La Formación de la Categoría de Raza

b. Ovarian failure. In primary ovarian failure, the ovaries develop but do not contain oocytes. This may be associated with chemotherapy, galactosemia, gonadotropin resistance, autoimmune ovarian failure, or failure secondary to prior infection. Treatment is usually by administration of exogenous estrogen and progesterone to avoid osteoporosis and facilitate development of secondary sexual characteristics.

2. Low follicle-stimulating hormone levels (less than 10 mIU/mL). The following conditions produce gonadotropins in insufficient quantities to allow follicular development and, therefore, sex steroid production.

a. Constitutional delay. Delay in the gonadotropin-releasing hormone (GnRH) pulse generator.

b. Syndromes. Kallmann syndrome is a classical triad of anosmia, hypogonadism, and color blindness. The hypothalamus cannot secrete GnRH due to a dysfunction in the arcuate nucleus. Therefore, there are few or no secondary sexual characteristics. Other syndromes associated with delayed puberty include Prader-Labhardt-Willi syndrome and Laurence-Moon-Biedl syndrome.

c. Hormone deficiencies. Any aberration of growth hormone or thyroid hormone levels will affect puberty. Therefore, these levels should be investigated and treated appropriately. In addition, hyperprolactinemia can cause a decrease in levels of FSH and luteinizing hormone (LH) and thus delay

puberty. These levels should be investigated as well.

d. Neoplasms. Both craniopharyngiomas and pituitary adenomas may cause delayed puberty. Visual symptoms are often associated with these tumors, as are short stature and diabetes insipidus. Diagnosis is by CT or MRI of the head. Treatment includes either surgical excision or radiotherapy.

e. Malnutrition. Both starvation and anorexia nervosa can cause pubertal delay.

3. Anatomic causes of primary amenorrhea a. Genital tract obstruction

1. Imperforate hymen. An imperforate hymen may be evident in a neonate and may regress as the girl enters childhood. After menarche, the

imperforate hymen may become evident as an abdominal mass when accumulated menstrual blood forms a hematocolpos. This requires surgical intervention to incise the hymen and allow the stored debris to escape.

2. Transverse vaginal septum is due to the failure of canalization of müllerian tubules and the sinovaginal bulb, which leaves a membrane present.

If it is thin, it can be incised and dilated. The edges can be sutured to the vagina. If the membrane is thick, a split-thickness skin graft may be required for repair.

b. Müllerian dysgenesis. Disorders of the outflow tract are sometimes accompanied by renal and skeletal anomalies. These anomalies are classified along a spectrum from complete müllerian agenesis to simple hypoplasia.

B. Asynchronous puberty

1. Androgen insensitivity. Androgen insensitivity is caused by either the absence or the insensitivity of androgen receptors. Chromosome analysis must reveal 46,XY. Such patients, however, are phenotypically female with a blind-ending vagina and no fallopian tubes or uterus. Bilateral testes are present along the line of descent. These patients present with breast development to Tanner stage 5 and decreased pubic and axillary hair relative to their breast development. Diagnosis can be made by a finding of very high levels of testosterone with normal levels of LH and FSH. Gonadectomy should be

performed and then exogenous estrogen supplied. Families must receive genetic counseling, as this disorder can be inherited in an X-linked fashion.

2. Incomplete androgen insensitivity. Infrequently, patients may have the findings described earlier as well as clitoral enlargement and labioscrotal fusion at puberty, thus demonstrating the presence of a few androgen receptors.

C. Precocious puberty

1. Definition. In North America, sexual precocity is defined as the appearance of any sign of secondary sexual characteristics at younger than 8 years of age (an age more than 3.0 standard deviations below the mean).

a. Central or true precocity. Complete isosexual precocity, also known as true or central precocious puberty, is the result of premature activation of the pulsatile hypothalamic GnRH mechanism. Isosexual refers to secondary sexual characteristics appropriate for the child's sex.

b. Idiopathic precocious puberty may manifest itself in infancy and is more common in girls (for whom age of onset is 6–7 years) than in boys. Inquiries should be made about a family history of early maturation, because true precocious puberty may be transmitted in an autosomal recessive fashion.

Physical findings in girls include development of breasts and pubic hair, enlargement of the labia minora, and maturation of the vaginal mucosa.

Usually, the development of secondary sexual characteristics progresses more rapidly than in normal puberty. The child may experience a course of development that fluctuates between progression and regression. Some girls may experience spontaneous regression, whereas in others secondary sexual characteristics may persist.

2. CNS tumors that result in true precocious puberty are equally prevalent among boys and girls. Astrocytomas; ependymomas; optic or hypothalamic gliomas or hamartomas, which are often associated with neurofibromatosis; tuberous sclerosis; suprasellar cyst; sarcoid granuloma; and

craniopharyngiomas may result in true precocious puberty.

a. Pathophysiology. The mechanism that causes precocious puberty is hypothesized to be either a mass effect of the growth, which impinges on the pathway that inhibits the GnRH pump in childhood; effects of the cranial radiation used to treat the tumor; or the presence of ectopic GnRH-secreting cells, which are usually associated with hamartomas. Accompanying features often include seizures, mental retardation, accelerated growth,

headaches, visual changes, and dysmorphic syndromes. These masses are diagnosed by CT of the head.

b. Treatment. The location of tumors leading to precocious puberty makes their surgical removal difficult. Management usually involves radiation therapy, chemotherapy, or both. Manifestations of precocious puberty can be treated with GnRH agonists depending on the age and psychological capabilities of the girl.

3. Other CNS disorders such as hydrocephalus, encephalitis, brain abscess, static cerebral encephalopathy, sarcoid granulomas, hypothalamic

tuberculous granulomas, and head trauma (associated with cerebral atrophy or focal encephalomalacia) can result in true precocious puberty. Arachnoid cysts, which emerge de novo as a consequence of infection, can cause precocious puberty (possibly with an associated growth hormone deficiency).

4. Congenital adrenal hyperplasia (CAH). Patients with CAH who either have been undertreated or have started treatment late may undergo early puberty.

Patients who have been treated for either CAH or virilizing tumors may develop precocious puberty after the lowering of androgen levels.

5. Primary hypothyroidism may result in premature breast development and galactorrhea. Both symptoms regress after the initiation of thyroid hormone replacement. The absence of a growth spurt may help to establish hypothyroidism as the cause of premature development.

D. Pseudoprecocious puberty. Incomplete isosexual precocity, also known as pseudoprecocious puberty or GnRH-independent sexual precocity, characterized by extrapituitary secretion of gonadotropins or gonadal steroid secretion that is independent of GnRH pulsatile stimulation.

1. Autonomous ovarian follicular cysts are the most common form of estrogen-secreting masses in children. Plasma levels of estradiol may be elevated.

A sonogram may reveal ovarian cysts. Exploratory laparotomy or laparoscopy is sometimes necessary to differentiate between these benign cysts and a malignant ovarian neoplasm. Removal of a hormonally active cyst may result in correction of the precocity. Autonomously secreting cysts are not

associated with increased LH pulsatile secretion or with a pubertal response of LH to GnRH.

2. Ovarian tumors (2%) may cause precocious puberty. Approximately 60% of ovarian tumors causing precocious puberty are granulosa cell tumors; the remainder are arrhenoblastomas, thecomas, or lipid cell tumors. Although LH and FSH levels usually are suppressed in patients with ovarian tumors, their plasma concentrations of estradiol are usually elevated. Sonography of the ovary facilitates the diagnosis. Subsequent to surgical removal of the tumor, measurements of plasma levels of estradiol may be used to screen for metastasis.

3. Peutz-Jeghers syndrome is characterized by mucocutaneous pigmentation and GI polyposis and is also associated with a rare sex cord tumor. The tumor's estrogen secretion may result in feminization and incomplete sexual precocity. Although rare, epithelial tumors of the ovary, dysgerminomas, or Sertoli-Leydig cell tumors have been found in patients with Peutz-Jeghers syndrome. Girls with Peutz-Jeghers syndrome should be evaluated with serial pelvic sonographic examinations for the presence of gonadal tumors.

4. McCune-Albright syndrome is characterized by irregular hyperpigmented macules (café au lait spots), polyostotic fibrous dysplasia (progressive bone disorder), and GnRH-independent sexual precocity. At least two of these three features must be present to make the diagnosis of McCune-Albright syndrome.

a. Pathophysiology. Sexual precocity results from an autonomous luteinized follicular cyst. The pubertal pattern of LH pulses is initially absent, but when the bone age approaches 12 years, the GnRH pulse mechanism is activated and ovulation is established, which results in a progression from GnRH-independent to GnRH-dependent puberty.

b. Treatment. GnRH agonists are not effective therapy for this disorder. Aromatase inhibitors [e.g., testolactone (Teslac)] have been shown to help to decrease symptoms.

5. Adrenal disorders such as adenomas can secrete estrogen alone and give rise to sexual precocity. Patients in whom CAH has been untreated may exhibit virilization as well as some breast development. Estrogen-secreting adrenal carcinomas may also produce other hormones that result in heterosexual precocity.

E. Heterosexual puberty. Contrasexual precocity results from increased androgen levels and leads to inappropriate virilization. In girls, virilization is an indicator of organic disease (with the exception of premature adrenarche).

1. Congenital adrenal hyperplasia

2. Cushing disease that results from an adrenal carcinoma may manifest as growth failure with or without virilization, obesity, striae, and moon facies.

3. Ovarian tumors such as arrhenoblastoma, lipoid cell tumor, and gonadoblastoma can be culprits in a virilizing girl. Arrhenoblastoma is the most common virilizing ovarian tumor.

a. History. Inquiries should be made about birth trauma, encephalitis, changes in personality, headaches, visual changes, seizures, abdominal pain, urinary or bowel changes, increased appetite, and use of medications or creams. In most cases, information about the age of onset of precocious puberty is not helpful in establishing a diagnosis. Also, the age of pubertal onset in the patient's mother, sisters, and grandmothers should be

ascertained. Any family history of neurofibromatosis and tuberous sclerosis should be noted. The child's growth pattern should be recorded in a chart, because accelerated growth and bone age may help to distinguish between premature thelarche and true precocious puberty.

b. Physical examination. On examination, evidence of papilledema, visual field defects, or café au lait spots should be sought. The child's head

circumference should be measured and recorded. The size and texture of the thyroid gland should be noted, and inquiries should be made about any hair or skin changes. The breasts and external genitalia should be closely inspected, and the degree of breast, pubic, and axillary hair growth and the appearance of the vaginal mucosa should be noted. Ovarian masses can often be palpated.

c. Laboratory testing depends on the initial evaluation. An extensive workup is indicated in the presence of vaginal estrogenization and acceleration of linear growth. If premature thelarche is found, however, a radiographic film of the wrist to document bone age and a vaginal smear to test for estrogen effect are indicated. A skeletal survey is indicated for patients in whom the McCune-Albright syndrome is suspected. Bone lesions may be detected by bone scan before they are apparent radiographically. A CT or MRI scan is often helpful in diagnosing CNS abnormalities. True precocity,

gonadotropin-independent precocity, and premature thelarche may be differentiated with a GnRH-stimulation test. Patients with pituitary insufficiency show a diminished (prepubertal) response to GnRH. In patients with gonadotropin-independent precocity, ovarian tumors, or premature thelarche, a prepubertal response to the GnRH test can be expected.

d. Findings. In patients with precocious puberty, bone age is greater than height age. Both gonadotropin and gonadal steroid concentrations in the plasma, as well as the LH response to GnRH and the frequency and amplitude of LH pulses, are in the normal pubertal range. In fact, although affected children may initially be tall, they have a short final height as a result of early epiphyseal closure. High levels of estradiol (100–200 pg/mL) and low gonadotropin levels indicate an estrogen-secreting cyst or tumor. High LH levels may signal a gonadotropin-producing tumor or

choriocarcinoma (which secretes human chorionic gonadotropin that cross-reacts with LH on the standard assay). A urine or serum pregnancy test would detect such a rise in human chorionic gonadotropin. Elevated LH alone does not lead to isosexual precocity in the absence of increased estrogen secretion. Elevated estradiol levels are seen in 50% of patients with theca-granulosa cell tumors.

e. Treatment varies according to the diagnosis. Ovarian tumors require surgical removal. Ovarian cysts may spontaneously regress or may require aspiration. In cases of recurrent cysts, cystectomy may be indicated. In patients with McCune-Albright syndrome, treatment of an ovarian cyst will fail to produce a regression of puberty. In central precocity, ovarian cysts should be followed with observation, because gonadotropin suppression is likely to result in their regression. GnRH agonists have been shown to suppress precocious puberty by selectively and reversibly suppressing LH and FSH secretion, restoring estradiol to its prepubertal level, and mediating the regression (or preventing progression) of breast development and the

cessation of menses. GnRH-agonist therapy is also effective in treating patients with precocity secondary to hypothalamic hamartomas and optic nerve gliomas (associated with neurofibromatosis). It is important to inform patients that their development is early, not abnormal. GnRH agonists will not lead to a decrease in estradiol levels or regression of puberty in girls with the following disorders: McCune-Albright syndrome,

gonadotropin-independent puberty, and cyclic gonadal steroid production.

f. Follow-up depends on the diagnosis. Patients undergoing treatment with GnRH agonists require close monitoring of bone age, vaginal cytologic study (for maturation index), physical examination, and maintenance of growth records. A pediatric endocrinologist should be consulted in cases of accelerated growth rate, advanced bone age, and vaginal estrogenization. Patients whose onset of puberty occurs after age 6 and whose prognosis for adult stature is favorable without intervention may require only careful follow-up, reassurance, and counseling. Medroxyprogesterone

(Depo-Provera) may be used to induce cessation of menses.

VIII. Thelarche is unilateral or bilateral breast development. Without other signs of sexual maturation, early breast development is referred to as premature thelarche. It commonly occurs by age 2 and is rare after age 4. Usually a regression of the breast enlargement occurs after a few months. It may persist for several years, however, or until the onset of puberty. In approximately 50% of patients, breast development lasts 3–5 years. Plasma estrogen levels may be elevated, and a urocystogram may demonstrate an estrogen effect on squamous epithelial cells in the urine. In affected patients, FSH serum concentrations may be in the pubertal range, with an FSH to LH ratio that is higher than in normal individuals or in girls with central precocious puberty. The LH response to GnRH is prepubertal. Ovarian sonography often reveals one or several cysts that appear and disappear with changes in the size of the breasts. The uterus, however, remains prepubertal in size.

A. Patient assessment includes a review of medications or creams used recently. Application of topical conjugated estrogens (Premarin) for longer than 2–3 weeks may result in breast changes. On examination, the appearance of the vaginal mucosa, breast size, and presence of a pelvic mass on rectal

examination should be noted. The uterus should not be enlarged, and growth charts should document a rate within the previously established percentile for

height and weight. A vaginal smear or urocystogram to assess estrogenization and a pelvic ultrasonographic study should be obtained.

B. Treatment is directed toward reassurance and follow-up to confirm that thelarche is not the first manifestation of precocious puberty. It is important to reassure the patient and her parents that, in most cases, pubertal development ensues at a normal, adolescent age.

IX. Ambiguous genitalia must be evaluated with a careful history taking, physical examination, and laboratory tests. Based on the karyotype, two groups of

patients with ambiguous genitalia can be distinguished: XX neonates and XY neonates. Patient assessment must include measurement of the stretched phallus from the pubis to the tip, with attention to the location of the urethra (perineal versus penile), evaluation of the degree of labial-scrotal fold fusion, and

determination of the presence or absence of gonads in the scrotum or inguinal rings. A digital rectal examination may reveal the presence of a cervix (usually easily palpable at birth due to stimulation by placental estrogen in utero).

A. Karyotype XX neonate

1. Congenital adrenal hyperplasia results from the excessive production of adrenal androgens caused by increased levels of adrenocorticotropic hormone.

Sustained levels of adrenocorticotropic hormone cause overstimulation of the adrenals and overproduction of adrenal androgens, which results in virilization. These disorders are autosomal recessive and manifest as varying degrees of virilization, depending on the degree of enzymatic block.

a. Etiology. The most common cause of CAH (95% of cases) is 21-hydroxylase deficiency. Virilization is the result of production of 17-hydroxyprogesterone (an androgen precursor), which leads to excess secretion of adrenal androgens.

b. Diagnosis. Patient assessment may reveal clitoromegaly, postvaginal fusion with wrinkling or pigmentation of the scrotal sac, and absence of a proper vesicovaginal septum (which results in a urogenital sinus). A genetic female may show a penile urethra as well as fully male external genital phenotype, with the exception of testes. The salt-losing form of CAH secondary to decreased aldosterone secretion is usually associated with more severe virilization. A male neonate may be discharged before the diagnosis is made, before the onset of the life-threatening hyponatremia that can result in shock and death. Virilized female neonates who do not manifest salt loss may go undiagnosed for years, until hyponatremia and shock occur when they are stressed, or until pubic hair, lower voice, abnormal muscular hyperplasia, or excessive growth develops within the first year of life. The diagnosis of 21-hydroxylase deficiency should be considered in any child with ambiguous genitalia in the absence of palpable testes; in a phenotypic male without palpable testes; in a male child with ambiguous genitalia and a history of severe vomiting, hypoglycemia, and shock; in a boy with premature virilization; and in a girl of any age with any degree of virilization.

2. Female pseudohermaphroditism is defined as the presence of normally developed ovaries and müllerian structures with ambiguous external genitalia.

In utero, the external genitalia feminize in the absence of testes. Therefore, a female fetus exhibits masculinization if exposed to androgens. Exposure to androgens after 12 weeks' gestation, after separation of the vagina and the urogenital sinus, results in clitoral hypertrophy. Earlier exposure leads to retention of the urogenital sinus and labioscrotal fusion; a penile urethra from labial fusion forms if exposure occurs early enough in differentiation. The uterus and the fallopian tubes are normal, even with severe masculinization, because regression of the müllerian duct requires secretion of antimüllerian hormone, formally referred to as müllerian inhibiting factor, by the fetal testes, an event that is not mimicked by androgens.

B. Karyotypes XX,XY or XX/XY can exhibit true hermaphroditism. True hermaphroditism must include evidence of both ovarian and testicular tissue in either the same or the opposite gonad. The presence of gonadal stroma in the absence of oocytes is insufficient to designate the rudimentary gonad as an ovary.

Evidence of a few oocytes in a streak gonad accompanying testicular tissue on the contralateral side is also insufficient to make this diagnosis.

1. Physical findings may reveal evidence of either female or male external genitalia, often ambiguous. As a result of the size of the phallus, 75% of affected children are raised as males. Hypospadias is common, with a penile urethra seen in some cases. The patient may present with cryptorchidism

1. Physical findings may reveal evidence of either female or male external genitalia, often ambiguous. As a result of the size of the phallus, 75% of affected children are raised as males. Hypospadias is common, with a penile urethra seen in some cases. The patient may present with cryptorchidism