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| CECIL |
| TEXT BOOK of MEDICINE |
Section XIX Women's Health
| 255 OVARIES AND DEVELOPMENT Robert W. Rebar • Gregory F. Erickson • |
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Definition
The ovaries episodically release female gametes (oocytes or eggs) and secrete sex steroid hormones, principally androstenedione, estradiol, and progesterone. Oocytes are released only during the adult reproductive years, when sex steroid secretion is also greatest, but the ovaries are physiologically active throughout life.
Sex steroids affect the growth, differentiation, and function of a variety of tissues and organs throughout the body; therefore, abnormalities of the ovaries and of sex steroid secretion should be recognized by all physicians. A rational approach to the diagnosis and treatment of reproductive disorders in women requires an understanding of the functions of the ovaries and of their most important unit, the follicle, throughout life.
Physiology
Embryology
Embryogenesis and Differentiation
Organogenesis of the ovaries occurs during fetal life. Ovarian cells are derived from two different sources: (1) primordial germ cells (PGCs) originate at a site outside the prospective gonads, and (2) somatic cells differentiate from the coelomic epithelium and gonadal mesenchyme. In females, PGCs become oocytes, whereas somatic cells differentiate into a variety of cell types, including granulosa, theca, and vascular cells.
PGCs in the human embryo can be distinguished at the gastrula stage (Fig. 255-1). Shortly after formation, PGCs migrate through the dorsal mesentery to the genital ridges. Chemotaxis plays a role in directing PGCs to the gonads. During migration, PGCs proliferate in response to growth factors, most notably kit ligand. The importance of kit is demonstrated by the finding that loss-of-function mutations result in a paucity of PGCs, which in turn results in premature ovarian failure.
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| FIGURE 255-1 Diagram illustrating the developmental timetable of the major events that ultimately lead to the formation of primordial follicles during the process of human ovary organogenesis. PGC = primordial germ cell. |
The genital ridges are characterized by a thickening of the coelomic epithelium and underlying primary mesenchyme. Initially, the gonads are sexually indifferent. Male gonadal differentiation is triggered by the Y chromosome–encoded testis-determining factor, SRY. SRY expression results in the differentiation of Sertoli cells and the secretion of müllerian-inhibiting substance, which induces regression of the müllerian ducts. Testicular interstitial cells differentiate into Leydig cells, which secrete testosterone, which in turn stimulates wolffian duct development. In the female, absence of müllerian-inhibiting substance and testosterone leads to the degeneration of the wolffian ducts and to the development of the müllerian ducts. Thus, the development of the ovaries and female reproductive system is considered a “default” pathway.
When PGCs enter the genital ridges, they begin gametogenesis (see Fig. 255-1). In females, this process is termed oogenesis and involves the differentiation of PGCs into oogonia and oocytes. When sex-specific differentiation of the ovary commences, the inactive X chromosome in the PGCs becomes active. This denotes the formation of mitotically active oogonia. The importance of two functional X chromosomes during oogenesis is emphasized by the fact that 45,X females lack oocytes and undergo premature menopause.
After repeated mitosis, oogonia initiate meiosis and become oocytes (see Fig. 255-1). At approximately the same time, granulosa cells differentiate within the gonadal mesenchyme and establish intimate associations with oocytes. Oocytes that become surrounded by granulosa cells stop meiosis after diplotene, and the bivalents enter an interphase state known as dictyotene. If an oocyte is not surrounded by granulosa cells, meiosis continues to diakinesis and the oocyte dies by apoptosis. Granulosa cells, therefore, are critical for oocyte survival. The majority of oocytes die during fetal ovary development (Fig. 255-2), apparently from a lack of contact with granulosa cells.
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| FIGURE 255-2 Changes in the total number of germ cells in the human ovaries during aging. At early to mid gestation, the number of germ cells increases to almost 7 million; shortly thereafter, the number declines rapidly to about 2 million at birth. The number continues to decline until no oocytes are detected at 50 years of age. (From Baker TG: Radiosensitivity of mammalian oocytes with particular reference to the human female. Am J Obstet Gynecol 1971;110:746–761, with permission.) |
With further development, the oocyte–granulosa cell complex becomes a primordial follicle. This occurs between the sixth and ninth months of gestation (Fig. 255-3). A primordial follicle consists of a single layer of squamous granulosa cells, a small (about 15 μm in diameter) dictyotene oocyte, and a thin basal lamina (see Fig. 255-3). In the human female, all potential future eggs have entered diplotene of meiosis at the time of birth, and no reserve oogonia remain.
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| FIGURE 255-3 A, Drawing showing gametogenesis in the human fetal ovary leading to the formation of primordial follicles. At 3 months (1), oogonia divide mitotically. At 4 months (2), some oogonia deep within the cortical cords enter meiosis (arrowheads). At 7 months (3), the cords are no longer distinct and all germ cells are in meiotic prophase I. At 9 months (4), some oocytes become associated with granulosa cells and appear as primordial follicles (asterisks). B, Electron micrograph of human primordial follicle. Granulosa cells (arrowheads), oocyte nucleus (N), and Balbiani body (asterisk) are shown. (From Erickson GF: The ovary: Basic principles and concepts. In Felig P, Baxter JD, Broadus AE, et al [eds]: Endocrinology and Metabolism, 3rd ed. New York, McGraw-Hill, 1995, with permission.) |
Anatomy
The Adult Ovary
The ovaries of normal cycling women are oval bodies that each measure 2.5 to 5.0 cm in length, 1.5 to 3 cm in width, and 0.6 to 1.5 cm in thickness. The medial edge is attached by the mesovarium to the broad ligament, which in turn extends from the uterus laterally to the wall of the pelvic cavity. The ovary is covered by cuboidal epithelium. Beneath the epithelium is a layer of dense connective tissue, the tunica albuginea, which contains the primordial follicles.
The ovaries are organized into two principal parts. A central zone, the medulla, is surrounded by a prominent peripheral zone, the cortex (Fig. 255-4). Growing follicles at different stages of development are present in the cortex. Typically, one follicle per cycle reaches maturity and ovulates its ovum. After ovulation, the follicle transforms into a corpus luteum. The corpus luteum of the cycle lasts for about 14 days, after which it dies and becomes a nodule of dense connective tissue, the corpus albicans (see Fig. 255-4).
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| FIGURE 255-4 Diagram showing the anatomy of the human ovary during the reproductive years. Developing follicles and corpora lutea are located in the cortex; the hilus cells, autonomic nerves, and spiral arteries are present in the medulla. (From Erickson GF: The ovary: Basic principles and concepts. In Felig P, Baxter JD, Broadus AE, et al [eds]: Endocrinology and Metabolism, 3rd ed. New York, McGraw-Hill, 1995, with permission.) |
The medulla is composed of loose connective tissue with numerous blood vessels and associated nerves. The arterial supply to the ovary originates from two principal sources, the ovarian artery and the uterine artery. These two vessels, which enter the medulla from opposite directions, form an anastomotic trunk and become a common vessel called the ramus ovaricus artery. This artery gives rise to a series of primary branches (spiral arteries) that enter the hilum. In the hilum, numerous secondary and tertiary branches are given off to supply the medulla and the follicles and luteal tissue in the cortex (see Fig. 255-4). The hilum also contains the hilus cells (see Fig. 255-4), which, like the testicular Leydig cells, contain Reinke crystals and secrete testosterone. The physiologic role of the hilus cells is still unknown.
Ovarian Function in Childhood and Puberty
Physical Changes at Puberty
Puberty extends from the earliest signs of sexual maturation until the attainment of physical, mental, and emotional maturity. Pubertal changes in girls result directly or indirectly from maturation of the hypothalamic-pituitary-ovarian unit. Human puberty is characterized hormonally by a resetting of the negative gonadal steroid feedback loop, the establishment of new circadian and ultradian (frequent) gonadotropin rhythms, and the acquisition in the female of a positive estrogen feedback loop controlling the menstrual cycle as interdependent expressions of the gonadotropins and ovarian steroids. In girls, pubertal development generally occurs between 8 and 14 years of age. The age at onset and the rate of progress through puberty are variable and depend on genetic, socioeconomic, nutritional, physical, and psychological factors.
Physical changes occur in an orderly sequence during a definite time frame in puberty (Fig. 255-5). Breast budding in girls is usually the first pubertal change, followed shortly by the appearance of pubic hair, with menarche occurring late in pubertal development. The time from breast budding (median age at onset, 9.8 years) to menarche approximates 2 years. Breast development results from increasing ovarian estrogen production, and pubic and axillary hair from increasing ovarian androgen production. Estrogens are required for growth of pubic hair as well.
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| FIGURE 255-5 Temporal sequence of events for thex “average” girl during puberty. (From Rebar RW: Practical evaluation of hormonal status. In Yen SSC, Jaffe RB, Barbieri RL [eds]: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th ed. Philadelphia, WB Saunders, 1999, p 710.) |
The ovarian sex steroids join with growth hormone and adrenal androgens to produce the adolescent growth spurt. Peak growth velocity is achieved relatively early with little growth observed after menarche. Lean body mass, skeletal mass, and body fat are equal in prepubertal boys and girls, but by maturity, women have twice as much body fat as men and less lean body mass and skeletal mass as a result of differences in sex steroid secretion beginning at puberty. Estrogens are necessary for normal formation, mineralization, and maturation of bones. Well-established standards exist for determining radiographically, typically by examination of radiographs of the bones of the wrist, whether bone age is appropriate for chronologic age. Estrogen deficiencies retard and excesses advance bone age in relation to chronologic age.
Hormonal Changes
The ovaries function even in early childhood. The low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that are normally present increase if the ovaries are removed before puberty, just as they do later in life, indicating exquisite sensitivity of the hypothalamic-pituitary unit to extremely low circulating sex steroid levels. As puberty nears, there is a progressive decrease in sensitivity of the hypothalamic-pituitary unit to sex steroids, leading to increased secretion of pituitary gonadotropins, stimulation of sex steroid output, and development of secondary sex characteristics. Increased secretion of both LH and FSH initially occurs at night with sleep and is associated with increased estradiol secretion the next morning (Fig. 255-6). As is true for most hormones, LH and FSH are secreted in an episodic or pulsatile rather than in a continuous fashion. It is possible that the sleep-entrained pulsatile secretion of gonadotropins commences in response to increased pulsatile secretion of gonadotropin-releasing hormone (GnRH). Later in puberty, secretion of LH and FSH is increased, relative to childhood, throughout the 24-hour period, except during the early follicular phase, when nighttime increases still occur. Basal levels of estradiol, the major estrogen secreted by the ovaries, increase throughout puberty. A “critical body mass” may be required for positive estrogen feedback and ovulation. During the first 2 years after menarche, up to 90% of menstrual cycles may be anovulatory because of a delay in the synchronization of the hypothalamic-pituitary-ovarian axis.
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| FIGURE 255-6 The changing patterns of LH, FSH, and estradiol (E2) concen-trations in peripheral blood throughout the life of a woman. Not shown is the fact that both LH and FSH are secreted in a pulsatile fashion. The pubertal period has been expanded to illustrate the sleep-associated increases in LH and FSH fol-lowed by morning increases in E2 that are observed during puberty. (Reprinted with permission from Endocrine and Metabolism Continuing Education Quality Control Program, 1982. Copyright American Association for Clinical Chemistry, Inc.) |
ABERRATIONS IN PUBERTAL DEVELOPMENT
Abnormalities of pubertal development can be divided into four major categories (Table 255-1), as follows.
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- Precocious puberty represents any pubertal changes before the age of 9 years in white girls and before the age of 8 years in African American girls. This is controversial. Some clinicians believe evaluation is warranted only if pubertal development begins before the age of 7 years in white girls and 6 years in African American girls. The nearer that pubertal development begins to the mean age at onset of puberty, the less likely it is to have a pathologic basis. The precocious development is isosexual when the development is common to the phenotypic sex of the individual and heterosexual when the development is characteristic of the opposite sex. True or central precocious puberty is due to premature maturation of the hypothalamic-pituitary axis. In the absence of increased hypothalamic-pituitary activity, precocious pseudopuberty (also known as precocious puberty of peripheral origin) exists.
- Delayed (or interrupted) puberty is defined as the absence of any secondary sex characteristics by the age of 13 years or of menarche by the age of 16 years or by passage of 5 years or more from breast budding to menarche.
- Asynchronous pubertal development occurs when there is deviation from the normal pattern of pubertal development.
- Heterosexual pubertal development is development that occurs at the appropriate time but with some features characteristic of the opposite sex.
Precocious Puberty
Diagnosis
Differential Diagnosis
The temporal sequence in which the signs and symptoms of sex steroid hormone excess appear is most important. Incomplete isosexual precocious puberty indicates premature development of only a single pubertal feature. If breast budding occurs before the age of 8 years in the absence of any other development, the diagnosis may be premature thelarche. Premature thelarche is believed to be due to transient increases in estrogen secretion or increased breast sensitivity to the small quantities of circulating estrogens present before puberty. Simple ovarian cysts may be present in some girls with this disorder. If pubic or axillary hair develops alone and persists, premature pubarche and adrenarche must be considered. These abnormalities are associated with slight increases in adrenal androgen secretion but not with clitorimegaly or other signs of virilization. These syndromes require no treatment, and affected girls typically begin true puberty at the usual age. Careful follow-up is required to distinguish these disorders from true precocious puberty.
When precocious development is isosexual, the purpose of evaluation is to determine if the cause is central (true precocious puberty). Careful questioning of the patient and her parents may indicate inadvertent ingestion or absorption of sex steroids (iatrogenic or factitious). About 10% of individuals with true precocious puberty have one of several organic brain diseases, including neoplasms, tuberous sclerosis, neurofibromatosis, encephalitis, meningitis, and hydrocephalus. The seriousness of intracranial lesions mandates that girls with precocious puberty have radiographic evaluation of the central nervous system, most effectively by magnetic resonance imaging. In almost 90% of girls with true precocious puberty, however, no cause is identified (idiopathic or constitutional).
The physical examination may also provide critical information about the cause of the precocious development. Cutaneous café au lait spots, facial asymmetry, polyostotic fibrous dysplasia and other skeletal abnormalities, cranial nerve deficits, and multiple ovarian follicular cysts suggest McCune-Albright syndrome in a girl with precocious puberty. It is now known that various clones of cells in the endocrine glands of girls with this disorder function autonomously with respect to cyclic adenosine monophosphate production as a consequence of a mutation within exon 8 of the G protein α subunit. This same mutation probably accounts for the bone lesions and café au lait hyperpigmentation. Precocious development associated with short stature, congenital body asymmetry, triangular facies, and clinodactyly suggests the Silver-Russell syndrome. Characteristic signs and symptoms may suggest the coexistence of primary hypothyroidism and precocious puberty, especially if galactorrhea is also present. In these patients, thyroid hormone replacement therapy halts progression of pubertal development until the expected age of puberty. (Enigmatically, primary hyperthyroidism may also lead to delayed pubertal development.)
Abdominal and rectal examination may reveal a mass, suggesting an adrenal or ovarian tumor. Because palpable ovarian cysts may develop rarely before ovulation in true precocious puberty, the presence of a mass need not confirm the diagnosis of precocious pseudopuberty.
When vaginal bleeding is the only sign of development, the diagnosis of sexual precocity should be suspect. Common causes of bleeding in this age group include irritation from a vaginal infection or foreign body, sexual assault, prolapse of the urethral meatus, and ingestion of estrogen-containing medications (most commonly, oral contraceptive preparations). A vaginal or cervical neoplasm is also a rare possibility. Thus, vaginal bleeding dictates the need for vaginal examination, often best performed under anesthesia, before further evaluation is undertaken.
Heterosexual precocity in an apparent prepubertal female is almost always due to congenital adrenal hyperplasia or to an androgen-secreting adrenal or ovarian neoplasm. Only very rarely must another disorder of sexual differentiation be considered (Chapter 252). It is important to examine the external genitalia carefully because congenital adrenal hyperplasia is usually associated with some degree of sexual ambiguity.
Excessive androgens produced endogenously by abnormal fetal adrenal glands in utero or diffusing across the placenta to the fetus from the mother can virilize the external genitalia and result in female pseudohermaphroditism. The extent of virilization varies from an enlarged clitoris only to sexual ambiguity sufficient to make gender assignment difficult.
Excessive maternal androgen secretion, typically from an ovarian or adrenal neoplasm, can lead to virilization of a female fetus. This occurs very rarely because of the great capacity of the placenta to aromatize naturally occurring androgens to estrogens. Virilization of a female fetus is much more likely to occur if a pregnant woman has ingested a synthetic steroid preparation with androgenic properties because available synthetic compounds generally cannot be aromatized.
Excessive androgen secretion beginning in utero is usually associated with defective cortisol synthesis. As a consequence, pituitary corticotropin secretion is increased, resulting in congenital adrenal hyperplasia and excessive androgen secretion. The three different enzyme defects in the steroidogenic pathway that can lead to virilization of the female fetus are described in Chapter 252. 21-Hydroxylase deficiency is the most common form of congenital adrenal hyperplasia, accounting for the disorder in more than 90% of affected individuals. The defect may vary from partial to complete deficiency of the enzyme.
Diagnostic Tests
Measurement of Peptide and Steroid Hormones
Increased levels of immunoreactive human chorionic gonadotropin (hCG) may suggest an hCG-secreting neoplasm, most commonly an ovarian teratoma or dysgerminoma. In such cases, the hCG, which is antigenically and biologically similar to LH, stimulates ovarian steroid secretion and pseudopubertal development. Because even specific LH immunoassays show some cross-reactivity with hCG, values for serum LH may be elevated in individuals with hCG-secreting tumors. Immunoreactive hCG is always elevated in the presence of such tumors. Levels and ratios of FSH and LH typical of pubertal as opposed to prepubertal girls help in diagnosis of true precocious puberty. Timed urine collections rather than blood samples can be used to measure gonadotropin secretion if necessary. The use of exogenous GnRH to stimulate endogenous LH and FSH secretion can help differentiate gonadotropin-dependent from gonadotropin-independent precocious puberty. Excessively high circulating levels of estrogen suggest an estrogen-producing neoplasm. High levels of serum testosterone suggest an ovarian source of excess androgen in girls with heterosexual development, whereas increased levels of dehydroepiandrosterone or its sulfate (the principal precursors of 17-ketosteroids) suggest an adrenal source. High levels of serum l7-hydroxyprogesterone imply congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency, whereas high levels of serum 11-deoxycortisol imply an 11β-hydroxylase deficiency. In congenital adrenal hyperplasia, these hormone levels should decrease promptly after oral administration of suppressive doses of dexamethasone. Suppression in response to exogenous corticoids occurs much less consistently in individuals with adrenal cortical adenomas and carcinomas and rarely in those with ovarian androgen-secreting neoplasms (Chapters 252 and 258).
Additional Studies
Ultrasonic scanning of the adrenals and ovaries and computed tomography of the adrenals may be indicated to confirm clinical suspicions. In girls with ovarian or adrenal neoplasms, the tumor can almost always be localized radiographically. Catheterization of the ovarian and adrenal veins and measurements of the effluent steroids from each gland should be pursued only when computed tomography, ultrasonography, or magnetic resonance imaging fails to identify what is suspected to be a neoplasm. Although plain skull films may be of use in screening for pituitary and parapituitary tumors, computed tomography or magnetic resonance imaging of the skull is indicated in the presence of definite neurologic deficits or if true precocious puberty is suspected. Radiographic estimation of bone age is indicated in all cases and serves as a useful tool to follow the results of treatment.
Treatment
Treatment of precocious puberty should be initiated promptly so that (1) the patient's ultimate height is not compromised as a result of sex steroid–induced premature epiphyseal closure and (2) emotional disturbances in the patient and her parents are prevented or attenuated.
GnRH analogues are now the preferred therapy for suppressing gonadotropin secretion and also may prevent early bone maturation. The analogues are not effective in children with McCune-Albright syndrome, and ketoconazole and testolactone have been only marginally successful. Aqueous depot medroxyprogesterone acetate (100 to 200 mg intramuscularly every 2 to 4 weeks) also may be used to suppress gonadotropin secretion. Medroxyprogesterone acetate, however, does not always prevent premature epiphyseal closure and the resultant short stature.
Individuals with central nervous system or steroid-secreting neoplasms must undergo therapy appropriate for the particular lesion. Girls with congenital adrenal hyperplasia are appropriately managed with glucocorticoids (plus mineralocorticoids when indicated) as outlined in Chapter 252.
Delayed Puberty
Girls with delayed puberty typically present at age 16 years or later because of primary amenorrhea, but younger girls may present because of failure to initiate pubertal development. Because of the anxiety generated by delayed puberty, some evaluation is always indicated regardless of the age of the patient.
When pubertal development progresses normally but menstruation does not begin, an abnormality in the genital tract should be considered. Congenital malformations of the müllerian ducts are uncommon, occurring in 0.02% of all women. Most do not cause amenorrhea, and many do not impair reproduction. The anomalies associated with amenorrhea vary in severity from an imperforate hymen to complete aplasia of all müllerian duct derivatives with vaginal atresia. Although aplasia generally involves all of the müllerian duct derivatives, defects may involve only a single part of the distal genital tract. Family aggregates of the most common disorders of müllerian differentiation in females—müllerian aplasia and incomplete müllerian fusion—do occur and are best explained by polygenic or multifactorial inheritance. It is clear that the HOX genes, a family of regulatory genes that encode transcription factors, are essential for proper development of the müllerian tract.
A müllerian duct anomaly is suggested by (1) normal levels of serum gonadotropins and steroids, (2) an abnormal outflow tract, (3) a history of cyclic abdominal pain with or without a palpable mass, and (4) normal development of secondary sex characteristics. Normal ovarian function still induces endometrial growth and shedding after menarche if the uterus is normal. In the absence of a normal outflow tract, however, the menstrual effluent is retained and may or may not be able to escape into the abdominal cavity. Free in the abdominal cavity, the effluent may cause endometriosis. Constrained to the uterine cavity, the effluent causes hematometra and a large abdominal mass. In the absence of a mass or cyclic pain, a karyotype is indicated in girls with evidence of an abnormal genital tract to rule out any of several disorders of sexual differentiation (Chapter 252). Such disorders, however, almost never occur together with completely normal pubertal development. In girls with a normal karyotype and a genital tract anomaly, examination under anesthesia and diagnostic laparoscopy should be undertaken to delineate the extent of the defect. When the abnormality consists of an imperforate hymen or transverse vaginal septum only, surgical restoration can be accomplished relatively simply. Attempts to provide an outflow tract for the uterus should not be undertaken if there is no cervix because of the high risk of recurrent pelvic infection. Even with a functional cervix, the construction of an outflow tract that permits successful pregnancy is unlikely. A functional vagina can be constructed surgically or by the daily use of ever-larger dilators. To prevent shrinkage and scarring, surgery should be deferred until the patient is willing to use dilators postoperatively on a daily basis or she is about to become sexually active.
Other causes of delayed puberty and primary amenorrhea are the same as those that may cause amenorrhea in older women (Chapter 256). When no apparent cause of delayed development is found, constitutional delayed puberty must be entertained as a diagnosis of exclusion. A strong family history of delayed maturation adds support to this presumption. Small doses of estrogen may be administered to induce some pubertal development but may obscure a pathologic cause of the delay and may compromise linear growth and ultimate height.
Asynchronous Pubertal Development
Asynchronous pubertal development is characteristic of male pseudohermaphroditism due to androgen insensitivity, especially complete testicular feminization. This syndrome of androgen insensitivity is inherited either as an X-linked recessive or as a sex-limited autosomal dominant trait. Despite the presence of intra-abdominal or inguinal testes, there is complete failure of virilization. Affected individuals develop breasts (but only to Tanner stage 3) and a typical female habitus with unambiguous female external genitalia but with absence of internal female structures, generally having only a foreshortened blind-ending vagina. Little or no pubic and axillary hair develops. The karyotype is 46,XY in these individuals. Circulating testosterone levels are equivalent to or higher than those found in normal men, and LH levels are elevated while FSH levels are normal compared with those in menstruating women.
For a more detailed description, see Chapter 252.
Heterosexual Pubertal Development
Polycystic Ovary Syndrome
Polycystic ovary syndrome, by far the most common cause of heterosexual pubertal development, is associated with the development of some secondary sex features characteristic of males at the normal age of puberty. Feminization occurs in affected girls, and they develop normal breasts and a typical female habitus, but masculinization also occurs. (In contrast, girls with congenital adrenal hyperplasia generally show little if any female development at puberty.) A heterogeneous syndrome, polycystic ovary syndrome most typically begins at or near puberty with hirsutism and irregular menses from the time of menarche. Many girls who develop polycystic ovary syndrome are overweight in childhood, and obesity is clearly a risk factor. Menarche may be delayed as well, so that young women may present with primary amenorrhea. Basal LH levels tend to be somewhat elevated in perhaps 80% of cases, and circulating levels of all androgens are elevated moderately. Some degree of insulin resistance is almost invariably present as well, and hypercholesterolemia may predispose to cardiovascular disease later in life. This is discussed more completely in Chapter 261.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is generally diagnosed before puberty, and heterosexual precocious pseudopuberty is typical. However, if the defect is mild and changes to the external genitalia are minimal, masculinization may occur at the expected age of puberty. This attenuated or nonclassic form of 21-hydroxylase deficiency seems to occur in families with a strong family history of hirsutism. Affected girls generally have some defeminization with flattening of the breasts, severe hirsutism, relatively short stature, and obesity.
For a more detailed description, see Chapter 252.
Mixed Gonadal Dysgenesis
Mixed gonadal dysgenesis designates asymmetrical 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. The extent of genital virilization before puberty is variable in this rare disorder. Most individuals are reared as girls, in whom virilization occurs at puberty; some may note breast development as well. Affected individuals generally have a mosaic karyotype, with 45,X/46,XY being most common. Short stature and other stigmata associated with a 45,X karyotype in Turner's syndrome are less common in patients with tumors than in patients with testes. Gonadectomy is indicated in all individuals with a Y chromosome to eliminate the increased neoplastic potential of such dysgenetic gonads and in all patients in whom virilization occurs at puberty to remove the source of androgen. Estrogen replacement therapy is warranted after gonadectomy. Other causes of male pseudohermaphroditism associated with heterosexual pubertal development are described in Chapter 252.
Other Causes
An androgen-producing adrenal neoplasm or Cushing's syndrome may occur rarely during the pubertal years and lead to heterosexual development.
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