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DIFFERENTIATION OF GONADS
FACTORS INFLUENCING NORMAL AND ABNORMAL GONADAL DIFFERENTIATION
Whether the primordial gonad differentiates as a testis or as an ovary is determined by genetic information coded on the X and Y chromosomes. The differentiation of all the other anatomic and functional features that distinguish male from female stem secondarily from the effect of testicular or ovarian secretions on their respective primordial structures. The Y chromosome possesses male-determining genes that direct the primitive gonad to develop as a testis, even in the presence of more than one X chromosome. Two X chromosomes are essential for the formation of normal ovaries; individuals with a single X chromosome (karyotype, 45,XO; Turner syndrome) develop gonads that usually display only the most rudimentary form of differentiation.
Although many patients with congenitally defective gonads have an abnormal karyotype caused by meiotic nondisjunction, similar patients may have normal-appearing sex chromosomes or chromosomal abnormalities not explainable on this basis. In individuals with chromosomal mosaicism, the various tissues may have multiple cell lines of differing chromosomal makeup. Mosaicism arises from mitotic nondisjunction or chromosomal loss occurring after fertilization. Other patients may have deletions or translocations of small chromosomal fragments. If these rearrangements disrupt the sex-determining genes, the effect on gonadal structure may be as devastating as in instances where a total chromosome is lost. In other individuals, mutations in sex-determining genes may cause a specific enzymatic error, leading to defective gonadal structure or hormonal secretion.
STAGES IN GONADAL DIFFERENTIATION
Undifferentiated Stage
At the sixth week of gestation, the primitive gonad is represented by a well-demarcated genital ridge running along the dorsal root of the mesentery. The cortical portion of the ridge consists of a cloak of coelomic epithelial cells. The mature ovary is derived principally from these cortical cells. Large primordial germ cells are also found in these superficial layers that are capable of differentiating as either oogonia or spermatogonia.
The medullary, or interior, portion of the primitive gonad is composed of a mesenchyme, in which sheets of epithelial cells are condensed to form the primary sex cords. This medullary portion has the potential to further differentiate as a testis.
Testicular Differentiation
Testicular differentiation is determined by the Y chromosome SRY gene and a related homeobox gene, SOX9 (an autosomal gene). SRY regulates SOX9 expression. SOX9 in turn directly regulates transcription of anti-müllerian hormone (AMH) by Sertoli cell precursors. AMH causes müllerian duct regression. As the primitive gonad becomes a testis, the inner portion of the primary sex cords becomes a collecting system connecting the seminiferous tubules with the mesonephric, or wolffian, duct. The peripheral portions of the sex cords join with ingrowths of coelomic epithelium (containing primordial germ cells) to form seminiferous tubules. Most of the cortex, however, becomes isolated by the tunica albuginea and the tunica vaginalis, which are the only cortical vestiges in the mature testis. Interstitial cells of Leydig become abundant at about 8 weeks and secrete androgenic hormone necessary for the development of male external genitalia. Leydig cells disappear shortly after birth and are not seen again until the onset of adolescence.
Ovarian Differentiation
Ovarian development occurs several weeks later than testicular differentiation. Ovarian differentiation is determined by the lack of expression of SRY , SOX9 , and AMH. There is likely a mechanism to repress autosomal testis-inducing genes (e.g., SOX9 ) and to activate ovary-inducing genes (e.g., WNT4 and NR0B1 [ DAX1 ]). At this time, the cortex undergoes intense proliferation, and strands of epithelial cells (called secondary sex cords) push into the interior of the gonad. Primordial germ cells are carried along in this inward migration. Clumps from the secondary sex cords fragment off to form primordial follicles. While the ovary is thus forming, the primary sex cords recede to the hilum, leaving stromal and connective tissue cells behind. Leydig cells and the rete ovarii persist as medullary remnants in the ovary. Proliferation of the cortex ceases at about 6 months.
DIFFERENTIATION OF GENITAL DUCTS
The early embryo of either sex is equipped with identical primitive gonads that have the capacity to develop into either testes or ovaries. In the case of the internal genital ducts, however, the early embryo has both a male and a female set of primordial structures. The müllerian ducts have the potential to develop into fallopian tubes, a uterus, and the upper portion of the vagina. The mesonephric, or wolffian, ducts have the capacity to develop into the vas deferens and the seminal vesicles. The large wolffian body, containing the proximal mesonephric ducts, becomes the epididymis.
During the third fetal month, either the müllerian or the wolffian structures normally complete their development, and involution occurs simultaneously in the other set. Vestigial remnants of the other duct system, however, persist into adult life. In females, the mesonephric structures are represented by the epoöphoron, paroöphoron, and the ducts of Gartner. In males, the only müllerian remnant normally present is the appendix testis.
The direction in which these genital ducts develop is a direct consequence of the gonadal differentiation that occurred somewhat earlier. Testicular differentiation is determined by the Y chromosome SRY gene and a related homeobox gene, SOX9 (an autosomal gene). SRY regulates SOX9 expression. SOX9 in turn directly regulates transcription of antimüllerian hormone (AMH) by Sertoli cell precursors. AMH causes müllerian duct regression through apoptosis and mesenchymal-epithelial cell remodeling. Müllerian ducts are nearly completely absent by 10 weeks; then the derivatives of the mesonephric system complete their normal male development.
Ovarian differentiation is determined by the lack of expression of SRY, SOX9 , and AMH. There is likely a mechanism to repress autosomal testis-inducing genes (e.g., SOX9 ) and to activate ovary-inducing genes (e.g., WNT4 and NR0B1 [ DAX1 ]). In this setting, the müllerian structures proceed to become the uterus and fallopian tubes, and the mesonephric structures become vestigial. It should be emphasized that female development is not dependent on any ovarian secretion because in the absence of any gonads at all, the uterus and fallopian tubes develop normally.
It is clear that SRY is the key factor in testis determination. However, multiple other factors must be repressed or activated for normal testicular development. This concept is evidenced by the findings of 46,XX males with testes who do not have a Y chromosome and by 46,XY females with gonadal dysgenesis who have an intact SRY gene. Thus, non–Y chromosomal factors must contribute in a clinically important way to testis determination.
DIFFERENTIATION OF EXTERNAL GENITALIA
Before the ninth week of gestation, both sexes have a urogenital sinus and an identical external appearance. At this undifferentiated stage, the external genitalia consist of a genital tubercle beneath which is a urethral groove, bounded laterally by urethral folds and labioscrotal swellings. The male and female derivatives of these structures are shown in Plate 4-3 .
The urogenital slit is formed at an even earlier stage when the perineal membrane partitions it from a single cloacal opening. Thereafter, the bladder and both genital ducts find a common outlet in this sinus.
The vagina develops as a diverticulum of the urogenital sinus in the region of the müllerian tubercle and becomes contiguous with the distal end of the müllerian ducts. About two-thirds of the vagina originates in the urogenital sinus, and about one-third is of müllerian origin.
In normal male development, the vaginal remnant is tiny because the müllerian structures atrophy before this diverticulum develops very far. In male pseudohermaphroditism, however, a sizable remnant of this vaginal diverticulum may persist as a blind vaginal pouch.
In normal female development, the vagina is pushed posteriorly by a downgrowth of connective tissue, so that by the 12th fetal week, it has acquired a separate external opening. In female pseudohermaphroditism, the growth of this septum is inhibited, leading to persistence of the urogenital sinus.
The principal distinctions between male and female external genitalia at this stage of development are the location and size of the vaginal diverticulum, the size of the phallus, and the degree of fusion of the urethral folds and labioscrotal swellings.
As in the case of the genital ducts, there is an inherent tendency for the external genitalia to develop along feminine lines. Masculinization of the external genitalia is brought about by exposure to androgenic hormones during the process of differentiation. Normally, the androgenic hormone is testosterone, derived from the Leydig cells of the fetal testis. The critical factor in determining whether masculinization will occur, however, is not the source of the androgen but rather its timing and its amount. In female pseudohermaphroditism caused by congenital adrenal hyperplasia, the fetal adrenal glands secrete sufficient androgen to bring about some masculinization of the external genitalia. In other instances, androgenic hormone may be derived from the maternal circulation.
Female and male derivatives of urogenital sinus and external genitalia
| Female derivative | Primordial structure | Male derivative |
|---|---|---|
|
Urogenital sinus |
|
|
|
|
| Labia minora | Urethral folds | Corpus spongiosum (enclosing penile urethra) |
| Labia majora | Labioscrotal swellings | Scrotum |
By the 12th fetal week, the vagina has migrated posteriorly, and androgens will no longer cause fusion of the urethral and labioscrotal folds. Clitoral hypertrophy, however, may occur at any time in fetal life or even after birth.
TESTOSTERONE AND ESTROGEN SYNTHESIS
Three glands that originate in the coelomic cavity—the adrenal cortex, the ovary, and the testis—produce steroids under the influence of tropic hormones of the anterior pituitary, corticotropin (adrenocorticotropic hormone [ACTH]) and gonadotropins. Cleaving cholesterol into pregnenolone (the C 21 precursor of all active steroid hormones) and isocaproaldehyde is the critical first step, and it occurs in a limited number of sites in the body (adrenal cortex, testicular Leydig cells, ovarian theca cells, trophoblast cells of the placenta, and certain glial and neuronal cells of the brain). The roles of different steroidogenic tissues are determined by how this process is regulated and how pregnenolone is subsequently metabolized. Androgens have 19 carbon atoms (C19 steroids), and estrogens have 18 carbon atoms (C18 steroids).
Pregnenolone is converted to 17α-hydroxypregnenolone by 17α-hydroxylase (P450c17). P450c17 also possesses 17,20-lyase activity, which results in the production of the C19 adrenal androgens (dehydroepiandrosterone [DHEA] and androstenedione). Most of the adrenal androstenedione production is dependent on the conversion of DHEA to androstenedione by 3β-hydroxysteroid dehydrogenase. Androstenedione may be converted to testosterone by 17β-ketosteroid reductase (17β-HSD3) in the adrenal glands or gonads.
Androstenedione and testosterone are secretory products of the Leydig cells, which are found in abundance in the testis but are present in only small numbers in the hilar region of the ovary. In men, 95% of testosterone (7 mg/d) is produced by the testicles under the control of luteinizing hormone. The local effect of testosterone can be amplified by conversion via type 2 5α-reductase to the more potent dihydrotestosterone. This local amplification system occurs at the hair follicle and the prostate gland. Testosterone is bound to sex hormone–binding globulin in the blood. Conjugation with glucuronic acid takes place in the liver. Much of the conjugated testosterone is excreted in its water-soluble form by the kidney with a little free, unconjugated testosterone.
DHEA, a precursor of androstenedione and testosterone, is found mostly in the 17-ketosteroid fraction in the urine and is derived largely from the adrenal cortex. It is a weak androgen that makes up more than 60% of the 17-ketosteroids. The normal excretion value for l7-ketosteroids is higher in men than in women, presumably because of the contribution by the testis of some DHEA and a variety of other 17-ketosteroids.
The ovary contains at least three differential secretory zones: the granulosa cells of the follicle, engaged in estrogen formation; the theca cells, having a tendency to produce somewhat more androgens; and the hilar cells, predominantly involved in androgen formation. The balance of these cellular elements ensures a normal degree of femininity; conversely, an imbalance leads to androgenicity. Within the ovary there are also the cells of the corpus luteum, which produce the bulk of progesterone.
Testosterone and androstenedione, respectively, are precursors of estradiol and estrone. Hydroxylation of the 19-carbon initiates a series of reactions that aromatize the A ring of the steroid nucleus, and this aromatization is, in fact, characteristic of estrogens. Estradiol is more potent than estrone; estriol is purely an excretory product, which is extremely weak biologically.
The estrogens are bound in blood by sex hormone–binding globulin and albumin. Inactivation of estrogen occurs in the liver through conversion to less active estrogens (i.e., estradiol to estrone to estriol), oxidation to totally inert compounds, or conjugation to glucuronic acid. There is considerable enterohepatic circulation because estrogens are excreted in the bile.
NORMAL PUBERTY
TIMING OF PUBERTY
Although it is often thought of as a distinct event, puberty is part of a lifelong process of hypothalamic–pituitary–gonadal development. Puberty is a biologic transition during which secondary sex characteristics develop, a linear growth spurt occurs, fertility is realized, and psychosocial changes occur. Adrenarche refers to the adrenal component of pubertal maturation and usually occurs earlier than gonadarche (the maturation of the hypothalamic–pituitary–gonadal system). Thelarche refers to pubertal breast development.
Before the onset of puberty, conspicuous physical differences between boys and girls are largely confined to the anatomy of their genital organs. The mean age of puberty onset is 10.6 years (range, 7–13 years) in white girls and 8.9 years (range, 6–13 years) in African American girls. The mean age of puberty onset in boys is 11 years (range, 9–14 years); some African American boys start puberty between 8 to 9 years.
The factors that lead to the maturation of the gonadotropin-releasing hormone pulse generator and thus trigger the onset of puberty are multiple and not yet fully understood. For example, body weight is one factor that triggers puberty, and the mechanism may involve leptin, a hormone produced in adipocytes. Puberty does not occur in animal models that are deficient in leptin but can be induced by leptin administration.
Most of the physical changes that begin at puberty are attributable to an increase in androgens and estrogens from the gonads and reticular zone of the adrenal cortex. The gonads are activated by pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which, until this time, are not secreted in clinically important amounts in normally developing children. Corticotropin (adrenocorticotropic hormone [ACTH]) and a yet to be identified adrenal androgen–stimulating factor (perhaps of pituitary origin) appear to be responsible for adrenarche.
The capacity to secrete both androgens and estrogens is inherent in the adrenal glands, as well as in the gonads of both sexes. Enlargement of the reticular zone of the adrenal cortex and increased secretion of adrenal androgens occur at about the same time that the ovaries exhibit heightened activity. Androgenic hormones from both the adrenals and ovaries increase the growth rate and the development of pubic hair, later axillary hair, and seborrhea and acne. Both androgens and estrogens have a stimulatory effect on epiphysial maturation, and as fusion occurs, the rate of linear growth rapidly decelerates.
Approximately 18% of total adult height accrues during the pubertal growth spurt. Although the pubertal growth velocity is slightly lower in girls, they reach their peak height velocity about 2 years earlier than boys. In boys, the peak height velocity is approximately 9.5 cm per year at an average age of 13.5 years, whereas, in girls, the peak height velocity is approximately 8.3 cm per year at an average age of 11.5 years. Because of a longer duration of pubertal growth, boys on average gain 10 more centimeters of increased height than girls through the pubertal growth spurt, thus accounting for the general difference in sex-dependent adult height. Normal growth spurt in girls is dependent on growth hormone, insulinlike growth factor 1 (IGF-1), and estrogen. In boys, growth is dependent on growth hormone, IGF-1, estrogen, and testosterone. Increased pubertal blood estradiol concentrations appear to trigger hypothalamic–pituitary activity that results in increased growth hormone pulse amplitude and frequency. Serum IGF-1 concentrations peak during puberty and remain increased for approximately 2 years after the pubertal growth spurt before falling into the adult reference ranges.
The upper body to lower body segment ratio (U : L ratio) is defined as the distance from the top of the head to the top of the pubic ramus, divided by the length from the bottom of the feet to the top of the pubic ramus. The U : L ratio is approximately 1.7 at birth, 1.4 at 1 year of age, 1.0 at 10 years of age, 0.92 in white adults, and 0.85 in African American adults. The U : L ratios are the same in females and males. Eunuchoid proportions (decreased U : L ratio) develop in patients with hypogonadism, in whom epiphyseal fusion is delayed and the extremities grow for a prolonged period of time. Eunuchoid proportions are also seen patients with estrogen receptor deficiency or defects in estrogen synthesis. Patients who produce excess estrogen (aromatase excess), however, have advanced skeletal maturation, an increased U : L ratio, and short adult height.
Almost 50% of total body calcium in girls and slightly more than 50% in boys is laid down in bone mineral during puberty. After puberty, boys have 50% more total body calcium than girls. During puberty, the hips enlarge more in girls, and the shoulders become wider in boys. The pelvic inset widens in girls because of the growth of the os acetabuli. Men have 50% more lean body mass and skeletal mass than women, and women generally have twice the amount of body adipose tissue (distributed in the upper arms, thighs, and upper back) than men. Cardiovascular changes that occur during puberty include a greater aerobic reserve.
Marshall and Tanner developed a staging system to document the sequence of changes of secondary sexual characteristics. The Tanner stages are based on visual criteria to document five stages of pubertal development with regard to breast and pubic hair development in girls and genital and pubic hair development in boys. Stage 1 is the prepubertal state, and stage 5 is the adult state.
FEMALE PUBERTY
The three main phenotypic pubertal events in girls are increased height velocity, breast development (thelarche, under the control of ovarian estrogen secretion), and growth of axillary and pubic hair (under the control of androgens secreted by the ovaries and adrenal glands). An increase in height velocity is usually the first sign of puberty in girls. Most girls grow only approximately 2.5 cm in height after menarche. The stages of breast and pubic hair development usually progress in concert, but discordance may occur, and they are best classified separately The mean age of puberty onset is 10.6 years (range, 7–13 years) in white girls and 8.9 years (range, 6–13 years) in African American girls.
Pubertal breast enlargement (thelarche) is associated with increased amounts of glandular and connective tissue. The size and shape of breasts are determined by genetic factors, nutritional factors, and exposure to estrogen. Initially, breast development may be unilateral and then asynchronous. In the prepubertal girl (Tanner stage 1), there is elevation of papilla (see Plate 4-5 ). Tanner stage 2 is the breast bud stage, with enlargement of the areolar diameter and elevation of breast and papilla as a small mound. The mean age of onset of Tanner stage 2 breast development is 10.3 years in white girls and 9.5 years in African American girls. In Tanner stage 3, there is further enlargement of breast and areola, but with no separation of their contours. In Tanner stage 4, the areola and papilla project above the level of the breast to form a secondary mound. In Tanner stage 5, the mature breast has formed, there is recession of the areola, and only the papilla projects from the surface of the breast. The diameter of the papilla increases from 3 to 4 mm (in Tanner breast stages 1 through 3) to an average diameter of 9 mm in Tanner stage 5.
In the prepubertal girl (Tanner pubic hair stage 1), there is vellus-type hair over the pubic region, but it is not different from that over the anterior abdominal wall (see Plate 4-6 ). In Tanner stage 2, early pubic hair becomes evident; it is slightly pigmented and straight or slightly curled, appearing along the labia. The mean age of onset of Tanner stage 2 pubic hair development is 10.4 years in white girls and 9.4 years in African American girls. During Tanner stage 3, the hair spreads sparsely over the pubic region, and it becomes coarser, darker, and curlier. In Tanner stage 4, the hair is adult in type, but it covers a smaller area than in most adults and it does not appear on the medial surface of the thighs. In Tanner stage 5, the appearance is that of an adult in distribution (including the medial surface of the thighs), quantity, and type.
During the progression through the pubic hair stages, the vaginal mucosa undergoes changes because of estrogen effects. The vaginal mucosa loses its prepubertal reddish glistening form and becomes thickened and dull because of cornification of the vaginal epithelium. Several months before menarche, there is vaginal secretion of clear or whitish discharge. The length of the vagina increases, and the labia minor and majora become thickened and rugated. There is a rounding of body contours, a fat pad develops in the mons pubis, and the clitoris increases in size. The uterus enlarges from a prepubertal length of 3 cm to a postpubertal length of 8 cm. The endometrium begins to proliferate during the first stages of puberty.
In white girls in the United States, the average age of menstruation (menarche) onset is 12.8 years; it is 6 months earlier in African American girls. Menarche occurs 1 to 3 years after the onset of puberty, typically during Tanner stage 4. Ovulation does not occur until some additional months have elapsed. Until then, the menses are often erratic, and even then, anovulatory cycles are common for the first 2 years after menarche. Progesterone is secreted only as corpora lutea are formed after ovulation. When this occurs, the proliferative endometrium is transformed into a secretory type. The peak in ovarian primordial follicles is reached at 20 weeks of fetal life, and no additional germ cells develop after this time point. Under gonadotropin stimulation during puberty, the ovaries become microcystic with the development of follicles more than 4 mm in diameter. The ovarian volume increases from a prepubertal size of 0.2 to 1.6 mL to 2.8 to 15 mL during puberty.
Axillary hair development is evident by age 12 years in more than 90% of African American girls and 70% of white girls. The development of acne—sometimes the most obvious initial sign of puberty in a girl—is caused by adrenal and ovarian androgen secretion. Acne represents a dysfunction of the pilosebaceous unit, where there is follicular occlusion and inflammation as a result of androgenic stimulation. Facial changes occur during puberty in both boys and girls with enlargement of the nose, mandible, maxilla, and frontal sinuses. In girls, the pituitary gland increases in height from an average of 6 mm before puberty to an average of 10 mm by Tanner stage 5.
MALE PUBERTY
The three main phenotypic pubertal events in boys are increased height velocity, genitalia development (under the control of pituitary gonadotropins and testicular testosterone secretion), and growth of axillary and pubic hair (under the control of androgens secreted by the testicles and adrenal glands). The first sign of puberty in boys is usually testicular growth; in the United States, this occurs approximately 6 months after the onset of breast development in girls.
Testicular volume, which correlates with the stages of puberty, can be measured by comparing the testes with model ellipsoids (orchidometer) that have volumes ranging from 1 to 35 mL. The increase in size is primarily caused by seminiferous tubule growth. The main cell type in the seminiferous cords before puberty is the Sertoli cell, whereas in mature men, germ cells are the predominant cell type. With the increased LH levels with puberty, adult-type Leydig cells appear. Spermatogenesis starts between ages 11 and 15 years. Onset of puberty is predicted when a testis is more than 4 mL in volume. In adults, the average testicle has a volume of 29 mL; the right testis is usually slightly larger than the left, and the left testis is usually located lower in the scrotum than the right testis. When the phallus is measured, it should be flaccid and stretched. The phallus length is approximately 6 cm prepubertally and 12 cm in white men. The male areolar diameter also increases during puberty. The normal age range for onset of puberty in boys is 9 to 14 years.
In Tanner genital development stage 1 (prepubertal), the penis, testes, and scrotum are the same as in early childhood (see Plate 4-7 ). In Tanner stage 2, the testes and scrotum start to enlarge, and the scrotal skin starts to redden and change in texture. The average age at Tanner genital stage 2 is 11.2 years. In Tanner stage 3, penile growth has started, more evident in length than width, and there is also further enlargement of the testes and scrotum. In Tanner stage 4, the penis increases in size (both length and width), and the glans of the penis starts to develop; the testicles and scrotum continue to enlarge, and the scrotal skin becomes darker. In Tanner stage 5, the genitalia are adult in size and shape, and no further enlargement occurs.
In Tanner pubic hair development stage 1 in boys, the hair over the pubic region is vellus in type and is the same as that on the abdominal wall (see Plate 4-7 ). In Tanner stage 2, there is sparse, straight or slightly cured, lightly pigmented hair that appears at the base of the penis. In Tanner stage 3, the hair is spread sparsely over the pubic area, and it is curlier, darker, and coarser. In Tanner stage 4, the hair, although adult in type, covers a smaller area than in most adults, and it has not yet spread to the medial surface of the thighs. In Tanner stage 5, the hair is adult in type and quantity and is distributed to the medial surface of the thighs.
The vocal cords lengthen during puberty, and the larynx, cricothyroid cartilage, and laryngeal muscles enlarge. The pitch of the voice changes dramatically between Tanner genital stages 3 and 4. The average age when the adult voice is reached is 15 years. During Tanner pubic hair stage 3, facial hair starts to appear, initially at the corners of the upper lip and cheeks, then spreading to below the lower lip and eventually (after achieving Tanner pubic and genital stages 5) extending to the sides of the cheeks and chin. Axillary hair development is evident at age 14 years in boys. Acne, caused by testicular and adrenal androgen secretion, appears at an average age of 12 years (range, 9–15 years) and progresses through puberty. Pubertal gynecomastia occurs in about 50% of normally developing boys at an average age of 13 years, and it usually resolves spontaneously over 1 to 2 years (see Plate 4-25 ).
Facial changes occur during puberty in both boys and girls with enlargement of the nose, mandible, maxilla, and frontal sinuses.
PRECOCIOUS PUBERTY
Precocious puberty is the initiation of puberty before the age of 8 years in girls and 9 years in boys. The cause may be benign (normal variant early adrenarche) or more serious (malignant germinoma). When the sexual characteristics are appropriate for the child's sex, it is termed isosexual precocious puberty . Inappropriate virilization in girls or feminization in boys is termed contrasexual precocious puberty . Precocious puberty is 10-fold more common in girls, in whom the cause is usually central in nature.
GONADOTROPIN-DEPENDENT PRECOCIOUS PUBERTY
Central or true precocious puberty is gonadotropin-dependent and attributable to early maturation of the gonadotropin-releasing hormone (GnRH) pulse generator, a finding that is 20-fold more common in girls than in boys. Although this form of precocious puberty may be triggered by a central nervous system (CNS) process, the cause cannot be identified in 90% of affected girls. This development leads to premature breast (thelarche) and pubic hair (pubarche) changes in girls and premature pubarche and testicular enlargement (gonadarche) in boys. When pubertal changes start, they progress at a pace and in an order found in puberty that starts at a normal age. The blood concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol are characteristic of those seen in normal puberty. These patients have an advanced bone age and accelerated growth for their age.
Although the etiology is usually idiopathic in girls, head magnetic resonance imaging (MRI) is indicated to exclude a CNS disorder. In boys with central precocious puberty, the etiology is idiopathic in half and a CNS abnormality in the other half. Some considerations in this setting include the following: hamartomas of the tuber cinereum that contain GnRH neurosecretory neurons and function as an ectopic GnRH pulse generator; astrocytoma; ependymoma; hypothalamic or optic gliomas in patients with neurofibromatosis type 1; any neoplasm in the hypothalamic region (e.g., craniopharyngioma) that impinges on the posterior hypothalamus; an adverse effect of CNS radiotherapy (e.g., for tumors or leukemia); hydrocephalus; CNS inflammatory disorder (e.g., sarcoidosis); congenital midline defects; and pineal neoplasms. Hamartomas of the tuber cinereum are not actually tumors but rather congenital malformations that appear on MRI as an isodense fullness of the prepontine, interpeduncular, and posterior suprasellar cisterns. When the diameter of the hamartoma exceeds 1 cm, there is a high risk for seizures, which may be gelastic (laughing), petit mal, or generalized tonic-clonic. A rare cause is a gonadotropin-secreting pituitary tumor. Exposure to androgens (exogenous or endogenous) can trigger maturation of the GnRH pulse generator and central precocious puberty.
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