Pediatric Endocrinology

Gonadotropins

Gonadotropins are glycoproteins secreted by the anterior pituitary gland. These glycoprotein hormones include follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pulsatile gonadotropin-releasing hormone (GnRH) secretion by the hypothalamic GnRH neurons, the so-called GnRH pulse generator, regulates pituitary secretion of LH and FSH. The GnRH neurons originally develop in the olfactory placode and migrate during early fetal development from the nose through the forebrain to the hypothalamus. The embryologic origin of the GnRH neurons results in the association of hypogonadotropic hypogonadism and anosmia. Pulsatile release of GnRH is important in the secretion of FSH and LH from the anterior pituitary gland. Continuous secretion of GnRH inhibits the release of FSH and LH.

The amplitude and frequency of GnRH pulses varies during the newborn period, infancy, childhood, puberty, and adulthood. After active secretion in late gestation and in the early neonatal period during the so-called “mini-puberty” of infancy, the GnRH pulse generator becomes quiescent until the onset of puberty. “Mini puberty” of infancy is a transient period of gonadal activation starting in the second week and ending by 4 to 6 months of life. Gonadarche is characterized by the resumption of GnRH secretion. The first sign of reactivation of the GnRH pulse generator, and onset of gonadarche, is increased nocturnal LH secretion. Hypogonadotropic hypogonadism is characterized by low gonadotropin concentrations. In primary gonadal failure, deficiency of sex steroids interferes with negative feedback inhibition, resulting in elevated gonadotropin secretion during early infancy, puberty, and adulthood ( Fig. 9.7 ). Measurement of random levels of FSH and LH from late infancy to the onset of puberty is typically not helpful because the GnRH pulse generator is quiescent.

The secretory activity of GnRH neurons represents the integrated response to many hormones, neurotransmitters, and environmental influences. Input signals include sex steroids, glucocorticoids, leptin, insulin, IGF-1, ghrelin, FGF21, orexigenic peptides, and anorexigenic peptides with the net effect being signal integration to govern pubertal maturation and ongoing reproductive function.

In males, LH binds to the LH receptor on Leydig cells to directly stimulate testosterone synthesis and secretion. In the testes, FSH supports Sertoli cell development and spermatogenesis. Sertoli cells secrete anti-Müllerian hormone (AMH) with elevated levels during fetal life, which decline with the onset of puberty. AMH provides a functional marker of immature Sertoli cells. AMH levels may be low in males with diminished Sertoli cell function such as anorchia, testicular failure secondary to chemotherapy, radiation therapy. At the onset of puberty, testosterone secreted by the Leydig cells suppresses AMH secretion by the maturing Sertoli cells. In the testis Sertoli cells and Leydig cells function in parallel. In Klinefelter syndrome, as an example, Leydig cell function with normal testosterone production persists despite diminishing Sertoli cell function; this leads to relatively normal LH concentrations and elevated FSH concentrations.

In females, the ovary is characterized by a two-cell model (in series) for steroidogenesis. LH stimulates ovarian theca cells to synthesize androstenedione, which serves as the precursor for estradiol synthesis. Subsequently, in the ovarian granulosa cells, FSH increases expression of aromatase, the enzyme that converts androgens to estrogens. Granulosa cells do not secrete AMH in fetal life. With the onset of puberty, granulosa cells of developing follicles increase AMH secretion. In females, AMH appear to be a marker of ovarian reserve by reflecting the number of small growing follicles. AMH concentrations are typically low in girls with Turner syndrome and may be elevated in women with polycystic ovary syndrome (PCOS).

Gonadotropin secretion, especially in females, is influenced by the metabolic state and by the degree of adiposity. Very athletic and lean girls experience delayed puberty with low gonadotropin levels. Girls with eating disorders of the restrictive type experience amenorrhea with suppressed gonadotropins. Pubertal development may be slow among boys who restrict food intake to maintain a low weight for wrestling. Leptin, a hormone produced by the adipose tissue, exerts a significant effect on the hypothalamus and is a major link between energy balance and gonadotropin secretion.

Delayed Puberty

Delayed puberty is defined in girls by the absence of breast development by 12 years of age and in boys by the lack of testicular enlargement by 14 years of age. Disorders of puberty can be classified as central (hypothalamic or pituitary) or peripheral (gonadal) in origin. Hypothalamic or pituitary disorders can be classified as permanent or transient hypogonadotropic hypogonadism. Primary gonadal failure is classified as hypergonadotropic hypogonadism.

A common cause of delayed puberty, especially in boys, is constitutional delay, which refers to a normal variant of the timing of puberty. There is usually a history of “late bloomers” in the family. Children are otherwise healthy without any symptoms or signs of underlying chronic medical problems. The bone age is typically delayed with good linear growth potential; the predicted final height is appropriate for the family. However, delayed or stalled puberty may be one of the first signs of many underlying medical conditions. Therefore, careful evaluation and follow up of children with presumed constitutional delay in puberty is required. In other words, constitutional delay of growth and puberty is a diagnosis of exclusion.

Hypogonadotropic hypogonadism may be suspected in boys with micropenis in the newborn period. Many genetic and acquired conditions are associated with hypogonadotropic hypogonadism. Kallmann syndrome refers to hypothalamic hypogonadism associated with anosmia due to impaired migration of GnRH and olfactory neurons; this form is often due to mutations in the ANOS1/KAL1 gene located at Xp22.31. Hypothalamic hypogonadism can also occur with a normal sense of smell. As noted earlier, the number of genes associated with delayed puberty has greatly expanded ( Box 9.3 ). The function of these genes ranges from the development and migration of the GnRH neurons during fetal life to genes regulating GnRH and gonadotropin secretion. Inheritance patterns include autosomal recessive, autosomal dominant, and X-linked. In some instances, variations in several different genes, oligogenicity, is associated with the phenotype of delayed puberty. For some genetic variants, the phenotype includes additional clinical features. CHARGE syndrome (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) due to mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene is associated with delayed puberty. Other disorders associated with delayed puberty include Prader-Willi, Noonan, and Bardet-Biedl syndromes.

Acquired gonadotropin deficiency can be due to trauma, neoplasms, radiation therapy, infiltrative disorders, hyperprolactinemia, or chronic illness. Undernutrition and chronic diseases, such as anorexia nervosa, inflammatory bowel disease, celiac disease, cystic fibrosis, hypothyroidism, glucocorticoid excess, poorly controlled type 1 diabetes mellitus, and sickle cell anemia can be associated with delayed or arrested puberty.

Hypergonadotropic hypogonadism is due to ovarian insufficiency/failure in girls and testicular failure in boys. Gonadotropin levels are typically elevated due to the absence of negative feedback because gonadal sex steroid (estrogen or testosterone) secretion is low. Delayed puberty due to hypergonadotropic hypogonadism can be congenital due to genetic conditions or acquired due to underlying causes such as autoimmune, vascular accidents, trauma, chemotherapy (alkylating agents have the highest risk), radiation to abdomen, pelvis, gonads, or total body radiation.

Several genetic conditions are associated with hypergonadotropic hypogonadism. Some genetic conditions are relatively common whereas others are rare and may be difficult to diagnose without extensive workup such as whole exome sequencing. Turner syndrome and Klinefelter syndrome are sex chromosome aneuploidies associated with gonadal insufficiency/failure and hypergonadotropic hypogonadism. Fragile X premutations and congenital disorders of glycosylation are other genetic conditions associated with hypergonadotropic hypogonadism and delayed puberty. Non-immune premature ovarian failure has been associated with galactosemia and with mutations in the forkhead box L2 (FOXL2) , newborn ovary homeobox (NOBOX) , factor in germline alpha (FIGLA) , and bone morphogenetic protein 15 (BMP15) genes. Premature ovarian insufficiency can be due to an autoimmune process—either isolated or associated with other autoimmune disorders such as adrenal and thyroid autoimmune disorders.

Complete androgen insensitivity syndrome can present as delayed/stalled puberty in phenotypic females with primary amenorrhea. Androgen insensitivity occurs secondary to mutations in the androgen receptor gene, which is located at Xq11-q12. Rarely, androgen insensitivity is associated with variants in other genes associated with androgen signaling. In utero , androgen action is essential for retention of wolffian duct derivatives, development of the prostate, and differentiation of male external genitalia. Common clinical presenting features of complete androgen insensitivity syndrome (CAIS) include inguinal or labial masses in an otherwise normal appearing female infant. The adolescent girl may present with breast development and primary amenorrhea. Breast development occurs because gonadotropin secretion at the time of puberty stimulates increased testosterone production, which is then aromatized to estradiol. Due to normal Sertoli cell function and AMH secretion, the uterus, cervix, and upper portion of the vagina are absent, and there is a blind ending vaginal pouch. In all instances, the karyotype is 46,XY. LH concentrations are generally elevated with normal FSH concentrations. The clinical features for patients with partial androgen insensitivity syndrome (PAIS) vary depending on the extent of receptor function. The phenotype can vary from female external genital appearance with mild clitoromegaly to a minimally undervirilized male with gynecomastia.

Some individuals with disorders of steroidogenesis or aberrant gonadal differentiation present with delayed puberty. Patients with 17-hydroxylase deficiency have mutations in the 17α-hydroxylase/17,20-lyase (CYP17A1) gene that encodes the P450c17 enzyme. This enzyme is essential to produce cortisol and sex steroids ( Fig. 9.8 ). In classic 17-hydroxylase deficiency, patients with both XX and XY karyotypes are phenotypic females and both present with lack of secondary sexual development. Females with P450-oxidoreductase deficiency due to POR mutations have been reported to have delayed puberty and ovarian cysts. Individuals with 17-hydroxysteroid dehydrogenase type 3 deficiency due to HSD17B3 variants or 5α-reductase deficiency due to SRD5A2 variants have 46,XY karyotype, genital ambiguity at birth, and typically virilize with the increased gonadotropin secretion of puberty.

Patients with XX or XY gonadal dysgenesis may present with delayed puberty. With the presence of a Y chromosome, patients with XY gonadal dysgenesis have an increased risk for gonadoblastoma or dysgerminoma in the dysgenetic gonad(s). Testicular regression syndrome, also known as vanishing testes or congenital anorchia, is typically diagnosed in infancy or early childhood, but it can present in peripubertal boys with nonpalpable testicles or delayed puberty. External genitalia are typically normal male but can vary from undervirilized male to normal male depending on the timing of in utero testicular loss; this disorder is presumed to be secondary to an in utero vascular event that disrupts testicular blood flow. Mutations in the DEAH-Box RNA helicase DHX37 gene have been identified in affected boys.

Another disorder that may present with primary amenorrhea is dysgenesis of the Müllerian ducts and uterus. Müllerian duct aplasia–renal agenesis–cervicothoracic somite dysplasia (MURCS) syndrome is an uncommon developmental disorder characterized by uterine hypoplasia or aplasia, renal agenesis or ectopy, vertebral anomalies, and short stature. Ultrasound studies to assess for the presence of the uterus should include renal ultrasounds. Isolated Müllerian duct agenesis without the other associations in 46, XX females is called Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS).

Precocious Puberty

Puberty reflects activation of the hypothalamic-pituitary-gonadal (HPG) axis. The physical manifestation of puberty is “gonadarche” characterized by breast development in girls and testicular enlargement in boys. During this process, ovarian and testicular volumes increase. The diagnosis of precocious or early development is considered when the physical signs of puberty develop prior to age 8 years in girls and 9 years in boys. Children presenting with early onset of puberty should be evaluated regarding the age at pubertal onset and the sequence of pubertal changes. Medical history should focus on the temporal sequence of pubertal changes. Clinical features of androgen and estrogen effects should be noted during the physical examination. Growth acceleration in girls is present at the onset of puberty and is a very sensitive sign of precocious puberty. Gonadotropin-dependent precocious puberty, also known as central precocious puberty or GnRH-dependent precocious puberty, is marked by a premature activation of the HPG axis and follows the same sequence as normal puberty. In girls, the causes of isosexual precocity (development along lines of the same sex) are related to alterations in gonadal or central nervous system (CNS) function. Gonadotropin-dependent precocious puberty follows an early onset of pulsatile LH and FSH secretion and the subsequent response of the ovary. Hypothalamic hamartomas are composed of structurally abnormal nervous system tissue and may be associated with GnRH-dependent precocious puberty ( Fig. 9.9 ). Gelastic seizures can be associated with hypothalamic hamartomas and precocious puberty. Intracranial neoplasms are more commonly associated with precocious puberty in boys as compared with girls. Low-dose radiation therapy for CNS tumors can result in hypothalamic dysfunction and present with precocious puberty. Obtaining family history of pubertal development can be helpful. Paternally inherited loss of function mutations in the makorin ring finger 3 (MKRN3) and delta homolog 1 (DLK1) genes are associated with precocious puberty. Available data suggest that the makorin ring finger 3 protein inhibits GnRH secretion; declining circulating levels are noted with the onset of puberty.

In GnRH-independent forms of precocious puberty, there is an increased production of gonadal steroids. This leads to the physical changes of puberty in the absence of activation of the HPG axis. McCune-Albright syndrome, characterized by irregular café-au-lait spots ( Fig. 9.10A ), polyostotic fibrous dysplasia (see Fig. 9.10B ), and sexual precocity, is one example of a GnRH-independent cause of precocious puberty. Physical changes may not follow the normal sequence of pubertal development seen in central precocious puberty. McCune-Albright syndrome is due to a somatic activating mutation of the gene encoding the α-subunit of G protein coupled receptor, which is located at chromosome 20q13.2. Other endocrine manifestations may include gigantism, Cushing syndrome, hyperprolactinemia, hyperthyroidism, and hyperparathyroidism.

Gonadal or adrenal neoplasms secreting sex steroids, such as Leydig cell tumors in boys, are rare causes of precocious puberty. The sequence of pubertal changes may differ from typical because rapid increase of sex steroids can cause rapid progression of pubertal signs. In boys, hCG-secreting tumors can also be a cause of isosexual precocity due to LH-like actions of hCG. Typically, hCG tumors do not cause precocious puberty in girls because estradiol is not produced in the absence of FSH stimulated aromatase expression. Familial male-limited precocious puberty or testotoxicosis is characterized by premature testicular testosterone production, testicular enlargement, and precocious puberty. It is due to constitutive activating mutations of the LH receptor (LHR) gene.

Long-standing and severe primary hypothyroidism in girls may be associated with isosexual precocity because of the partial structural homology between thyrotropin (TSH) and the gonadotropins (LH, FSH). In addition to signs of hypothyroidism, girls may have breast development and vaginal bleeding. This is also known as the Van Wyk-Grumbach syndrome. Boys with severe hypothyroidism may have enlargement of the testes due to the same mechanism. In these boys, testicular enlargement is often not associated with other secondary sexual characteristics such as pubic hair development and genital enlargement.

Exposure to exogenous hormones such as estrogens, estrogen-like substances including phytoestrogens, and testosterone may cause the development of secondary sexual characteristics and mimic precocious puberty.

Premature Adrenarche

Premature adrenarche describes the early onset of the normal increase in adrenal androgen production. Adrenarche is considered early when it occurs before 8 years of age in girls and 9 years of age in boys. Clinical features of adrenarche include acne, adult type body odor, axillary hair, and pubic hair development (pubarche). Children with premature adrenarche are characterized by a premature increase in DHEAS concentrations. Premature isolated (benign) adrenarche is not associated with pubertal signs such as breast development in girls and testicular enlargement in boys. Premature adrenarche progresses slowly; other pubertal signs do not develop early. Bone age is typically normal but may rarely be advanced. Height prediction is normal for genetic potential. Differential diagnostic considerations include late onset CAH and androgen-secreting tumors. Androgen-secreting adrenal or gonadal tumors are extremely rare. In children with benign premature adrenarche, adrenal steroid hormone concentrations may be elevated for chronologic age but are normal for the degree of pubic hair development. Although advanced skeletal maturation is more common in CAH, ACTH stimulation tests may be necessary to distinguish late-onset CAH from benign premature adrenarche. To diagnose late-onset CAH, the ACTH-stimulated 17-OH-Progesterone level is typically greater than 1500 ng/dL.

Premature Pubarche

Premature pubarche refers to the development of pubic hair (pubarche) before 8 years of age in girls and 9 years of age in boys ( Fig. 9.11 ). Associated findings may include axillary hair, adult-type body odor, and acne. Typically, DHEAS concentrations are normal for age. Premature pubarche is often a normal variant. Rapid progression of pubarche should prompt evaluation for other disorders such as adrenal or gonadal androgen secreting tumors, disorders of steroidogenesis, or environmental exposures. On occasion, young infants may present with coarse hairs in the genital area (typically the scrotum in boys and the inner aspect of the labia majora in girls) which disappear spontaneously in late infancy, suggesting that this is a benign phenomenon. Progressive increase of hair in these areas should alert the clinician to the possibility of pathologic causes.

Premature Thelarche

Premature thelarche is a transient and self-limited condition defined by the early onset of isolated breast development. Typically, premature thelarche develops during the first or second year of life without any other signs of puberty. The breast tissue may appear unilaterally or bilaterally and may regress or persist ( Fig. 9.12 ). Typically, there is a waxing and waning pattern to breast enlargement. Other features of pubertal development, including growth acceleration and pubic hair development, are absent. In most cases, breast enlargement does not progress beyond Tanner stage III. Hence, premature thelarche is a diagnosis of exclusion and cannot be made in the presence or progression of other pubertal signs. The ingestion of exogenous estrogens, such as oral contraceptives, should always be suspected in cases of breast enlargement. One should query regarding exposure to phytoestrogens such as lavender and tea tree oils. Premature thelarche must be differentiated from other forms of progressive precocious puberty. Breast enlargement secondary to maternal hormones may occur in either sex in the immediate neonatal period. The etiology of premature thelarche is unclear. In some instances, activating mutations of the GNAS1 gene, encoding the α-subunit of the Gs protein have been described in the absence of other elements of McCune-Albright syndrome. Some young girls develop significant estradiol secretion and exaggerated thelarche that does not progress to complete puberty. These girls do not show the typical activation of pituitary-ovarian axis seen in central precocious puberty. Close follow up is recommended. Transient ovarian cysts in young girls can secrete estradiol and present with transient stimulation of breast tissue which resolves spontaneously.

Lipomastia/Adipomastia

Lipomastia/adipomastia refers to the presence of adipose tissue in the pectoral area that may resemble breast development. This is frequently seen in obesity, both in boys and girls. True breast tissue is palpable underneath the nipple/areola, whereas in pure lipomastia there is no palpable glandular tissue under the nipple, giving the impression of a “donut” with a hollow center surrounded by a rim of adipose tissue.

Isolated Vaginal Bleeding

The first vaginal bleeding, known as “menarche,” typically occurs 2 years after the onset of breast development. It coincides with Tanner stages IV and V breast development. Isolated vaginal bleeding in prepubertal girls does not follow this typical sequence and is abnormal. It should raise suspicion for foreign body in the genital tract and warrants thorough evaluation. The possibility of sexual abuse needs to be excluded. Isolated benign ovarian cysts are another common cause of vaginal bleeding in prepubertal girls. This can be seen in normal girls as a benign self-limiting condition or if it is recurrent, it can be a manifestation of McCune-Albright syndrome. Rapidly growing, estrogen-producing adrenal or ovarian tumors may present with vaginal bleeding; often other signs of puberty are present.

Gynecomastia

Gynecomastia means female–like breasts seen in males. It should not be used to describe breast development in females, which is “thelarche.” Gynecomastia is common in adolescent males. Up to 70% of adolescent males may develop gynecomastia. Typically, gynecomastia is benign and regresses during the later portion of puberty. True gynecomastia should be differentiated from lipomastia, which is seen in overweight individuals. Estrogens stimulate and testosterone inhibits the proliferation of breast tissue. Estrogen-to-testosterone ratio is more important than the absolute levels of estrogen in gynecomastia. Phytoestrogens, lavender oil, and tea tree oil mimic the action of estrogens and can stimulate the development of breast tissue. Good history and examination should differentiate the benign conditions from the less common nonbenign causes of gynecomastia.

Physiological neonatal gynecomastia is common in newborns due to the transfer of maternal estrogen through the placenta. It can be associated with milk secretion, the so called “witch’s milk.” Stagnation of milk and superadded infection can result in mastitis and breast abscess, which may require surgical drainage. Neonatal gynecomastia is usually self-remitting as the effects of maternal estrogen wear off. Minimal manipulation is recommended to prevent further stimulation of breast tissue and the introduction of infection.

Pubertal gynecomastia results from relative estrogen excess due to variable amounts of aromatization of adrenal and testicular androgens to estrogens in peripheral tissues, particularly adipose tissue, and liver, while testosterone levels are not yet robust. Physiological pubertal gynecomastia can be unilateral and usually resolves spontaneously over 1 to 2 years ( Fig. 9.13 ). It might persist longer in obese boys or never resolve due to the higher estrogen levels from aromatization of androgens in peripheral fat tissue and permanent glandular breast tissue formation. Decreased androgen production in boys with testicular hypogonadism such as seen in boys with Klinefelter syndrome can cause progressive gynecomastia. Decreased androgen effect due to androgen receptor mutations seen in androgen insensitivity syndrome results in high testosterone which is aromatized to estradiol and results in stimulation of breast development. Typically, the phenotype is female in CAIS. Other conditions that can cause decreased androgen synthesis and gynecomastia are 5α reductase deficiency, 17β hydroxysteroid dehydrogenase type 3 deficiency. Increased estrogen production from adrenal or testicular tumors, hCG-secreting tumors, and familial aromatase excess syndrome are rare causes of gynecomastia. Obesity, malnutrition, chronic liver disease, hyperthyroidism, and breast cancer (rare) are other nonbenign causes of gynecomastia. Drug-induced gynecomastia should be considered in boys who are taking chronic medication or taking substances such as marijuana.

Breast Asymmetry

Breast asymmetry is the finding of mild-moderate difference in breast size, shape, and position on a clinical examination. It is common in pubertal adolescent girls and can be a feature of physiological pubertal gynecomastia in boys (see Fig. 9.13 ). It is mostly due to the fluctuating response of breast tissue to the hormonal environment during puberty. In most instances where the asymmetry is due to hormonal fluctuations, it resolves as breast development is completed. Other causes such as breast mass or abscess are rare. Breast asymmetry is a feature of Poland syndrome, which is an uncommon congenital malformation affecting the chest wall, shoulder, arm, and hand.

Galactorrhea

Galactorrhea means “milk flow,” derived from the Greek word “galakt” meaning milk and “rhoia” meaning flow. Galactorrhea describes the milk production outside of pregnancy or breastfeeding in females. Galactorrhea can occur in males as well. Prolactin secreted from the anterior pituitary lactotrophs is the key hormone in milk production. The hypothalamus secretes dopamine, which inhibits pituitary prolactin production. Several hypothalamic releasing factors increase prolactin secretion. Vasoactive intestinal polypeptide (VIP) secreted by the hypothalamus has a stimulatory effect on lactotrophs. Thyrotropin releasing hormone (TRH), which stimulates the anterior pituitary to secrete thyroid stimulating hormone (TSH), has a minor stimulating effect on the prolactin secretion. Estrogens directly stimulate pituitary lactotrophs and prolactin secretion. Physiologic causes of galactorrhea include nipple stimulation and placental transfer of maternal hormones in newborns. Pathologic causes include CNS lesions that interfere with the hypothalamic inhibitory function on prolactin synthesis and secretion such as tumors in the hypothalamic pituitary area (craniopharyngioma, meningioma, germinoma) or prolactin-secreting adenomas of the pituitary gland (prolactinomas). Local lesions of the breast such as herpes zoster, burns, trauma, and systemic disease such as renal failure and hypothyroidism may cause galactorrhea. Antipsychotics such as risperidone, gastrointestinal motility promoting agents (metoclopramide), and antihypertensive medication (verapamil, methyldopa) can cause galactorrhea as a side effect.

Macromastia/Gigantomastia

Gigantomastia is a rare condition characterized by the diffuse enlargement of both breasts. It occurs mostly in peripubertal girls or in the postpartum period. It can be physically and psychologically disabling. Often, etiology is unknown. Most cases occur during significant changes in endogenous hormones such as during puberty and pregnancy. It is thought to be due to abnormal stimulation of breast tissue from circulating physiologic levels of hormones or due to hormonal excess. Drug-induced gigantomastia has been described with penicillamine and cyclosporine.