations arise as a consequence of the hyperandrogenism and often include hirsutism beginning at or near puberty and irregular menses from the age of menarche because of oligoovulation or anovulation. Clinical manifestations are as follows: 1.


Gynecology_Novak

Gynecology_Novak. Affected girls may be but are not necessarily somewhat overweight. 2. In rare instances, menarche may be delayed, and primary amenorrhea may occur. 3. Basal levels of LH tend to be elevated in most affected individuals, and androgen production is invariably increased, even though circulating levels of androgens may be near the upper limits of the normal range in many affected women. Figure 29.21 Typical facial hirsutism in three women with polycystic ovarian syndrome. A: 25-year-old. 4. In anovulatory women, estrone levels are typically greater than estradiol levels. 5. Because circulating levels of estrogens are not diminished in PCOS and androgen levels are only mildly elevated, affected girls become both feminized and masculinized at puberty. This is an important feature because girls with classic forms of CAH who do not experience precocious puberty (and even those who do) only become masculinized at puberty (i.e., they do not develop breasts). 6.


Gynecology_Novak

Gynecology_Novak. 6. Some degree of insulin resistance may be present, even in the absence of overt glucose intolerance (93). 7. Polycystic ovaries are frequently, but not always present in ultrasound exami nation. Distinguishing PCOS from the nonclassic forms of CAH is problematic and controversial (94,95). The evaluation is as follows: 1. Some clinicians advocate measurement of 17α-hydroxyprogesterone in all women who develop hirsutism. Although values of 17α-hydroxyprogesterone are commonly elevated more than 100-fold in individuals with classic 21-hydroxylase deficiency, they may or may not be elevated in nonclassic late-onset forms of the disorder. 2. Measurement of 17α-hydroxyprogesterone can identify women with various forms of 11-hydroxylase deficiency. 3. Basal levels of DHEAS and 17α-hydroxyprogesterone may be moderately elevated in patients with PCOS, making the diagnosis even more difficult. 4. To screen for CAH, 17α-hydroxyprogesterone should be measured in early morning. 5.


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Gynecology_Novak. 4. To screen for CAH, 17α-hydroxyprogesterone should be measured in early morning. 5. In women with regular cyclic menses, it is important to measure 17αhydroxyprogesterone only in the follicular phase because basal levels increase at midcycle and in the luteal phase. Figure 29.21 (Continued ) B: 21-year-old C: 17-year-old. Measurements of 17α-hydroxyprogesterone appear to be of value in populations at high risk for nonclassic late-onset 21-hydroxylase deficiency. In the white population, the gene occurs in only about 1 in 1,000 individuals, but it occurs in 1 in 27 Ashkenazi Jews, 1 in 40 Hispanics, 1 in 50 Yugoslavs, and 1 in 300 Italians (84). The incidence is increased among Eskimos and French Canadians. Alternatively, screening might be restricted to hirsute teenagers presenting with the more “typical” features of nonclassic 21-hydroxylase deficiency, including severe hirsutism beginning at puberty, “ﬂattening” of the breasts (i.e., defeminization), shorter


Gynecology_Novak

Gynecology_Novak. Figure 29.22 Left: A 19-year-old girl with secondary amenorrhea and severe acne and hirsutism beginning at the normal age of puberty. Stimulatory testing with corticotropin documented nonclassic 21-hydroxylase deficiency. Flattening of the breasts is apparent. She was shorter than her one sister and her mother.


Gynecology_Novak

Gynecology_Novak. Figure 29.23 Right: Newborn girl with 46,XX karyotype and genital ambiguity. There is obvious clitoral hypertrophy, paired frenula, so-called scrotalization of the labia, and a common urogenital sinus (shown by the probe). She had 21-hydroxylase deficiency. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.) stature than other family members, and increased DHEAS levels (between 5,000 and 7,000 ng/mL). Women with a strong family history of hirsutism or hypertension might be screened (49) (Fig. 29.22).


Gynecology_Novak

Gynecology_Novak. Basal Levels of 17α-Hydroxyprogesterone Basal levels of 17α-hydroxyprogesterone higher than 800 ng/dL are virtually diagnostic of CAH. Levels between 300 and 800 ng/dL require stimulatory testing with corticotropin to distinguish between PCOS and CAH. To complicate the situation even further, nonclassic 21-hydroxylase deficiency may occur even when basal levels of 17α-hydroxyprogesterone are below 300 ng/dL, thus requiring stimulatory testing in those cases.


Gynecology_Novak

Gynecology_Novak. Cosyntropin Stimulation Test The most commonly used stimulatory test involves measurement of 17α-hydroxyprogesterone 30 minutes after administration of a bolus of 0.25 mg of synthetic cosyntropin (Cortrosyn) (96). In normal women, this value seldom exceeds 400 ng/dL. Patients with classic 21-hydroxylase deficiency achieve peak levels of 3,000 ng/dL or higher. Patients with nonclassic 21-hydroxylase deficiency commonly achieve levels of 1,500 ng/dL or more. Heterozygous carriers achieve peak levels up to about 1,000 ng/dL. In hirsute women with hypertension, 11-deoxycortisol levels can be determined during the test. If both 11-deoxycortisol and 17α-hydroxyprogesterone levels are increased, the rare 11-hydroxylase deficiency is present. Only measurements of several steroid precursors after corticotropin stimulation can identify individuals with nonclassic forms of 3β-HSD deficiency.


Gynecology_Novak

Gynecology_Novak. The elevated levels of 17α-hydroxyprogesterone present in all forms of 21-hydroxylase deficiency are rapidly suppressed by administration of exogenous corticoids. Even a single dose of a glucocorticoid such as dexamethasone will suppress 17α-hydroxyprogesterone in CAH but not in virilizing ovarian and adrenal neoplasms. Hirsutism It is suggested that androgen-receptor blockade may be preferable to glucocorticoids as primary treatment of nonclassic 21-hydroxylase deficiency (97). Although menses usually (but not always) become regular shortly after beginning therapy with glucocorticoids, the hirsutism in this disorder is remarkably refractory to glucocorticoids. Distinguishing nonclassic forms of CAH from idiopathic hirsutism may be problematic.


Gynecology_Novak

Gynecology_Novak. Distinguishing nonclassic forms of CAH from idiopathic hirsutism may be problematic. Individuals with idiopathic hirsutism have regular ovulatory menses, thus effectively eliminating PCOS from consideration. Confusion can be created by the fact that some women with nonclassic CAH may continue to ovulate. Basal levels of 17α-hydroxyprogesterone are normal in idiopathic hirsutism, as is the response to adrenocorticotropic hormone stimulation. Idiopathic hirsutism represents enhanced androgen action at the hair follicle (98).


Gynecology_Novak

Gynecology_Novak. Mixed Gonadal Dysgenesis The term mixed gonadal dysgenesis is used to designate those individuals with asymmetric gonadal development, with a germ cell tumor or a testis on one side and an undifferentiated streak, rudimentary gonad, or no gonad on the other side. Most individuals with this rare disorder have a mosaic karyotype of 45,X/46,XY and are raised as girls who experience virilization at puberty. Gonadectomy is indicated to remove the source of androgens and eliminate any risk for neoplasia. Rare Forms of Male Pseudohermaphroditism Individuals who have rare forms of male pseudohermaphroditism, especially 5α-reductase deficiency (the so-called penis at 12 syndrome) and the Reifenstein syndrome, generally have ambiguous female genitalia with variable virilization at puberty. Cushing syndrome may occur rarely during the pubertal years, as may adrenal or ovarian androgen-secreting neoplasms.


Gynecology_Novak

Gynecology_Novak. Ambiguous external genitalia in a newborn constitutes a major diagnostic challenge. Prompt evaluation is of critical importance to identify a possible life-threatening disorder and to assign the appropriate gender. The prime diagnosis until ruled out is CAH because it is the only condition that is life-threatening. Extreme sensitivity is required in interacting with the family, and no attempt should be made to guess the sex of the baby. The incidence of genital ambiguity is 1 in 4,500, although some degree of male undervirilization, or female virilization may be present in as many as 2% of live births (99,100).


Gynecology_Novak

Gynecology_Novak. Physical Signs During the 3 to 4 days required for evaluation, it is important to be supportive of the parents. Many clinicians believe that it is important not to attach any unusual significance to the genital ambiguity and to treat the abnormality as just another “birth defect.” Physicians should emphasize that the child should undergo normal psychosexual development regardless of the sex-of-rearing selected. Either a name compatible with either sex should be chosen or the naming of the infant should be delayed until the studies are completed.


Gynecology_Novak

Gynecology_Novak. Although the diagnosis is not usually obvious on examination, there are some helpful distinguishing features (Fig. 29.23). In normal boys, there is only a single midline frenulum on the ventral side of the phallus; in normal girls, there are two frenula lateral to the mid-line. A girl with clitoral enlargement still has two frenula, and a boy with hypospadias has a single midline frenulum or several irregular fibrous bands (chordee). It is important to determine whether any m¨ullerian derivatives are present. Studies suggest that MRI may be the most effective way of evaluating the infant for the presence of m¨ullerian tissue (101).


Gynecology_Novak

Gynecology_Novak. The location or consistency of the gonad may be helpful in deducing its composition. A gonad located in the labial or inguinal regions almost always contains testicular tissue. A testis is generally softer than an ovary or a streak gonad and is more apt to be surrounded by blood vessels imparting a reddish cast. An ovary is more often white, fibrous, and convoluted. A gonad that varies in consistency may be an ovotestis or a testis or a streak gonad that underwent neoplastic transformation. If a well-differentiated fallopian tube is absent on only one side, the side without the tube probably contains a testis or ovotestis. The fact that there is uncertainty about the sex of one’s baby is devastating and incomprehensible for most parents. Parents require reassurance that either a male or female gender will be assigned ultimately. Optimum clinical management should comprise of the following (67): 1. Gender assignment must be avoided before expert evaluation of newborns. 2.


Gynecology_Novak

Gynecology_Novak. Gender assignment must be avoided before expert evaluation of newborns. 2. Evaluation and long-term management must be performed at a center with an experienced multidisciplinary team (pediatric endocrinologist, pediatric urologist, geneticist, clinical psychologist, and gynecologist). 3. All individuals should receive a gender assignment after appropriate assessment. 4. Open communication with patients and families is essential, and participation in decision making should be encouraged. 5. Patient and family concerns should be respected and addressed in strict confidence. First-line testing in newborns includes: 1. Karyotyping with X-and Y-specific probe detection (even when prenatal karyotype is available) 2. Measurement of serum 17-hydroprogesterone, testosterone, gonadotropins, antim¨ullerian hormone, and electrolytes 3. Abdominopelvic ultrasound (to assess anatomy of the vagina, uterus, or urogenital sinus, exclude renal anomalies, and locate any inguinal gonads) 4.


Gynecology_Novak

Gynecology_Novak. Abdominopelvic ultrasound (to assess anatomy of the vagina, uterus, or urogenital sinus, exclude renal anomalies, and locate any inguinal gonads) 4. Urinalysis (to check for protein as a screen for any associated renal anomaly) The results of these investigations are generally available within 48 hours and sufficient to develop a working diagnosis. If needed, additional testing may include (102): 1. Human chorionic gonadotropin-and adrenocorticotropin-stimulation tests to assess testicular and adrenal steroid biosynthesis 2. 3. 4. Biopsies of gonadal material 5.


Gynecology_Novak

Gynecology_Novak. Human chorionic gonadotropin-and adrenocorticotropin-stimulation tests to assess testicular and adrenal steroid biosynthesis 2. 3. 4. Biopsies of gonadal material 5. Although genital ambiguity is usually identified at birth, it may not be recognized for several years. Questions about changing the sex-of-rearing may arise. It was believed that sexof-rearing may be changed before 2 years of age without psychologically damaging the child, but experience with individuals with 5α-reductase deficiency suggests that gender changes may be made after 2 years of age in certain instances (103). In any case, surgery for genital ambiguity to make the external genitalia (and development) as compatible with the sex-of-rearing of the child is warranted but was not always successful. Clitoral recession and clitorectomy are the most frequently performed surgical procedures.


Gynecology_Novak

Gynecology_Novak. Masculinized external genitalia can be classified into five “Prader” stages. Excessive androgen exposure results in virilization to varying degrees, including clitoral enlargement, labial fold fusion, and rostral migration of the urethral/vaginal perineal orifice. Prader stage V defines virilization resulting in complete labioscrotal fusion, a penile phallus with the urethra opening on the glans. Clitoroplasty is required at an early stage after it is established that a Prader stage V “male” has CAH and needs to be reassigned to the female sex (104).


Gynecology_Novak

Gynecology_Novak. Teratogens It is important to recognize that ambiguous genitalia can result from the maternal ingestion of various teratogens, most of which are synthetic steroids (Table 29.3). Exposure to the teratogen must occur early in pregnancy, during genital organogenesis. Not all exposed fetuses manifest the same anomalies or even the presence of any anomalies. In principle, most synthetic steroids with androgenic properties, including weakly androgenic progestins, can affect female genital differentiation. The doses required to produce genital ambiguity are generally so great that the concern is only theoretical. The one agent that can lead to genital ambiguity when ingested in


Gynecology_Novak

Gynecology_Novak. Table 29.3 Androgens and Progestogens Potentially Capable of Producing Genital Ambiguitya aThose agents proved to cause genital ambiguity do so only when administered in relatively high doses. Insufficient data exist regarding effects of dimethisterone and norgestrel. In low doses (e.g., as in oral contraceptives), progestins, even including norethindrone, seem unlikely to virilize a female fetus. clinically used quantities is danazol. There is no evidence that inadvertent ingestion of oral contraceptives, which contain relatively low doses of either mestranol or ethinyl estradiol and a 19-nor-steroid, results in virilization (105,106). 1. Tanner JM. Growth at adolescence. 2nd ed. Oxford, UK: Blackwell Scientific Publications, 1962. 2. Teilmann G, Pedersen CB, Skakkebaek NE, et al. Increased risk of precocious puberty in internationally adopted children in Denmark. Pediatrics 2006;118:e391–e399. 3.


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Gynecology_Novak. 2. Teilmann G, Pedersen CB, Skakkebaek NE, et al. Increased risk of precocious puberty in internationally adopted children in Denmark. Pediatrics 2006;118:e391–e399. 3. Parent AS, Teilmann G, Juul A, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003;24:668–693. 4. Matchock RL, Susman EJ. Family composition and menarcheal age: anti-inbreeding strategies. Am J Hum Biol 2006;18:481–491. 5. Zacharias L, Wurtman RJ. Blindness: its relation to age of menarche. Science 1964;144:1154–1155. 6. Kaplowitz PB, Oberfield SE, for the Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics 1999;104:936–941. 7.


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Gynecology_Novak. 7. Frisch RE. Body fat, menarche, and reproductive ability. Semin Reprod Endocrinol 1985;3:45–49. 8. Maclure M, Travis LB, Willett W, et al. A prospective cohort study of nutrient intake and age at menarche. Am J Clin Nutr 1991;54:649– 656. 9. deRidder CM, Thijssen JHH, Bruning PF, et al. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab 1992;75:442–446. 10. Marshall WA, Tanner JM. Variations in patterns of pubertal changes in girls. Arch Dis Child 1969; 44:291–303. 11. Cutler GB Jr. The role of estrogen in bone growth and maturation during childhood and adolescence. J Steroid Biochem Mol Biol 1997;61:141–144. 12. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. London, England: Oxford University Press, 1959. 13.


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Gynecology_Novak. 12. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. London, England: Oxford University Press, 1959. 13. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr 1952;40:423–441. 14. Kaplan SL, Grumbach MM, Aubert ML. The ontogeny of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent Prog Horm Res 1976;32:161–243. 15. Conte FA, Grumbach MM, Kaplan SL. A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 1975;40:670–674. 16. Boyar RM, Finkelstein JW, Roffwarg HP, et al. Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 1972;287:582–586. 17.


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Gynecology_Novak. 16. Boyar RM, Finkelstein JW, Roffwarg HP, et al. Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 1972;287:582–586. 17. Boyar RM, Rosenfeld RS, Kapen S, et al. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest 1974;54:609–618. 18. Boyar RM, Wu RHK, Roffwarg H, et al. Human puberty: 24hour estradiol patterns in pubertal girls. J Clin Endocrinol Metab 1976;43:1418–1421. 19. Grumbach MM. The neuroendocrinology of puberty. In: Krieger DT, Hughes JC, eds. Neuroendocrinology. Sunderland, MA: Sinauer Associates, 1980:249–258. 20. Penny R, Olambiwonnu NO, Frasier SD. Episodic ﬂuctuations of serum gonadotropins in pre-and post-pubertal girls and boys. J Clin Endocrinol Metab 1977;45:307–311. 21. Korth-Schutz S, Levine LS, New MI. Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche. J Clin Endocrinol Metab 1976;42:117–124. 22.


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Gynecology_Novak. 21. Korth-Schutz S, Levine LS, New MI. Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche. J Clin Endocrinol Metab 1976;42:117–124. 22. Ducharme J-R, Forest MG, DePeretti E, et al. Plasma adrenal and gonadal sex steroids in human pubertal development. J Clin Endocrinol Metab 1976;42:468–476. 23. Lee PA, Xenakis T, Winer J, et al. Puberty in girls: correlation of serum levels of gonadotropins, prolactin, androgens, estrogens and progestin with physical changes. J Clin Endocrinol Metab 1976;43:775–784. 24. Judd HL, Parker DC, Siler TM, et al. The nocturnal rise of plasma testosterone in pubertal boys. J Clin Endocrinol Metab 1974;38:710– 713. 25. Grumbach MM, Kaplan SL. The neuroendocrinology of human puberty: an ontogenetic perspective. In: Grumbach MM, Sizonenko PC, Aubert ML, eds. Control of the onset of puberty. Baltimore, MD: Williams & Wilkins, 1990:1–62. 26.


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Gynecology_Novak. 26. Rosenfield RL. Current age of onset of puberty. Pediatrics 2000;105:622. 27. Buttram VC Jr, Gibbons WE. M¨ullerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril 1979;32:40–46. 28. Smith FR. The significance of incomplete fusion of the m¨ullerian ducts in pregnancy and parturition with a report on 35 cases. Am J Obstet Gynecol 1931;22:714–728. 29. Herbst AL, Hubby MM, Azizi F, et al. Reproductive and gynecological surgical experience in diethylstilbestrol-exposed daughters. Am J Obstet Gynecol 1981;141:1019–1028. 30. Simpson JL. Genetics of the female reproductive ducts. Am J Med Genet 1999;89:224–239. 31. Taylor HS. The role of HOX genes in the development and function of the female reproductive tract. Semin Reprod Med 2000;18:81– 89. 32.


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Gynecology_Novak. 31. Taylor HS. The role of HOX genes in the development and function of the female reproductive tract. Semin Reprod Med 2000;18:81– 89. 32. Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab 2008;93:895– 900. 33. Buttram VC Jr, Reiter RC. Surgical treatment of the infertile female. Baltimore, MD: Williams & Wilkins, 1985:89. 34. Pellerito JS, McCarthy SM, Doyle MB, et al. Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal sonography, and hysterosalpingography. Radiology 1992;183:795–800. 35. Simpson JL. Localizing ovarian determinants through phenotypickaryotypic deductions: progress and pitfalls. In: Rosenfield R, Grumbach M, eds. Turner syndrome. New York: Marcel Dekker, 1990:65–77. 36.


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Gynecology_Novak. 36. Van Dyke DL, Wiktor A, Palmer CG, et al. Ullrich-Turner syndrome with a small ring X chromosome and the presence of mental retardation. Am J Med Genet 1992;43:996–1005. 37. Ellison JW, Wardak Z, Young MF, et al. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 1997;6:1341–1347. 38. Cools M, Drop SL, Wolffenbuttel KP, et al. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 2006;27:468–484. 39. Bremer GL, Land JA, Tiebosch A, et al. Five different histological subtypes of germ cell malignancies in an XY female. Gynecol Oncol 1993;50:247–248. 40. Karnis MF, Zimon AE, Lalwani SI, et al. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501. 41. Matura LA, Ho VB, Rosing DR, et al. Aortic dilatation and dissection in Turner syndrome. Circulation 2007; 116:1663– 1670. 42.


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Gynecology_Novak. 41. Matura LA, Ho VB, Rosing DR, et al. Aortic dilatation and dissection in Turner syndrome. Circulation 2007; 116:1663– 1670. 42. Rosenfeld RG, Frane J, Attie KM, et al. Six-year results of a randomized prospective trial of human growth hormone and oxandrolone in Turner syndrome. J Pediatr 1992;121:49–55. 43. Sas TC, de Muinck Keizer-Schrama S, Stijnen T, et al. Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial. J Clin Endocrinol Metab 1999;84:4607–4612. 44. Sas TC, Gerver WJ, De Bruin R, et al. Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial. J Clin Endocrinol Metab 1999;84:4622–4628. 45. Rosenfeld RG, Attie KM, Frane J, et al. Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr 1998;132:319–324. 46.


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Gynecology_Novak. 45. Rosenfeld RG, Attie KM, Frane J, et al. Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr 1998;132:319–324. 46. Chernausek SD, Attie KM, Cara JF, et al. Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group. J Clin Endocrinol Metab 2000;85:2439–2445. 47. Hogler W, Briody J, Moore B, et al. Importance of estrogen on bone health in Turner syndrome: a cross-sectional and longitudinal study using dual-energy x-ray absorptiometry. J Clin Endocrinol Metab 2004;89:193–199. 48. Rebar RW, Cedars MI. Hypergonadotropic amenorrhea. In: Filicori M, Flamigni C, eds. Ovulation induction: basic science and clinical advances. Amsterdam, Netherlands: Elsevier Science B.V., 1994:115–121. 49. Kustin J, Rebar RW. Hirsutism in young adolescent girls. Pediatr Ann 1986;15:522. 50.


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Gynecology_Novak. 49. Kustin J, Rebar RW. Hirsutism in young adolescent girls. Pediatr Ann 1986;15:522. 50. Achermann JC, Jameson JL. Advances in the molecular genetics of hypogonadotropic hypogonadism. J Pediatr Endocrinol Metab 2001;14:3–15. 51. Herbison AE. Genetics of puberty. Horm Res 2007;68:75–79. 52. Kallmann FJ, Schoenfeld WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Ment Defic 1944;48:203–236. 53. Schwanzel-Fukuda M, Jorgenson KL, Bergen HT, et al. Biology of normal luteinizing hormone-releasing hormone neurons during and after their migration from olfactory placode. Endocr Rev 1992;13:623–634. 54. Crowley WF Jr, Jameson JL. Clinical counterpoint: gonadotropinreleasing hormone deficiency: perspectives from clinical investigation. Endocr Rev 1992;13:635–640. 55. Henek M, Wevrick R. The role of genomic imprinting in human developmental disorders: lessons from Prader-Willi syndrome. Clin Genet 2001;59:156–164. 56.


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Gynecology_Novak. 55. Henek M, Wevrick R. The role of genomic imprinting in human developmental disorders: lessons from Prader-Willi syndrome. Clin Genet 2001;59:156–164. 56. Beales PL, Warner AM, Hitman GA, et al. Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J Med Genet 1997;34:92–98. 57. Tomlinson JN, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 2001;357:425–431. 58. Vance ML. Hypopituitarism. N Engl J Med 1994;330:1651–1662. 59. Braunstein GD, Whitaker JN, Kohler PO. Cerebellar dysfunction in Hand-Sch¨uller-Christian disease. Arch Intern Med 1973;132:387– 390. 60. Spitzer R. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994:53. 61. Vigersky RA, Loriaux DL, Andersen AE, et al. Anorexia nervosa: behavioral and hypothalamic aspects. J Clin Endocrinol Metab 1976;5:517–535. 62.


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Gynecology_Novak. 61. Vigersky RA, Loriaux DL, Andersen AE, et al. Anorexia nervosa: behavioral and hypothalamic aspects. J Clin Endocrinol Metab 1976;5:517–535. 62. Gold PW, Gwirtsman H, Avgerinos PC, et al. Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa: pathophysiologic mechanisms in underweight and weight-corrected patients. N Engl J Med 1986;314:1335–1342. 63. Vigersky RA, Andersen AE, Thompson RH, et al. Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 1977;297:1141–1145. 64. Morris JM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol 1953;65:1192. 65. Griffin JE. Androgen resistance the clinical and molecular spectrum. N Engl J Med 1992;326: 611–618. 66. Gottlieb B, Pinsky L, Beitel LK, et al. Androgen insensitivity. Am J Med Genet 1999;89:210–217. 67.


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Gynecology_Novak. 66. Gottlieb B, Pinsky L, Beitel LK, et al. Androgen insensitivity. Am J Med Genet 1999;89:210–217. 67. Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. Pediatrics 2006;118:e488– e500. 68. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990;71:1251. 69. Van Winter JT, Noller KL, Zimmerman D, et al. Natural history of premature thelarche in Olmsted County, Minnesota, 1940 to 1984. J Pediatr 1990;116:278. 70. Haber HP, Wollmann HA, Ranke MB. Pelvic ultrasonography: early differentiation between isolated premature thelarche and central precocious puberty. Eur J Pediatr 1995;154:182– 186. 71. Ibanez L, DiMartino-Nardi J, Potau N, et al. Premature adrenarche—normal variant of forerunner of adult disease? Endocr Rev 2000;21:671–696. 72.


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Gynecology_Novak. 71. Ibanez L, DiMartino-Nardi J, Potau N, et al. Premature adrenarche—normal variant of forerunner of adult disease? Endocr Rev 2000;21:671–696. 72. Partsch CJ, Heger S, Sippell WG. Management and outcome of central precocious puberty. Clin Endocrinol 2002;56:129–148. 73. Mahachoklertwattana P, Kaplan SL, Grumbach MM. The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. J Clin Endocrinol Metab 1993;77:118–124. 74. Feuillan PP, Jones JV, Barnes K, et al. Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: a long term follow-up comparing girls with hypothalamic hamartoma and idiopathic precocious puberty. J Clin Endocrinol Metab 1999;84:44–49. 75. Hochman HI, Judge DM, Reichlin S. Precocious puberty and hypothalamic hamartoma. Pediatrics 1981;67:236–244. 76.


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Gynecology_Novak. 75. Hochman HI, Judge DM, Reichlin S. Precocious puberty and hypothalamic hamartoma. Pediatrics 1981;67:236–244. 76. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:e752–e762. 77. Carel JC, Roger M, Ispas S, et al. Final height after long-term treatment with triptorelin slow-release for central precocious puberty: importance of statural growth after interruption of treatment. J Clin Endocrinol Metab 1999;84:1973–1978. 78. Arrigo T, Cisternino M, Galluzzi F, et al. Analysis of the factors affecting auxological response to GnRH agonist treatment and final height outcome in girls with idiopathic central precocious puberty. Eur J Endocrinol 1999;141:140–144. 79. Oostdijk W, Rikken B, Schreuder S, et al. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 1996;75:292–297. 80.


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Gynecology_Novak. 79. Oostdijk W, Rikken B, Schreuder S, et al. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 1996;75:292–297. 80. Lyon AJ, DeBruyn R, Grant DB. Transient sexual precocity and ovarian cysts. Arch Dis Child 1985;60:819–822. 81. Ein SH, Darte JM, Stephens CA. Cystic and solid ovarian tumors in children: a 44-year review. J Pediatr Surg 1970;5:148–156. 82. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;325:1688–1695. 83. Eugster EA, Rubin SD, Reiter EO,et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003;143:60–66. 84. Speiser PW. Congenital adrenal hyperplasia. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, PA: JB Lippincott, 1995:686–695. 85.


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Gynecology_Novak. 84. Speiser PW. Congenital adrenal hyperplasia. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, PA: JB Lippincott, 1995:686–695. 85. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21hydroxylase deficiency. Endocr Rev 2000;21:245–291. 86. Engster EA, Dimeglio LA, Wright JC, et al. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001;138:3–5. 87. Lajic S, Wedell A, Bui T, et al. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 1998;83:3872–3880. 88. New MI, Carlson A, Obeid J, et al. Extensive personal experience: prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86:5651–5657. 89.


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Gynecology_Novak. 88. New MI, Carlson A, Obeid J, et al. Extensive personal experience: prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86:5651–5657. 89. Fern´andez-Balsells MM, Muthusamy K, Smushkin G, et al. Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia due to 21 hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses. Clin Endocrinol (Oxf) 2010;73:436–444. 90. Futterweit W. Pathophysiology of polycystic ovarian syndrome. In: Redmond GP, ed. Androgenic disorders. New York: Raven Press, 1995:77–166. 91. Rebar RW. Disorders of menstruation, ovulation, and sexual response. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, PA: Lippincott, 1995:880– 899. 92.


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Gynecology_Novak. 92. The Rotterdam ESHRE/ASRM-Sponsored PCOS Concensus Workshop Group. Revised 2003 concensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. 93. Lewy VD, Danadian K, Witchel SF, et al. Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr 2001;138:38–44. 94. Lobo RA, Goebelsmann U. Adult manifestation of congenital hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease. Am J Obstet Gynecol 1980;138:720– 726. 95. Chrousos GP, Loriaux DL, Mann DL, et al. Late-onset 21hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease. Ann Intern Med 1982;96:143–148. 96. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320–326. 97.


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Gynecology_Novak. 96. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320–326. 97. Spritzer P, Billaud L, Thalabard J-C, et al. Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia. J Clin Endocrinol Metab 1990;70:642–646. 98. Horton R, Hawks D, Lobo R. 3a, 17b-Androstanediol glucuronide in plasma: a marker of androgen action in idiopathic hirsutism. J Clin Invest 1982;69:1203–1206. 99. Hamerton JL, Canning N, Ray M, et al. A cytogenetic survey of 14,069 newborn infants. Incidence of chromosome abnormalities. Clin Genet 1975;4:223–243. 100. Blackless M, Charuvastra A, Derryck A, et al. How sexually dimorphic are we? Am J Hum Biol 2000;12:151–166. 101. Hricak H, Chang YCF, Thurner S. Vagina: evaluation with MR imaging. I. Normal anatomy and congenital anomalies. Radiology 1991;179:593. 102.


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Gynecology_Novak. 101. Hricak H, Chang YCF, Thurner S. Vagina: evaluation with MR imaging. I. Normal anatomy and congenital anomalies. Radiology 1991;179:593. 102. Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child 2004;89:401–407. 103. Imperato-McGinley J, Guerrero L, Gautier T, et al. Steroid 5a-reductase deficiency: an inherited form of male pseudohermaphroditism. Science 1974;186:1213–1215. 104. Hughes IA. Congenital adrenal hyperplasia: a lifelong disorder. Horm Res 2007;68:84–89. 105. Schardein JL. Congenital abnormalities and hormones during pregnancy: a clinical review. Teratology 1980;22:251–270. 106. Bracken MB. Oral contraception and congenital malformations in offspring: a review and meta-analysis of the prospective studies. Obstet Gynecol 1990;76:552–557. Valerie L. Baker Wendy J. Schillings Howard D. McClamrock


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Gynecology_Novak. Valerie L. Baker Wendy J. Schillings Howard D. McClamrock Girls experienced menarche at increasingly younger ages during the past century. Primary amenorrhea is defined as absence of menses at age 13 years when there is no visible development of secondary sexual characteristics or age 15 years in the presence of normal secondary sexual characteristics. Absent or irregular menses may be an indication that a woman has a medical condition that can affect her overall health. The health implications can vary depending on the etiology of the amenorrhea. Therefore, a cause for amenorrhea should be established whenever possible. When gonadal failure occurs in conjunction with primary amenorrhea, it is associated with a high incidence of abnormal karyotype. The anatomic causes of amenorrhea are relatively few, and the majority may be diagnosed by history and physical examination.


Gynecology_Novak

Gynecology_Novak. The anatomic causes of amenorrhea are relatively few, and the majority may be diagnosed by history and physical examination. The most important elements in the diagnosis of amenorrhea include physical examination for secondary sexual characteristics and anatomic abnormalities, measurement of human chorionic gonadotropin (hCG) to rule out pregnancy, serum prolactin and thyroid stimulating hormone (TSH) levels, and assessment of follicle-stimulating hormone (FSH) levels to differentiate between hypergonadotropic and hypogonadotropic forms of hypogonadism.


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Gynecology_Novak. Therapeutic measures may include specific therapies (medical or surgical) aimed at correcting the primary cause of amenorrhea, hormone therapy to initiate and maintain secondary sexual characteristics and provide symptomatic relief, treatments to maximize and maintain peak bone mass including hormone therapy, calcium, and vitamin D for cases where circulating estrogen levels are low, and ovulation induction for patients desiring pregnancy. A complex hormonal interaction must take place in order for normal menstruation to occur. The hypothalamus must secrete gonadotropin-releasing hormone (GnRH) in a pulsatile fashion, which is modulated by neurotransmitters and hormones. The GnRH stimulates secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary, which Causes of Primary Amenorrhea


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Gynecology_Novak. Causes of Primary Amenorrhea Hypergonadotropic Hypogonadism Associated with Absence of Secondary Sexual Characteristics promotes ovarian follicular development and ovulation. A normally functioning ovarian follicle secretes estrogen; after ovulation, the follicle is converted to corpus luteum, and progesterone is secreted in addition to estrogen. These hormones stimulate endometrial development. If pregnancy does not occur, estrogen and progesterone secretion decrease and withdrawal bleeding begins. If any of the components (hypothalamus, pituitary, ovary, uterus, and outﬂow tract) are nonfunctional, bleeding cannot occur.


Gynecology_Novak

Gynecology_Novak. The mean age of menarche became younger during this century. Therefore, the definition of primary amenorrhea changed: Primary amenorrhea is defined as the absence of menses by 13 years of age when there is no visible development of secondary sexual characteristics or by 15 years of age in the presence of normal secondary sexual characteristics. The ages defining primary amenorrhea were decreased by 1 year to continue to represent two standard deviations above the mean age of developing secondary sexual characteristics and menses (1). Failure to begin breast development by age 13 warrants investigation. A woman who previously menstruated can develop secondary amenorrhea, which is defined as absence of menstruation for three normal menstrual cycles (2). A woman with regular cycles and a delay of menses of even a week may warrant assessment with a pregnancy test. It is reasonable to evaluate a woman who has fewer than nine cycles per year. With a few exceptions, the causes of primary


Gynecology_Novak

Gynecology_Novak. delay of menses of even a week may warrant assessment with a pregnancy test. It is reasonable to evaluate a woman who has fewer than nine cycles per year. With a few exceptions, the causes of primary amenorrhea are similar to the causes of secondary amenorrhea.


Gynecology_Novak

Gynecology_Novak. Patients may develop slight alterations in the hypothalamic–pituitary–ovarian axis that are not severe enough to cause amenorrhea but instead cause irregular menses (oligomenorrhea) associated with absent or infrequent ovulation. These patients may bleed excessively during menstruation because estrogen is unopposed. The etiologies of oligomenorrhea overlap with the etiologies of amenorrhea, with the exception that certain anatomic (e.g., absent uterine development) and karyotypic abnormalities (e.g., Turner syndrome), are largely associated with primary amenorrhea.


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Gynecology_Novak. The World Health Organization (WHO) described three classes of amenorrhea. WHO Group I includes women with no evidence of endogenous estrogen production, normal or low FSH levels, normal prolactin levels, and no lesion in the hypothalamic-pituitary region. WHO Group II is associated with evidence of estrogen production and normal levels of prolactin and FSH. WHO Group III includes individuals with elevated serum FSH indicating gonadal insufficiency or failure. To detect the cause of amenorrhea, it is useful to determine whether secondary sexual characteristics are present (Fig. 30.1). The absence of secondary sexual characteristics indicates that a woman was never exposed to estrogen.


Gynecology_Novak

Gynecology_Novak. Although the diagnosis and treatment of disorders associated with hypogonadism were discussed in another chapter (see Chapter 29), they will be mentioned here because these conditions may present as primary amenorrhea. Because breast development is the first sign of estrogen exposure in puberty, patients without secondary sexual characteristics typically have primary, not secondary, amenorrhea (Fig 30.1). It is helpful to categorize the causes of amenorrhea in the absence of breast development on the basis of gonadotropin status.


Gynecology_Novak

Gynecology_Novak. Gonadal dysgenesis is a term typically used to describe abnormal development of the gonads, typically resulting in streak gonads. Gonadal dysgenesis is associated with high levels of LH and FSH because the gonad fails to produce the steroids and inhibin that would normally feed back to the pituitary gland to suppress pituitary production of LH and FSH. Karyotypic abnormalities are common in women with primary amenorrhea associated with gonadal failure (Table 30.1). In one series, approximately 30% of patients with primary amenorrhea had an associated karyotypic abnormality (3). Turner syndrome (45,X) and its variants represent the most common form of hypergonadotropic hypogonadism in women with primary amenorrhea.


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Gynecology_Novak. Secondary sexual characteristics Present Primary Pregnancy hCG −hCG +Yes No Physical exam • If risk of endometrial scarring, advise HSG saline hysterogram or hysteroscopy & culture’s to exclude Asherman's, cervical stenosis and infection Normal Abnormal – consider karyotype TSH, PRL, FSH, clinical evaluation of estrogen status Abnormal TSH Normal TSH Normal PRL High PRL Hyperprolactinemia Absent Physical exam Normal Normal or low Absent uterus FSH level High Karyotype • 5α-reductase deficiency • 17–20 lyase deficiency • 17α-hydroxylase deficiency (all with XY karyotype) • Kallman's syndrome • Physiologic delay • Disorders of low estrogen status before puberty • XX • Y line • Turner (XO) • Hyperthyroidism • Hypothyroidism • Mlerian anomaly • Androgen insensitivity • True hermaphrodite


Gynecology_Novak

Gynecology_Novak. Figure 30.1 Decision tree for evaluation of amenorrhea. FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; HSG, hysterosalpingogram; TSH, thyroid-stimulating hormone; PRL, prolactin; CT, computed tomography; MRI, magnetic resonance imaging; EEG, electroencephalogram; SHG, saline hysterogram.


Gynecology_Novak

Gynecology_Novak. Normal PRL Normal FSH Normal estrogen Low estrogen Neurological exam. CT/MRI, EEG Normal • Feedback disorders hypothalmic dysfunction • Obesity • Cushing's syndrome • Androgen-secreting adrenal tumors • Congenital adrenal hyperplasia • Ovarian neoplasm • Granulosa cell androgen-secreting • Chronic disease pulmonary renal liver diabetes • Addison's disease • Hypothalmic dysfunction • Anorexia • Exercise-induced • Stress • Pseudocyesis • Malnutrition High FSH • Ovarian insufficiency-45 XO, mosaic FMR1 premutation chromosomal radiation chemotherapy infections autoimmune • Galactosemia • Idiopathic Abnormal • Pituitary-hypothalmic lesions tumors infection infarction pituitary failure Sheehan's • Diabetic vasculitis • Toxic-lead • Chronic anovulatory • Polycystic ovarian syndrome • Idiopathic Table 30.1 Amenorrhea Associated with a Lack of Secondary Sexual Characteristics 5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY individual


Gynecology_Novak

Gynecology_Novak. Table 30.1 Amenorrhea Associated with a Lack of Secondary Sexual Characteristics 5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY individual Partial deletion of X chromosome syndrome initially have normal ovarian development in utero. Amenorrhea is the result of accelerated atresia of the follicles. The fibrotic ovaries are called streak ovaries. In addition to gonadal failure, there are associated stigmata with Turner syndrome that include short stature, webbed neck, shield chest, cubitus valgus (increased carrying angle of the arms), low hair line, high arched palate, multiple pigmented nevi, and short fourth metacarpals (4). X inactivation is a process that inactivates most of the genes on one X chromosome. Of the genes on the X chromosome, 20% escape X inactivation, and it is believed that loss of the second copy of these genes in a 45,X patient causes the stigmata associated with Turner syndrome (5).


Gynecology_Novak

Gynecology_Novak. After the diagnosis of Turner syndrome is confirmed by karyotype, studies should be performed to ensure that cardiac (30% have coarctation of the aorta), renal (especially horseshoe kidney), and autoimmune (thyroiditis) abnormalities are diagnosed and treated. Cardiac magnetic resonance imaging (MRI) should be used in addition to echocardiography (6). Evaluation should be performed in childhood to identify potential attention-deficit or nonverbal learning disorders. Women with Turner syndrome should be screened for diabetes mellitus, aortic enlargement, hypertension, and hearing loss throughout their lives (6).


Gynecology_Novak

Gynecology_Novak. Abnormal X Chromosome Those 46,XX individuals with partial deletions of the X chromosome have variable phenotypes depending on the amount and location of the missing genetic material. Patients with a deletion of the long arm of the X chromosome (Xq−) from Xq13 to Xq26 have sexual infantilism, normal stature, no somatic abnormalities, and streak gonads (7). Some patients may be eunuchoid in appearance and have delayed epiphyseal closure. Patients with a deletion of the short arm of the X chromosome (Xp) usually are phenotypically similar to individuals with Turner syndrome (8). Many genes on the Xp chromosome escape X inactivation and act similarly to genes on autosomes. The effective monosomy created by the deletion results in the phenotypic features of Turner syndrome (5). Most patients with a ring X have ovarian failure and phenotypes similar to Turner syndrome, although some are able to reproduce successfully. These patients differ from those with Turner syndrome in that they are


Gynecology_Novak

Gynecology_Novak. with a ring X have ovarian failure and phenotypes similar to Turner syndrome, although some are able to reproduce successfully. These patients differ from those with Turner syndrome in that they are more likely to have intellectual disability and have syndactyly. Patients with isochrome of the long arm of the X chromosome (i[Xq]) are similar to XO patients, with the exception that autoimmune disorders are more common. Half of the women with balanced translocations of the X chromosome to an autosome have gonadal failure. Typically, the normal X is inactivated to preserve the balance of autosomal genes. The gonadal failure can be caused by the chromosomal break occurring in a gene that is required for ovarian function, abnormal meiosis, or X inactivation of the translocated X and adjacent autosomal genes (5,9).


Gynecology_Novak

Gynecology_Novak. Mosaicism Primary amenorrhea is associated with various mosaic states, the most common of which is 45,X/46,XX (10). The clinical findings in 45,X/47,XXX and 45,X/46, XX/47,XXX are similar to those in 45,X/46,XX and vary in estrogen and gonadotropin production, depending on the number of follicles in the gonads. When compared with the pure 45,X cell line, individuals with 45,X/46,XX are taller and have fewer abnormalities, although 80% of those with 45,X/46,XX mosaics are shorter than their peers, and 66% have some somatic abnormalities. Spontaneous menstruation occurs in approximately 20% of these patients (10).


Gynecology_Novak

Gynecology_Novak. Pure Gonadal Dysgenesis Individuals who are phenotypically female with sexual infantilism, primary amenorrhea, normal stature, and no karyotypic abnormalities (46,XX or 46,XY) have pure gonadal dysgenesis. The gonads are usually streaks, but there may be some development of secondary sexual characteristics, and a few episodes of uterine bleeding. Pure gonadal dysgenesis in a 46,XY individual (previously known as Swyer syndrome) can occur when mutations in the SRY (sex-determining region gene on the Y chromosome) located at Yp11 result in XY females without proper gonad development (11,12).


Gynecology_Novak

Gynecology_Novak. Mutations in many other genes such as SOX9, DAX1, WT-1, and SF1, which affect testicular differentiation and inhibit antim¨ullerian hormone production, result in XY pure gonadal dysgenesis (13). The SOX9 gene located at 17q24 has a role in testis differentiation and promotes antim¨ullerian hormone secretion. Some but not all mutations in the SOX9 gene cause XY sex reversal, along with camptomelic dysplasia (severe skeletal abnormalities) (14,15). Duplications of the DAX1 gene at Xp21 cause dose-sensitive XY sex reversal (16). DAX1 is hypothesized to antagonize the SRY gene, preventing testis development. Transgenic XY mice with overexpression of the DAX1 gene develop as phenotypic females, supporting this hypothesis (17). Mutation in the WT1 gene (Wilms’ tumor suppressor gene 1) located at 11p13 causes several different syndromes, depending on where the mutation in the gene occurs. In Frasier syndrome, there is alternative splicing, which causes the protein product to lack a highly


Gynecology_Novak

Gynecology_Novak. at 11p13 causes several different syndromes, depending on where the mutation in the gene occurs. In Frasier syndrome, there is alternative splicing, which causes the protein product to lack a highly conserved KTS triplet repeat. The normal +KTS isoform of the protein is believed to synergize with SF1 (steroidogenic factor 1) to promote the expression of antim¨ullerian hormone (AMH). Lack of the +KTS isoform in an XY patient results in normal female internal and external genitalia, streak gonads, and progressive glomerulopathy. These women frequently develop gonadoblastomas but rarely develop Wilms’ tumor, which is associated with mutations in other locations in the WT1 gene. XX patients with the mutation that prevents the +KTS isoform have similar kidney abnormalities but develop normal ovaries and genitalia (17–19). One XY patient with a heterozygous mutation of the SF1 gene had adrenal failure and sex reversal (20). SF1 is an orphan nuclear receptor that regulates AMH expression and


Gynecology_Novak

Gynecology_Novak. and genitalia (17–19). One XY patient with a heterozygous mutation of the SF1 gene had adrenal failure and sex reversal (20). SF1 is an orphan nuclear receptor that regulates AMH expression and regulates all the cytochrome P450 steroid hydroxylase enzymes (19). Duplication of 1p, which encodes the WNT4 gene, causes XY sex reversal. WNT4 may upregulate DAX1 transcripts. A TRX mutation causes XY sex reversal. Other genes that cause XY gonadal dysgenesis are likely to be identified. Mutations at 9p24 and 10q cause XY sex reversal, but the exact genes causing the defects are not elucidated (17,19,21).


Gynecology_Novak

Gynecology_Novak. XX pure gonadal dysgenesis can be caused by the presence of small Y chromosome fragments in the genome. It is estimated that 5% to 40% of patients with Ullrich-Turner syndrome have Y sequences by polymerase chain reaction (PCR), depending on the DNA sequences targeted for testing (22,23). If Y sequences are present, gonadectomy is advised because of the risk of gonadoblastoma (22). In other patients with XX gonadal dysgenesis, the condition is likely to be caused by gene mutations that lead to ovarian insufficiency before pubertal development or after the development of secondary sexual characteristics, as discussed later in this chapter. Mixed Gonadal Dysgenesis Most patients with mixed gonadal dysgenesis are XY and have ambiguous genitalia with a streak gonad on one side and a malformed testis on the opposite. A small proportion of these patients have mutations in the SRY gene (17).


Gynecology_Novak

Gynecology_Novak. Congenital Lipoid Adrenal Hyperplasia Patients with this autosomal recessive disorder are unable to convert cholesterol to pregnenolone, which is the first step in steroid hormone biosynthesis. A defect was not found in the P450scc gene, which is the conversion enzyme responsible for this step in the pathway. Instead, 15 different mutations were identified in the steroidogenic acute regulatory protein (StAR), which facilitates the transport of cholesterol from the outer to the inner mitochondrial membrane. This protein appears to be the rate-limiting step for steroid hormone biosynthesis stimulated by tropic hormones. These patients present in infancy with hyponatremia, hyperkalemia, and acidosis. Both XX and XY individuals are phenotypically female. Genetic clusters of the disorder are found in the Japanese, Korean, and Palestinian Arab populations. With appropriate mineralocorticoid and glucocorticoid replacement, these patients can survive into adulthood. Most patients are XY and


Gynecology_Novak

Gynecology_Novak. found in the Japanese, Korean, and Palestinian Arab populations. With appropriate mineralocorticoid and glucocorticoid replacement, these patients can survive into adulthood. Most patients are XY and do not have a uterus. Without hormone replacement, they remain sexually infantile. XX patients may acquire secondary sexual characteristics at puberty but develop large ovarian cysts and early ovarian failure (24,25).


Gynecology_Novak

Gynecology_Novak. 17´a-Hydroxylase and 17,20-lyase Deficiency Mutations in the CYP17 gene cause abnormalities in both the 17α-hydroxylase and 17,20-lyase functions of the protein that is active in the adrenal and gonadal steroidogenic pathways. More than 20 mutations that alter the reading frame of the gene are identified, even though very few people have the disorder (26). Patients have either 46,XX or 46,XY karyotypes. The uterus is absent in individuals with 46,XY karyotype, a feature distinguishing them from individuals with the 46,XX karyotype. Individuals with CYP17 mutations have primary amenorrhea, no secondary sexual characteristics, female phenotype, hypertension, and hypokalemia (27). The diminished levels of 17α-hydroxylase that characterize this disorder lead to a reduction in cortisol production, which in turn causes an increase in adrenocorticotropic hormone (ACTH). 17-hydroxylase is not required for production of mineralocorticoids; thus, excessive amounts of mineralocorticoid are


Gynecology_Novak

Gynecology_Novak. which in turn causes an increase in adrenocorticotropic hormone (ACTH). 17-hydroxylase is not required for production of mineralocorticoids; thus, excessive amounts of mineralocorticoid are produced, resulting in sodium retention, loss of potassium, and hypertension. Patients with 17α-hydroxylase deficiency have primordial follicles, but gonadotropin levels are elevated because the enzyme deficiency prevents synthesis of sex steroids.


Gynecology_Novak

Gynecology_Novak. Aromatase Deficiency This very rare autosomal recessive abnormality prevents the affected individual from aromatizing androgens to estrogen (28). This syndrome may be suspected even before birth because most mothers of affected children become virilized during pregnancy. This occurs because the placenta cannot convert the fetal androgens to estrogen and they diffuse into the maternal circulation. At birth, a female child has clitoromegaly and posterior labioscrotal fusion (ambiguous genitalia). At puberty, there is no breast development, primary amenorrhea, worsening virilization, absent growth spurt, delayed bone age, and multicystic ovaries. The diagnostic hormonal pattern consists of an elevation of FSH, LH, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels, and undetectable levels of estradiol. Estrogen therapy improves the ovarian and skeletal abnormalities but must be titrated to mimic normal estrogen levels. Estrogen administration should be minimal during


Gynecology_Novak

Gynecology_Novak. levels of estradiol. Estrogen therapy improves the ovarian and skeletal abnormalities but must be titrated to mimic normal estrogen levels. Estrogen administration should be minimal during childhood and increased at puberty (29,30).


Gynecology_Novak

Gynecology_Novak. Galactosemia In girls, galactosemia often is associated with ovarian failure, but this condition usually is detected by newborn screening programs. A galactose-1 phosphate uridyl transferase level can be measured to assess the patient for galactosemia or carrier status. Luteinizing Hormone Receptor Mutation Inactivation of LH receptors is identified in XY pseudohermaphrodites with primary amenorrhea in the absence of secondary sexual characteristics caused by homozygous premature stop codon, deletions, and missense mutations in the LHR gene located on chromosome 2. The Leydig cells in these individuals are unable to respond to LH, causing Leydig cell hypoplasia. This leads to early testicular failure and prevents masculinization. XX siblings with the same mutations develop normal secondary sexual characteristics but are amenorrheic with elevated LH levels, normal FSH levels, and cystic ovaries (31,32).


Gynecology_Novak

Gynecology_Novak. Follicle-Stimulating Hormone Receptor Mutation An autosomal recessive single amino acid substitution in the extracellular domain of the FSH receptor, which prevents FSH binding, was identified in six families in Finland. This condition leads to primary or early secondary amenorrhea, variable development of secondary sexual characteristics, and high levels of FSH and LH (33). Other Causes of Primary Ovarian Failure without Secondary Sexual Characteristics


Gynecology_Novak

Gynecology_Novak. Other Causes of Primary Ovarian Failure without Secondary Sexual Characteristics Severe damage to the ovaries before the onset of puberty can lead to ovarian insufficiency and failure to develop secondary sexual characteristics. Ovarian dysfunction can occur in association with irradiation of the ovaries, chemotherapy with alkylating agents (e.g., cyclophosphamide), or combinations of radiation and other chemotherapeutic agents (34,35). Other causes of premature ovarian failure (also known as primary ovarian insufficiency) are more commonly associated with amenorrhea after the development of secondary sexual characteristics, as described below. Hypogonadotropic Hypogonadism Associated with the Absence of Secondary Sex Characteristics Primary amenorrhea resulting from hypogonadotropic hypogonadism occurs when the hypothalamus fails to secrete adequate amounts of GnRH or when a pituitary disorder associated with inadequate production or release of pituitary gonadotropins is present.


Gynecology_Novak

Gynecology_Novak. Physiologic Delay Physiologic or constitutional delay of puberty is the most common manifestation of hypogonadotropic hypogonadism. Amenorrhea may result from the lack of physical development caused by delayed reactivation of the GnRH pulse generator. Levels of GnRH are functionally deficient in relation to chronologic age but normal in terms of physiologic development. Kallmann Syndrome The second most common hypothalamic cause of primary amenorrhea associated with hypogonadotropic hypogonadism is insufficient pulsatile secretion of GnRH (Kallmann syndrome), which has varied modes of genetic transmission. Insufficient pulsatile secretion of GnRH leads to deficiencies in FSH and LH (36). Kallmann syndrome is often associated with anosmia (inability to perceive odors), although a woman may not be aware of her impaired sense of smell. The hypogonadism and anosmia arise because of failure of proper neuronal migration during fetal development.


Gynecology_Novak

Gynecology_Novak. Other Causes of Gonadotropin-Releasing Hormone Deficiency Deficiencies in GnRH may be caused by developmental or genetic defects, inﬂammatory processes, tumors, vascular lesions, or trauma. Central nervous system tumors that lead to primary amenorrhea, the most common of which is craniopharyngioma, are usually extracellular masses that interfere with the synthesis and secretion of GnRH or stimulation of pituitary gonadotropins. Virtually all of these patients have disorders in the production of other pituitary hormones and LH and FSH (37,38). Prolactin-secreting pituitary adenomas are rare in childhood and more commonly occur after development of secondary sexual characteristics.


Gynecology_Novak

Gynecology_Novak. Genetic Disorders 5α-Reductase Deficiency 5α-Reductase deficiency should be considered a cause of amenorrhea (39). Patients with this disorder are genotypically XY, frequently experience virilization at puberty, have testes (because of functioning Y chromosomes), and have no m¨ullerian structures as a result of functioning AMH. 5α-Reductase converts testosterone to its more potent form, dihydrotestosterone. Patients with 5-reductase deficiency differ from patients with androgen insensitivity because they do not develop breasts at puberty (Fig. 30.2). These patients have low gonadotropin levels as a result of testosterone levels that are sufficient to suppress breast development and allow normal feedback mechanisms to remain intact. Normal male differentiation of the urogenital sinus and external genitalia do not occur because dihydrotestosterone is required for this development. Normal internal male genitalia derived from the wolffian ducts are present because this development


Gynecology_Novak

Gynecology_Novak. and external genitalia do not occur because dihydrotestosterone is required for this development. Normal internal male genitalia derived from the wolffian ducts are present because this development requires only testosterone. Male pattern hair growth, muscle mass, and voice deepening are testosterone dependent.


Gynecology_Novak

Gynecology_Novak. Gonadotropin-Releasing Hormone Receptor Mutations Several mutations are identified in the GnRH receptor gene that causes abnormal GnRH function. Most affected patients are compound heterozygotes, but homozygous autosomal recessive mutations are identified. The GnRH receptor is a G-protein–coupled receptor. Functional studies show that the mutations cause marked decrease in binding of GnRH to its receptor or prevent second-messenger signal transduction. Without a functional signal transduction, FSH and LH are not stimulated and are unable to promote follicular growth (40). All patients are normosomic. Receptor mutations in GnRH cause 17% of sporadic cases of idiopathic hypogonadotropic hypogonadism with normal olfaction (41). Follicle-Stimulating Hormone Deficiency Patients with FSH deficiency usually seek treatment for delayed puberty and primary amenorrhea associated with hypoestrogenism.


Gynecology_Novak

Gynecology_Novak. Follicle-Stimulating Hormone Deficiency Patients with FSH deficiency usually seek treatment for delayed puberty and primary amenorrhea associated with hypoestrogenism. They are distinguished from other hypoestrogenic patients by having decreased FSH levels and increased LH levels. These patients have low serum androgen levels despite the abnormal LHto-FSH ratio, indicating that FSH-stimulated follicular development is a prerequisite for thecal cell androgen production. In some of these patients, autosomal recessive mutations in the FSHβ subunit, which impair dimerization of α and β subunits and prevent binding to the FSH receptor, are identified (42). Pregnancy was achieved in one patient after induction of ovulation with injectable gonadotropins (43).


Gynecology_Novak

Gynecology_Novak. Functional gonadotropin deficiency results from malnutrition, malabsorption, weight loss or anorexia nervosa, excessive exercise, chronic disease, neoplasias, and marijuana use, although these conditions are more commonly associated with amenorrhea accompanied by secondary sexual characteristics that developed before the onset of the problem, which is discussed in detail below (44–48). Hypothyroidism, polycystic ovarian syndrome (PCOS), Cushing syndrome, hyperprolactinemia, and infiltrative disorders of the central nervous system are more commonly associated with amenorrhea in the presence of development of secondary sexual characteristics, but can lead to amenorrhea accompanied by delayed puberty (49,50). Constitutional delay without underlying causes is less common in girls than in boys, and the reason for lack of development should be vigorously pursued (51). Evaluation of Women with Amenorrhea Associated with the Absence of Secondary Sexual Characteristics


Gynecology_Novak

Gynecology_Novak. Evaluation of Women with Amenorrhea Associated with the Absence of Secondary Sexual Characteristics A careful history and physical examination are necessary to appropriately diagnose and treat primary amenorrhea associated with hypogonadism. The physical examination may be particularly helpful in patients with Turner syndrome. A history of short stature but consistent growth rate, a family history of delayed puberty, and normal physical findings (including assessment of smell, optic discs, and visual fields) may suggest physiologic delay. Headaches, visual disturbances, short stature, symptoms of diabetes insipidus, and weakness of one or more limbs suggest central nervous system lesions (38). Galactorrhea may be seen with prolactinomas, a condition more commonly associated with secondary amenorrhea in the presence of normal secondary sexual characteristics. The diagnostic workup is summarized as follows: 1.


Gynecology_Novak

Gynecology_Novak. The diagnostic workup is summarized as follows: 1. The initial laboratory test should be assessment of serum FSH and LH levels unless the history and physical examination suggest otherwise in order to differentiate hypergonadotropic and hypogonadotropic forms of hypogonadism. If the FSH level is elevated, a karyotype should be obtained. An elevated FSH level in combination with a 45,X karyotype confirms the diagnosis of Turner syndrome. Partial deletion of the X chromosome, mosaicism, pure gonadal dysgenesis, and mixed gonadal dysgenesis are diagnosed by obtaining a karyotype. 2. Because of the association with coarctation of the aorta (up to 30%) and thyroid dysfunction, patients with Turner syndrome should undergo echocardiography every 3 to 5 years and thyroid function studies yearly. Cardiac MRI is considered an important component of the cardiac evaluation (6). Patients with Turner syndrome should be evaluated for hearing loss, renal malformations, diabetes, and hypertension.


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Gynecology_Novak. 3. If the karyotype is abnormal and contains the Y chromosome, as in gonadal dysgenesis, the gonads should be removed to prevent tumors (13). 4. If the karyotype is normal and the FSH level is elevated, it is important to consider the diagnosis of 17-hydroxylase deficiency because it may be a life-threatening disease if untreated. This diagnosis should be considered when testing indicates elevated serum progesterone (>3.0 ng/mL) level, a low 17α-hydroxyprogesterone (0.2 ng/mL) level, and an elevated serum deoxycorticosterone level (52). The diagnosis is confirmed with an ACTH stimulation test. After ACTH bolus administration, affected individuals have markedly increased levels of serum progesterone compared with baseline levels and no change in serum 17α-hydroxyprogesterone levels. 5.


Gynecology_Novak

Gynecology_Novak. 5. If the screening FSH level is low, the diagnosis of hypogonadotropic hypogonadism is established. Central nervous system lesions should be ruled out by imaging using computed tomography (CT) or MRI, especially if galactorrhea, headaches, or visual field defects are identified. Suprasellar or intrasellar calcification in an abnormal sella is found in approximately 70% of patients with craniopharyngioma (38). 6. Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from insufficient GnRH secretion. The diagnosis can be supported by a history suggesting physiologic delay, an x-ray showing delayed bone age, and the absence of a central nervous system lesion on CT or MRI scanning. Treatment of Amenorrhea Associated with the Absence of Secondary Sexual Characteristics


Gynecology_Novak

Gynecology_Novak. Treatment of Amenorrhea Associated with the Absence of Secondary Sexual Characteristics Individuals with primary amenorrhea associated with all forms of gonadal failure and hypergonadotropic hypogonadism need cyclic estrogen and progestogen therapy to initiate, mature, and maintain secondary sexual characteristics. Prevention of osteoporosis is an additional benefit of estrogen therapy: 1. Therapy is usually initiated with 0.3 to 0.625 mg per day of conjugated estrogens or 0.5to 1 mg perday of estradiol. 2. If the patient is short in stature, higher doses should not be used because premature closure of the epiphyses should be avoided. Most of these patients are of normal height, and higher estrogen doses may be used initially and reduced to the maintenance doses after several months. 3.


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Gynecology_Novak. 3. Estrogen can be given daily in combination with progestogen (medroxyprogesterone acetate or progesterone) to prevent hyperplasia that could result from unopposed estrogen stimulation of the endometrium in patients with a uterus. Medroxyprogesterone acetate may be administered at a dose of 2.5 mg daily every day of the month or 5 to 10 mg for 12 to 14 days per month. Oral micronized progesterone may be administered at a daily dose 100 mg every day of the month or 200 mg daily for 12 to 14 days per month. Cyclic hormone therapy (with 12 to 14 days of progestogen per month) more closely mimics the natural menstrual cycle. Progesterone suppositories may be administered at a dose of 50 mg daily or 100 mg for 12 to 14 days monthly. 4. Occasionally, individuals with mosaicism and gonadal streaks may ovulate and be able to conceive either spontaneously or after the institution of estrogen therapy. 5.


Gynecology_Novak

Gynecology_Novak. 4. Occasionally, individuals with mosaicism and gonadal streaks may ovulate and be able to conceive either spontaneously or after the institution of estrogen therapy. 5. If 17α-hydroxylase deficiency is confirmed, treatment is instituted with corticosteroid replacement and estrogen. Progestogen should be added to protect the endometrium from hyperplasia. If possible, therapeutic measures are aimed at correcting the primary cause of amenorrhea: 1. Craniopharyngiomas may be resected with a transsphenoidal approach or during craniotomy, depending on the size of the tumor. Some studies show improved prognosis with radiation therapy used in combination with limited tumor removal (38,53). 2. Germinomas are highly radiosensitive, and surgery is rarely indicated (54). 3. Prolactinomas and hyperprolactinemia often may respond to dopamine agonists (bromocriptine or cabergoline) (55). 4.


Gynecology_Novak

Gynecology_Novak. Specific therapies are directed toward malnutrition, malabsorption, weight loss, anorexia nervosa, exercise amenorrhea, neoplasia, and chronic diseases. Logically, it would appear that patients with hypogonadotropic hypogonadism of hypothalamic origin should be treated with long-term administration of pulsatile GnRH. This form of therapy is impractical because it requires the use of an indwelling catheter and a portable pump for prolonged periods and the lack of availability of this equipment in the United States. The primary focus of treatment should be to correct the underlying problem that is causing the menstrual dysfunction (e.g., malnutrition). If a patient is unable to correct the underlying condition, she may be treated with cyclic estrogen and progestogen therapy at least until sexual maturity is achieved. Once sexual maturation is achieved, hormone therapy can be continued to treat hypoestrogenic symptoms until the underlying disorder leading to amenorrhea can be adequately


Gynecology_Novak

Gynecology_Novak. maturity is achieved. Once sexual maturation is achieved, hormone therapy can be continued to treat hypoestrogenic symptoms until the underlying disorder leading to amenorrhea can be adequately treated.


Gynecology_Novak

Gynecology_Novak. 5. Patients with Kallmann syndrome, and patients with other etiologies for hypothalamic amenorrhea, can be treated with hormone replacement, as described above. For individuals with anorexia, intensive treatment to achieve weight gain and emotional well-being is preferable to long-term treatment with hormone therapy (56). 6. If the patient has physiologic delay of puberty, the only management required is reassurance that the anticipated development will occur eventually.


Gynecology_Novak

Gynecology_Novak. 6. If the patient has physiologic delay of puberty, the only management required is reassurance that the anticipated development will occur eventually. Individuals whose karyotypes contain a Y cell line (45,X/46,XY mosaicism, or pure gonadal dysgenesis 46,XY) are predisposed to gonadal ridge tumors, such as gonadoblastomas, dys germinomas, and yolk sac tumors. The gonads of these individuals should be removed when the condition is diagnosed to prevent malignant transformation. There is some evidence that hirsute individuals without Y chromosomes should undergo gonad removal. One patient with hirsutism and the karyotype 45,X was noted to have a streak gonad; the contralateral gonad was dysgenic and contained developing follicles, well-differentiated seminiferous tubules, and Leydig cells. This patient was found to be HY antigen–positive (57).


Gynecology_Novak

Gynecology_Novak. Clomiphene citrate is most often ineffective for inducing ovulation in patients with hypogonadism who desire pregnancy because such patients are hypoestrogenic. In patients with hypogonadism, ovulation induction with injectable gonadotropins is generally successful. In patients without ovarian function, oocyte donation may be appropriate. There are reports of deaths in pregnant patients with Turner syndrome resulting from aortic dissection and rupture (58). Careful counseling and investigation should be undertaken in patients with Turner syndrome before treating them with donated oocytes. Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomy


Gynecology_Novak

Gynecology_Novak. Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomy Amenorrhea occurs if there is blockage of the outﬂow tract, if the outﬂow tract is missing, or if there is no functioning uterus (Table 30.2) In order for menses to occur, the endometrium must be functional and there must be patency of the cervix and vagina. Most women with m¨ullerian abnormalities will have normal ovarian function and thus will have normal secondary sexual characteristic development. Table 30.2 Anatomic Causes of Amenorrhea Secondary to prior uterine or cervical surgery Curettage, especially postpartum Secondary to infections


Gynecology_Novak

Gynecology_Novak. Table 30.2 Anatomic Causes of Amenorrhea Secondary to prior uterine or cervical surgery Curettage, especially postpartum Secondary to infections Any transverse blockage of the m¨ullerian system will cause amenorrhea (59). Such outﬂow obstructions include imperforate hymen, transverse vaginal septum, and absence of the cervix or vagina. Transverse blockage of the outﬂow tract with an intact endometrium frequently causes cyclic pain without menstrual bleeding in adolescents. The blockage of blood ﬂow can cause hematocolpos, hematometra, or hemoperitoneum, and endometriosis.


Gynecology_Novak

Gynecology_Novak. Mayer-Rokitansky-K¨uster-Hauser syndrome includes vaginal agenesis with variable m¨ullerian duct abnormalities accompanied in some cases by renal, skeletal, and auditory abnormalities (60). M¨ullerian agenesis accounts for approximately 10% of cases of primary amenorrhea (2). Of the patients with this syndrome, 15% have an absent, pelvic, or horseshoe kidney, 40% have a double urinary collecting system, and 5% to 12% have skeletal abnormalities(61–63).Mayer-Rokitansky-K¨uster-Hausersyndrome isassociated with abnormal galactose metabolism (64). Absence of Functioning Endometrium Amenorrhea may occur if there is no functioning endometrium. When the findings of the physical examination are normal, anatomic abnormalities of the uterine cavity should be considered. A congenitally absent endometrium is a rare finding in patients with primary amenorrhea.


Gynecology_Novak

Gynecology_Novak. Asherman syndrome, which is more common with secondary amenorrhea or hypomenorrhea, may occur in patients with risk factors for endometrial or cervical scarring (Fig. 30.3). Such risk factors include a history of uterine or cervical surgery, infections related to use of an intrauterine device, and severe pelvic inﬂammatory disease. Asherman syndrome is found in 39% of patients undergoing hysterosalpingography who previously underwent postpartum curettage (65). Infections such as tuberculosis and schistosomiasis may cause Asherman syndrome but are not common for women who have lived their whole lives in the United States. Cervical stenosis resulting from surgical removal of dysplasia (cone biopsy, loop electroexcision procedure) may lead to amenorrhea.


Gynecology_Novak

Gynecology_Novak. Androgen Insensitivity Phenotypic females with complete congenital androgen insensitivity (previously called testicular feminization) develop secondary sexual characteristics but do not have menses (Fig. 30.2). Genotypically, they are male (XY) but have a defect that prevents normal androgen receptor function, leading to the development of the female phenotype. Serum testosterone is in the normal male range. The vagina may be absent or short.


Gynecology_Novak

Gynecology_Novak. Defects in the androgen receptor gene located on the X chromosome include absence of the gene that encodes for the androgen receptor and abnormalities in the binding domains of the receptor. Androgen receptor deficits are diverse and may result from diminished receptor function or concentration. The diversity of androgen receptor mutations may be related to diversity in phenotype. More than 250 extremely diverse mutations are described, with amino acid substitution being by far the most common (66,67). Postreceptor defects can exist (68). Total serum testosterone concentration is in the range of normal males. Because antim¨ullerian hormone is present and functions normally in these patients, internal female (m¨ullerian) structures such as a uterus, vagina, and fallopian tubes are absent. Testes rather than ovaries are present in the abdomen or in inguinal hernias because of the presence of normally functioning genes on the Y chromosome. Patients have a blind vaginal pouch and scant or


Gynecology_Novak

Gynecology_Novak. rather than ovaries are present in the abdomen or in inguinal hernias because of the presence of normally functioning genes on the Y chromosome. Patients have a blind vaginal pouch and scant or absent axillary and pubic hair. These patients experience abundant breast development at puberty; however, the nipples are immature and the areolae are pale. Testosterone is not present during development to suppress the formation of breast tissues; at puberty, the conversion of testosterone to estrogen stimulates breast growth. Patients are unusually tall with eunuchoidal tendency (long arms with big hands and feet).


Gynecology_Novak

Gynecology_Novak. True Hermaphroditism True hermaphroditism is a rare condition that should be considered as a possible cause of amenorrhea. Both male and female gonadal tissues are present in these patients, in whom XX, XY, and mosaic genotypes are found. Two-thirds of the patients menstruate, but menstruation was never reported in XY genotypes. The external genitalia usually are ambiguous, and breast development frequently occurs in these individuals. Fifteen percent of XX true hermaphrodites have SRY translocations, and another 10% have Y chromosomal mosaicism within the gonad (17). Evaluation of Women with Amenorrhea, Normal Secondary Sexual Characteristics, and Suspected Anatomic Abnormalities


Gynecology_Novak

Gynecology_Novak. Evaluation of Women with Amenorrhea, Normal Secondary Sexual Characteristics, and Suspected Anatomic Abnormalities Figure 30.2 A: A well-developed patient with complete androgen insensitivity. Note the characteristic paucity of pubic hair and well-developed breasts. (From Yen SSC, Jaffe RB. Reproductive endocrinology. 3rd ed. Philadelphia, PA: WB Saunders, 1991:497, with permission.) B: Another patient with androgen insensitivity syndrome with a contrasting thin body hiatus. This is a 17-year-old twin 46,XY. (From Jones HW Jr, Scott WW. Hermaphrodism, genital anomalies, and related endocrine disorders. 2nd ed. Baltimore, MD: Williams & Wilkins, 1971, with permission.) Most congenital abnormalities can be diagnosed by physical examination: 1.


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Gynecology_Novak. Most congenital abnormalities can be diagnosed by physical examination: 1. An imperforate hymen is diagnosed by the presence of a bulging membrane that distends during Valsalva maneuver. Ultrasonography or MRI is useful to identify the m¨ullerian anomaly when the abnormality cannot be found by physical examination. The patient should be examined for skeletal malformations and assessed with intravenous pyelography or renal ultrasound to detect concomitant renal abnormalities. These abnormalities occur less frequently than in m¨ullerian agenesis (63). 2.


Gynecology_Novak

Gynecology_Novak. 2. It is difficult to differentiate a transverse septum or complete absence of the cervix and uterus in a female from a blind vaginal pouch in a male pseudohermaphrodite by examination alone. Androgen insensitivity is likely when pubic and axillary hair is absent. To confirm the diagnosis, a karyotype determination should be performed to see whether a Y chromosome is present. In some patients, the defect in the androgen receptor is not complete and virilization occurs. 3.


Gynecology_Novak

Gynecology_Novak. An absent endometrium is an outﬂow tract abnormality that cannot be diagnosed by physical examination in a patient with primary amenorrhea. This abnormality is so rare that in a patient with normal physical findings (normal vagina, cervix, and uterus), it may be advisable to proceed with evaluation of endocrine abnormalities. Although in most cases performance of the progestogen challenge test is not recommended, this test may be of value to confirm the rare diagnosis of congenitally absent endometrium. In this case, progestogen can be administered to a woman who appears to have normal estrogen production (or if estrogen status is questioned, 2.5 mg conjugated estrogen or2 mg micronized estradiol can be given for 25 days with 5 to 10 mg of medroxyprogesterone acetate added for the last 10 days). Congenital absence of the endometrium is confirmed if no bleeding occurs with this regimen in a patient with primary amenorrhea and no physical abnormalities. This is a very rare diagnosis and


Gynecology_Novak

Gynecology_Novak. days). Congenital absence of the endometrium is confirmed if no bleeding occurs with this regimen in a patient with primary amenorrhea and no physical abnormalities. This is a very rare diagnosis and routine performance of progestogen challenge is not recommended. Transvaginal ultrasound to assess endometrial thickness may be helpful, with a thickened endometrial lining indicating endometrial response to estrogen.


Gynecology_Novak

Gynecology_Novak. 4. Asherman syndrome cannot be diagnosed by physical examination. It is diagnosed by performing hysterosalpingography, saline infusion sonography (also known as saline hysterogram), or hysteroscopy. These tests will show either complete obliteration or multiple filling defects caused by synechiae. If tuberculosis or schistosomiasis is suspected, endometrial cultures should be performed. Figure 30.3 A: Intrauterine adhesion seen on hysterosalpingogram in a patient with Asher-man syndrome. (From Donnez J, Nisolle M. The encyclopedia of visual medicine series—an atlas of laser operative laparoscopy and hysteroscopy. New York: Parthenon, 1994:306, with permission.) Treatment of Women with Amenorrhea, Normal Secondary Sexual Characteristics, and Abnormalities of Pelvic Anatomy Figure 30.3 (Continued ) B: Hysteroscopic view of intrauterine adhesion in a patient with Asherman syndrome. The treatment of congenital anomalies can be summarized as follows: 1.


Gynecology_Novak

Gynecology_Novak. Figure 30.3 (Continued ) B: Hysteroscopic view of intrauterine adhesion in a patient with Asherman syndrome. The treatment of congenital anomalies can be summarized as follows: 1. Treatment of an imperforate hymen involves making a cruciate incision to open the vaginal orifice. Most imperforate hymens are not diagnosed until a hematocolpos forms. It is unwise to place a needle into a hematocolpos without completely removing the obstruction because a pyocolpos may occur. 2. If a transverse septum is present, surgical removal is required. Forty-six percent of transverse septa occur in the upper third of the vagina, and 40% occur in the middle third of the vagina (69). Frank dilators should be used to distend the vagina until it is healed to prevent vaginal adhesions (70). Patients have a fully functional reproductive system after surgery; however, patients with repaired high transverse septa may have lower pregnancy rates (71). 3.


Gynecology_Novak

Gynecology_Novak. 3. Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to treat than other outﬂow obstructions. Surgery to repair the cervix is rarely successful, and hysterectomy is typically required (72). Endometriosis is a common finding, and it is questionable whether this condition should be treated initially with surgery or if it will resolve spontaneously after surgical repair of the obstruction. The ovaries should be retained to provide the benefits of estrogen and to allow for the possibility of future childbearing by removing mature oocytes for in vitro fertilization and transfer of embryos to a gestational carrier. 4.


Gynecology_Novak

Gynecology_Novak. 4. If the vagina is absent or short, progressive dilation is usually successful in making it functional (70,73). If dilation fails or the patient is unable to perform dilation, the McIndoe split thickness graft technique may be performed (62,74,75). Controversy exists as to the best technique (60). The initial use of vaginal dilators is required to maintain a functional vagina. 5.


Gynecology_Novak

Gynecology_Novak. 5. In patients with complete androgen insensitivity, the testes should be removed after pubertal development is complete to prevent malignant degeneration (76). In patients with testes, 52% develop a neoplasia, most often a gonadoblastoma. Almost one-half of the testicular neoplasms are malignant (dysgerminomas), but transformation usually does not occur until after puberty (77). In patients who develop virilization and have an XY karyotype, the testes should be removed immediately to preserve the female phenotype and to promote female gender identity. Bilateral laparoscopic gonadectomy is the preferred procedure for removal of intra-abdominal testes. 6.


Gynecology_Novak

Gynecology_Novak. 6. Adhesions in the cervix and uterus (Asherman syndrome) can be removed using hysteroscopic resection with scissors or electrocautery. It is reasonable to place a pediatric Foley catheter in the uterine cavity for 7 to 10 days postoperatively (along with systemic administration of broad-spectrum antibiotic therapy). A 2-month course of high-dose estrogen therapy with monthly progestogen withdrawal is used to prevent reformation of adhesions. Eighty percent of patients thus treated achieve pregnancy, but complications including miscarriage, preterm labor, placenta previa, and placenta accreta can occur (78). Cervical stenosis can be treated by cervical dilation. Amenorrhea with Secondary Sexual Characteristics and Normal Pelvic Anatomy


Gynecology_Novak

Gynecology_Novak. Amenorrhea with Secondary Sexual Characteristics and Normal Pelvic Anatomy Although the complete list of potential causes is long, as noted below, the most common causes of amenorrhea in women with normal secondary sexual characteristics and normal pelvic are pregnancy, polycystic ovarian syndrome, hyperprolactinemia, primary ovarian insufficiency (also known as premature ovarian failure), and hypothalamic dysfunction. Pregnancy must be considered in all women of reproductive age with amenorrhea.


Gynecology_Novak

Gynecology_Novak. PCOS is a medical condition associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (79). All definitions of PCOS exclude patients with significantly elevated prolactin, significant thyroid dysfunction, adult-onset congenital adrenal hyperplasia, and androgen-secreting neoplasms from being classified as PCOS. The National Institutes of Health (NIH) 1990 criteria included hyperandrogenism and oligomenorrhea or amenorrhea as required for PCOS diagnosis. The Rotterdam 2003 criteria required two of three of the following for PCOS diagnosis: hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by ultrasound (80). Although insulin resistance is noted among women with PCOS, it is not included in any of the diagnostic criteria. Obesity is common, but approximately 20% of women with PCOS are not obese. Women with PCOS are often subfertile caused by infrequent or absent ovulation. PCOS can have other general health implications, including increased risk for


Gynecology_Novak

Gynecology_Novak. 20% of women with PCOS are not obese. Women with PCOS are often subfertile caused by infrequent or absent ovulation. PCOS can have other general health implications, including increased risk for endometrial hyperplasia and cancer, diabetes, and possibly cardiovascular disease.


Gynecology_Novak

Gynecology_Novak. Even though PCOS usually causes irregular bleeding rather than amenorrhea, it remains one of the most common causes of amenorrhea (2). The etiology of PCOS remains largely unknown. In patients who are hirsute and amenorrheic and appear to have PCOS, androgen-secreting adrenal tumors and congenital adrenal hyperplasia should be considered. Elevations in androgens (e.g., Sertoli-Leydig, hilus, and lipoid cell tumors) and estrogens (e.g., granulosa cell tumors) by ovarian tumors may lead to abnormal menstrual patterns, including amenorrhea. A history of rapid onset of hirsutism is suggestive of a tumor. other central nervous system (CNS) lesions that disrupt the normal transport of dopamine down the pituitary stalk, and by medications that interfere with normal dopamine secretion (such as antidepressants, antipsychotics including risperidone, metoclopramide, some antihypertensives, opiates, and H2-receptor blockers).


Gynecology_Novak

Gynecology_Novak. If elevated TSH and elevated prolactin levels are found together, the hypothyroidism should be treated before hyperprolactinemia is treated. Often, the prolactin level will normalize with treatment of hypothyroidism because thyroid-releasing hormone, which is elevated in hypothyroidism, stimulates prolactin secretion.


Gynecology_Novak

Gynecology_Novak. Primary ovarian insufficiency is suggested as the preferred term for the condition that otherwise was referred to as premature ovarian failure or premature menopause (82,83). Overt primary ovarian insufficiency (POI) is defined as the presence of amenorrhea for 4 months or more accompanied by two serum FSH levels in the menopausal range for a woman who is less than 40 years of age. Ovarian “insufficiency” is suggested to be more appropriate than “failure” in part because ovarian function can wax and wane, and function can resume even after it appears that a woman transitioned into menopause. Ovarian insufficiency may be caused by decreased follicular endowment or accelerated follicular atresia (82). Over 75% of women with POI will have at least intermittent symptoms including hot ﬂushes, night sweats, and emotional lability (84). Symptoms are uncommon among women with primary amenorrhea who never received estrogen.


Gynecology_Novak

Gynecology_Novak. If the ovary does not develop or stops its hormone production before puberty, the patient will not develop secondary sexual characteristics without exogenous hormone therapy. If ovarian insufficiency begins later in life, the woman will have normal secondary sexual characteristics. POI clearly compromises the chance of a woman conceiving with autologous oocytes. However, 5% to 10% of women with a diagnosis of premature ovarian failure achieve pregnancy, with approximately 80% of these pregnancies resulting in the delivery of a healthy child (85). It can be difficult to determine which women will be able to conceive. Published studies of testing for ovarian reserve have not specifically focused on the POI populations, and pregnancies may occur despite very unfavorable results for tests of ovarian reserve such as serum FSH, estradiol, and AMH.


Gynecology_Novak

Gynecology_Novak. POI is a heterogenous disorder with many potential causes. POI may be caused by sex chromosome disorders, mutations of single genes, and by FMR1 premutations. Radiation or chemotherapy may lead to POI. The cause of POI may be autoimmune. The cause remains unknown in a majority of cases (Table 30.3). Sex Chromosome and Single Gene Disorders Associated with Primary Ovarian Insufficiency Deletion of the X chromosome (Turner syndrome) is associated with primary ovarian insufficiency, despite normal development of the ovaries, because of accelerated atresia of the follicles (86). Although Turner syndrome may often be associated with primary Table 30.3 Causes of Ovarian Insufficiency or Failure after Development of Secondary Sexual Characteristics Chromosomal etiology (e.g., Turner mosaic) Iatrogenic causes: radiation, chemotherapy, surgical damage to ovarian blood supply or ovary


Gynecology_Novak

Gynecology_Novak. Chromosomal etiology (e.g., Turner mosaic) Iatrogenic causes: radiation, chemotherapy, surgical damage to ovarian blood supply or ovary Idiopathic (80%–90% of cases) amenorrhea with absence of secondary sexual characteristics, breast development may occur if ovarian function is initially present. Mosaicism of an XO or XY cell line may cause ovarian insufficiency. Individuals with a 47,XXX karyotype may develop ovarian failure (87). The most common physical features of 47,XXX are tall stature, epicanthal folds, hypotonia, and clinodactyly.