PUBERTY ABNORMALITIES
Abnormalities
of puberty are generally due to issues of timing or dosage of sex steroids that
normally govern phenotypic change. As discussed in Plate 1-5, androgens are
converted to estrogens in the male by aromatase and because of this, male
adolescence is frequently (80%) accompanied by gynecomastia. Issues of delayed
puberty are a consequence of the lack of gonadotropinreleasing hormone (GnRH)
stimulation in patients with hypogonadotropic hypogonadism, as typified by
Kallmann syndrome and its variants and Prader-Willi syndrome (Plate 1-7).
Idiopathic hypogonadotropic hypogonadism (IHH) or Kallman syndrome is
characterized by hypogonadism. Most patients experience a delay in puberty,
although those with less severe defects may present with only infertility.
Other findings include anosmia and midline abnormalities such as cleft palate
and small testes. When anosmia is not present, the condition is termed IHH. The
clinical diagnosis is con- firmed by blood tests revealing a low total
testosterone associated with low luteinizing hormone (LH) and low follicle
stimulation hormone (FSH) levels in combination with normal prolactin. The condition
is inherited as a familial disorder in one third of cases. X-linked and
autosomal inheritance patterns have been described. In the X-linked recessive
form, deletions occur in KAL1 (kallman-interval 1), a gene responsible
for the migration of GnRH and olfactory neurons to the preoptic area of the
hypothalamus during development. As a consequence, there is failure of
testicular stimulation by the anterior pituitary and hypothalamus and thus
testis failure in addition to anosmia. Mutations in other genes have also been
associated with IHH, including Dax1 on the X chromosome (associated with
congenital adrenal hyperplasia [CAH]), the GnRH receptor and PC1 (associated
with diabetes and obesity). Low testosterone is generally treated with
testosterone replacement. Infertility due to azoospermia (no ejaculated sperm)
can be treated with gonadotropin (LH and FSH) replacement over 12 to 18 months,
which induces sperm in the ejaculate in 80% of affected men.
Primary testis failure, causing an inadequate
testosterone surge at puberty and exemplified by Klinefelter syndrome, may also
produce a delay in the onset or sequence of pubertal events (Plate 1-7).
Klinefelter syndrome is an abnormality of chromosomal number in which 90% of
men carry an extra X chromosome (47,XXY) and 10% are mosaic with a combination
of XXY/XY chromosomes. It is thought that approximately half of XXY cases are
paternally derived, and recent evidence
suggests that its occurrence may correlate with advanced paternal age. This
syndrome may present with delayed puberty, increased height, decreased
intelligence, varicosities, obesity, diabetes, leukemia, increased likelihood
of extragonadal germ cell tumors, and breast cancer (20-fold higher than normal
males). Testis biopsies show sclerosis and hyalinization. In adults, hormones
usually demonstrate a low testosterone and frankly elevated LH and FSH levels
and generally require testosterone replacement. Natural paternity with this
syndrome is possible, but almost exclusively with the mosaic or milder form of
the disease. Biologic paternity in cases of pure XXY males is now possible with
assisted reproduction.
Sexual precocity, or the early onset
of puberty, has a variety of causes in males (Plate 1-8). In idiopathic form
(50% of cases), puberty proceeds in a normal pattern but begins earlier and is
compressed into a shorter time frame. Although affected males are tall for their
age during early puberty, the premature closure of the epiphyses results in a
markedly short stature in adulthood. Central causes of precocious puberty
include brain tumors near the third ventricle, including astrocytoma,
meningioma, or pinealoma, and are usually accompanied by diabetes insipidus and
visual field defects. It can also be associated with congenital mal- formations
such as hematomas of the brain.
Other
causes of male precocious puberty are adrenal in origin and include CAH and benign or malignant
virilizing adrenal cortical tumors (Plates 1-8 and 1-9). There are two major
types of CAH: classic and nonclassic. The classic form is the more severe of
the two and affects very young children and newborns. The nonclassic form is
milder and usually develops in late childhood or early adulthood. Signs and
symptoms of classic CAH in infants include an enlarged penis in boys
(macrogenitosomia), failure to regain birth weight, weight loss, acne,
dehydration, vomiting, and pigmentation of the scrotum and perianal regions.
Signs and symptoms of the classic condition in older children and adults
include rapid growth during childhood, very early puberty with the development
of pubic hair and deepening of the voice, shorter than average final height, and
infertility. Nonclassic CAH generally presents with rapid growth during
childhood and early puberty, severe acne, nausea, fatigue, low blood pressure,
low bone density, high cholesterol, and obesity. Children can also often have
slow recovery from infections and colds. Fundamentally, CAH results from a
deficiency of one of the hydroxylase enzymes that are required for cortisol
synthesis from 17-hydroxyprogesterone. Impaired cortisol secretion activates
pituitary gland secretion of
excessive ACTH, and the adrenal gland undergoes compensatory hypertrophy as a
result. In addition, large quantities of cortisol precursors are made that form
the substrates for androgens. Excessive androgens contribute to the
virilization and also down- regulate pituitary gonadotropin secretion, so that
the testes remain small and infantile despite other pubertal changes. The
clinical signs of a virilizing adrenal adenoma or cortical carcinoma are
similar to those induced by any other cause (Plate 1-8). These conditions can
be differentiated from other causes by the lack of suppression of
17-ketosteroid secretion with exogenous glucocorticoids.
Primary
testicular tumors can also cause precocious puberty (Plate 1-9). Based on
proliferation of interstitial Leydig cells, these tumors can usually be
palpated as nodular enlargement of one testis with a contralateral atrophic
testis. Again, 17-ketosteroids are usually not suppressed with glucocorticoids
in this condition, and the adrenal glands are normal on imaging. Clumps of
adrenal cells termed adrenal rests can also descend with the testis into the
scrotum and be metabolically active and induce virilization. Adrenal rests are
more likely to become active in cases of CAH in which there is excessive
adrenal stimulation and can present as testis or peritestis enlargement. Even
more rare are teratomatous rests in the scrotum that secrete excessive amounts
of chorionic gonadotropin (hCG) that is similar to the gonadotropin LH and
stimulates androgen production. These rests are highly malignant and are
associated with growth of the contralateral testis as a result of
gonadotropic-like stimulation.
PUBERTY ABNORMALITIES IN FEMALES
Delayed
puberty may occur for several years and then proceed normally in what is
referred to as constitutional delay. It may also be due to poor nutrition from
anorexia, extreme athleticism, and systemic disease such as chronic renal
failure, hypothyroidism, and Cushing syndrome. Reproductive disorders such as
Kallmann syndrome or Prader-Willi syndrome, gonadal defects characteristic of
Turner syndrome, or a lack of response to sex steroids associated with androgen
insensitivity disorders (in a genetic male) may also occur (Plate 1-10). Turner
syndrome or Ullrich Turner
syndrome (a form of gonadal dysgenesis) occurs when one of the two female X
chromosomes is constitutionally missing.
When only a part of
the X chromosome is missing, mosaic Turner syndrome may be present. Because
this syndrome only affects the second X chromosome, the syndrome is only
present in females. Occurring in 1 of every 2500 girls, the syndrome presents
with characteristic physical abnormalities, such as short stature, broad chest,
low hairline, low-set ears, and webbed neck. Girls with Turner syndrome
typically have gonadal dysfunction (nonworking ovaries) that results in
amenorrhea and sterility. Other health concerns include con- genital heart
disease, hypothyroidism, diabetes, vision and hearing problems, and autoimmune
disease. Finally, there is also a characteristic pattern of cognitive deficits
observed, with difficulties in visuospatial, mathematic, and memory areas.
Rarely, cystic fibrosis and Frasier syndrome can result in delayed puberty.
There are
two benign variants of sexual precocity in females: premature thelarche (benign
mammoplasia) and premature pubarche. In the former, there is isolated premature
development of breast tissue and in the latter, isolated pubic hair. Both may
be associated with childhood obesity. True sexual precocity is usually due to
central (nervous system) or ovarian causes (Plate 1-11). Adrenal tumors or
hyperplasia in the female most commonly causes virilization and not true sexual
precocity. Idiopathic sexual precocity is more common in girls than boys and
presents with advanced stature and bone age, breast enlargement, vaginal wall
thickening, pubic hair, and acne. Axillary hair is rarely found but adult
perspiration odors can be obvious. In addition, uterine enlargement can occur
and irregular menstrual bleeding
is possible. Central stimulation by gonadotropins can also result in large
follicular cysts in the ovary, which may be difficult to distinguish from
primary ovarian tumors. Spontaneous remission of idiopathic sexual precocity is
not uncommon.
McCune–Albright syndrome, caused by a sporadic
mutation in the GNAS1 gene, is a special form of central precocity that
is associated with polyostotic fibrous dysplasia, a nonmetabolic skeletal
disorder in which scar forms
in bone that can lead to deformities and fractures (Plate 1-11). In this
condition, sexual precocity is combined with lesions in the long bones and café
au lait spots that stop at the midline. Thyroid enlargement is common, often
with thyrotoxicosis. Affected girls may also have frontal bone and zygomatic
arches, features characteristic of acromegaly, and polycystic ovaries and
hirsutism. Primary hypothyroidism can present with breast enlargement, early
menstruation, and galactorrhea.
These symptoms regress when thyroid replacement is given and suggest that
pituitary gonadotropin hyperstimulation may be associated with excess
thyroid-stimulating hormone (TSH) stimulation.
Feminizing
tumors of the ovary are a relatively common cause of sexual precocity in girls
(Plate 1-11). Granulosa-theca cell tumors, more commonly known as granulosa
cell tumors, belong to the sex cord–stromal group and include tumors made up of
granulosa cells, theca cells, and fibroblasts in varying degrees. About 5% of
these tumors occur in juveniles and the majority of the rest occur in
postmenopausal women. Both types commonly produce estrogen, and estrogen
production often is the reason for early diagnosis. Theca cell tumors almost
always are benign and carry an excellent prognosis. The rare malignant thecoma
likely represents a tumor with a small admixture of granulosa cells. It is not
exactly known how these tumors arise but it has been proposed that they are
derived from either the mesenchyme of the developing genital ridge or
precursors within the mesonephric and coelomic epithelium. Granulosa-theca cell
tumors can be large, palpable, and can secrete large amounts of estrogen that
causes heavy feminization. Some features of the syndrome, such as the growth of
pubic and axillary hair, are attributed to associated pituitary stimulation.
Complete tumor resection is mandatory for cure of these symptoms. Rarer, but
far more malignant, tumors of the ovary that can cause similar symptoms are
progesterone-secreting luteomas and chorionepitheliomas. Exogenous estrogen
intake through contaminated medications, foods, cosmetics, or exposure to
endocrine disruptors such as bisphenol A and phthalates and estrogenic
pesticides may underlie some cases of prior unexplained precocious puberty
(Plate 1-11). Bisphenol A is an organic phenol compound that has been used
primarily to make plastics
for more than 50 years. It is used to make polyesters, plasticizers,
polycarbonate and epoxy resins, and is found in baby and water bottles, sports
equipment, medical and dental devices, dental fillings and sealants, eyeglass
lenses, CDs and DVDs, and household electronics. Although good-quality human
studies are currently lacking, animal studies have shown that excessive
exposure to bisphenol A may be related to changes in anogenital distance,
early puberty, changes in breast tissue that may predispose to carcinogens, and
decreased maternal behavior. Phthalates are a class of widely used industrial
compounds known technically as alkyl aryl esters and are used as softeners of
plastics, oily additives in perfumes, additives to hairsprays, lubricants, and
wood finishers, and they hav been linked to premature breast development in
girls.
