Delayed Or Absent Puberty
Delayed puberty is defined as the absence of
secondary sexual characteristics at age 13 in girls and 16 in boys (Chapters 11
and 12). It may result from: (i) a nonpathologic constitutional delay accompanying
a growth delay; (ii) disorders of the hypothalamus or pituitary gland that
result in inadequate gonadotropin secretion (hypogonadotropic hypogonadism);
and (iii) disorders of the gonads that prevent adequate sex steroid secretion (hypergonadotropic
hypogonadism) (Table 29.1). In girls, secondary sexual characteristics may
develop without progression to menarche. This form of pubertal dysfunction and
other causes of primary amenorrhoea are discussed in Chapter 30. It is
important to diagnose and treat delayed or absent puberty because: (i) serious
underlying conditions may be present; (ii) abnormal persistence of a child-like
phenotype has profound social implications for the teenager and young adult;
(iii) prolonged absence of gonadal steroid exposure leads to osteopenia, a
failure of normal bone formation. Osteopenia is associated with an increased
risk of fractures in weight-bearing bones such as vertebrae, hips and long
bones. Treatment of delayed or absent puberty aims to correct underlying disorders.
Hormone replacement with estrogen/progesterone or testosterone is often
required if hypogonadism is prolonged or age-appropriate sex steroid secretion patterns cannot be
restored.
Constitutional pubertal delay
Pathologic causes of delayed
puberty must be excluded before the diagnosis of constitutional pubertal delay
can be considered. Constitutional pubertal delay is characterized by linear
growth velocities and gonadotropin-releasing hormone (GnRH) secretory patterns
that are appropriate for the individual’s bone age. In girls, it has been
observed that puberty begins at a bone age of 12 years. Therefore, a
13-year-old girl who has a bone age of 11 and has not developed secondary
sexual characteristics may have constitutional delay.
Hypogonadotropic hypogonadism
This is characterized by deficiencies
in pulsatile GnRH, folliclestimulating hormone (FSH) or luteinizing hormone
(LH) secretion that result in sexual infantilism. GnRH deficiencies arise
via three general mechanisms: genetic defects of the hypothalamus, developmental
defects of the hypothalamus and destructive lesions involving the hypothalamus
or pituitary stalk.
The best characterized and most
common of the genetic defects producing hypogonadotropic hypogonadism is Kallmann
syndrome, which is typified by GnRH deficiency associated with hyposmia and
hypoplasia of the olfactory lobes of the brain. It is inherited either as an
X-linked recessive trait or as an autosomal dominant trait with variable
penetrance. Kallmann syndrome is much more common in boys than in girls. Half
of patients with Kallmann syndrome have mutations in the KAL gene on
chromosome Xp22.3. This gene encodes an extracellular matrix protein that
regulates axonal pathfinding and cellular adhesion. Deficiencies in the
amounts, or function, of this protein explain the cluster of abnormalities
associated with Kallmann syndrome: fetal GnRH neurosecretory neurons fail to migrate
normally from the olfactory placode to the medial basal hypothalamus, resulting
in inappropriate olfactory bulb development, anosmia and GnRH deficiencies.
Less common developmental defects
have been associated with delayed or absent puberty due to hypogonadotropic
hypogonadism. These also affect midline central nervous system (CNS)
development.
Some have been described in
association with visual abnormalities that result from developmental
abnormalities in the optic tracts. GnRH deficiencies are often associated with
other hypothalamic–pituitary functional abnormalities. As a result, delayed
puberty is typically accompanied by short stature [growth hormone (GH)
deficiency]. This can make differentiation from constitutional delay
challenging. A familial form of isolated gonadotropin deficiency has also been
described. Unlike most other forms of hypogonadotropic hypogonadism in which GH
is also deficient, patients with familial isolated gonadotropin deficiency have
normal height for bone age.
CNS tumors result in delayed puberty more often than precocious
puberty. Most neoplasms that
interfere with pubertal development are extrasellar and inhibit the production,
or delivery, of the pituitary trophic hormones to the pituitary gland.
Deficiencies in multiple pituitary hormones are common. Of these tumors,
craniopharyngiomas are the most common cause of delayed or absent puberty. They
originate from cells within the developmental anlagen of the anterior
pituitary–Rathke’s pouch, and are almost always located in or near the
hypothalamus or pituitary. Many pituitary tumors that are common in adults are
notably rare in prepubertal children. One, the prolactinsecreting adenomas,
may occur among teenagers. Girls with prolactin-secreting pituitary adenomas
may present to medical providers complaining of primary amenorrhea in the
presence of secondary sexual characteristics. Neurofibromas of the CNS that
develop as part of von Recklinghausen syndrome (neurofibromatosis) and
germ-cell tumors can also be associated with sexual infantilism.
Functional gonadotropin
deficiencies can arise from malnutrition, psychiatric disorders and from a
large array of chronic diseases. Girls seem more sensitive than boys to the
effects of malnutrition. In girls, a reduction to less than 80% of ideal body
weight can be associated with delayed or arrested puberty. By contrast,
starvation of famine proportions is necessary to interfere with male puberty.
Anorexia nervosa is a
serious psychiatric disorder characterized by a distorted body image, an
obsessive fear of obesity and associated food avoidance. It can cause severe,
and sometimes fatal, weight loss. While not restricted by age or gender,
anorexia nervosa is more common in girls than boys and most often begins during
adolescence. Associated with delayed puberty, it can be accompanied by primary
or secondary amenorrhea, depending on the age at onset. The hypogonadotropic
hypogonadism of anorexia nervosa is related only in part to the weight loss
associated with the disorder. In fact, in postpubertal girls, secondary
amenorrhea may precede severe weight loss. Affected individuals will have a
reversion of LH secretion to a prepubertal circadian rhythm. Recovery of normal
weight will correct many of the coexisting endocrine and metabolic
abnormalities, including: low cortisol and triiodothyronine, increased GH and
decreased IGF-1 and a blunted pituitary response to trophic hormones. Amenorrhea
accompanying anorexia nervosa may persist long after otherwise adequate weight
gain. Bulimia nervosa, a variant of anorexia nervosa associated with food
gorging, induced vomiting and laxative abuse, produces amenorrhea unassociated
with weight loss. This suggests the amenorrhea of anorexia and bulimia nervosa
may have a primary hypothalamic origin.
Intense exercise and athletic training may delay or arrest puberty due to inhibition of GnRH secretion. Again,
this is more common in girls than boys. Distance runners, gymnasts and dancers
are at highest risk. Interruption of training by injury
advances puberty before weight gain occurs, suggesting a direct effect of the
physical activity on GnRH secretion. Female athletes with normal body weight,
but less body fat than nonathletic girls (e.g., swimmers and ice skaters) are
also at risk for hypogonadotropic hypogonadism and delayed puberty.
Hypergonadotropic hypogonadism
Gonadal dysgenesis is the
most common cause of hypergonadotropic hypogonadism. Primary gonadal failure
results in decreased or absent gonadal steroid secretion. Lack of adequate
circulating estrogen or androgen reduces negative feedback actions of the
hypothalamus on pituitary gland resulting in elevated FSH and LH secretion.
Klinefelter syndrome is the most common cause of gonadal dysgenesis, occurring in 1 in 500–1000 of all
phenotypic boys. Typical features of the Klinefelter phenotype are a
eunuch-like body habitus, gynecomastia and small testes. The testes of most
patients with Klinefelter syndrome have a distinctly limited capacity to
secrete testosterone. The Leydig cells in the testis do not respond normally to
LH or FSH stimulation; plasma testosterone levels range from 10% of normal in
severely eunuchoid boys to about 50% of normal in those less severely affected.
Estrogen production is also proportionally elevated compared to the amount of
testosterone produced, and gynecomastia is a frequent clinical finding. Boys
with Klinefelter syndrome who have circulating testosterone levels in the low
normal range will demonstrate puberty and normal height. Those with extremely
low circulating testosterone levels will be very tall because of the failure of
the epiphyses to close in a timely fashion. Most men with Klinefelter syndrome
have normal adrenal androgen production; most will have pubic hair, regardless
of circulating testosterone levels.
Boys with Klinefelter syndrome
have a progressive loss of sperma- togenic activity in the testes after
puberty. In normal pubertal boys, about 80% of the seminiferous tubules will
contain spermatogonia. In boys with Klinefelter syndrome, only 20% of tubules
will contain germ cells. This percentage declines as the tubules gradually
sclerose. Adults with Klinefelter syndrome are infertile. Most will require
androgen replacement therapy to obtain or maintain an adult male phenotype.
Ninety per cent of men with
Klinefelter syndrome have a 47XXY karyotype. The other 10% display an
array of extra X chromosome states. Some have a 46XX karyotype with translocation
of the male sex-determining region (SRY) on to the X chromosome (Chapter 5).
Still others carry additional X chromosomal material as a mosaicism.
Klinefelter mosaics account for the largest proportion of affected men who
retain partial testicular function. Fertile 46XY mosaics have been reported.
Turner syndrome is the second most common form of gonadal dysgenesis, occurring in about 1 in 5000 liveborn
girls. Typical features of the Turner phenotype include short stature, short
webbed neck, micrognathia, broad shield-like chest, anomalies of the left side
of the heart (coarctation of the aorta, aortic stenosis, bicuspid aortic valve
and dissecting aortic aneurysms) and renal and gastrointestinal anomalies. The
ovaries of women with Turner syndrome are typically replaced by connective
tissue and are called streak gonads. True streak gonads contain no germ cells
and cannot produce reproductive steroids. The uterus and fallopian tubes are
present in women with Turner syndrome, but they are typically infantile due to
lack of estrogen stimulation. External genitalia and gender orientation are
female.
The karyotype of a woman with
Turner syndrome is typically 45X. Like Klinefelter syndrome, structural
abnormalities of the X chromosome and mosaicism are also common. Mosaicism and
structural abnormalities account for the varied
phenotypes reported with the syndrome, which range from that described here to
both healthy males and females. Of conceptuses with the 45X karyotype, 99%
miscarry. This supports the systemic nature of the abnormalities seen with complete
absence of the second sex chromosome and suggests that most surviving Turner
syndrome women are undiagnosed mosaics.
Patients with Turner syndrome are
usually smaller than average at birth. They grow normally for the first few
years after infancy and then begin to slow. Most fail to demonstrate a pubertal
growth spurt. This characteristic growth defect appears to be related to the
single copy of a gene on the X chromosome known as PHOG or SHOX. PHOG
is a transcription factor expressed in osteoblasts.
Some patients with Turner
syndrome will have complex karyotypes with mosaicism involving the Y
chromosome. The presence of all or part of the Y chromosome may result in
phenotypes with the classic Turner phenotype described but ambiguous genitalia
or normal male external genitalia. Such patients may have gonadal structures
ranging from a streak gonad to a functioning testis. Individuals with a Y cell
line or abnormalities involving the Y chromosome are at an increased risk for
neoplastic transformation in their gonads. Gonadectomy should be performed at
the time of diagnosis.
Genetic disorders of steroidogenesis can cause delayed puberty. They are a large group of rare disorders that
cause hypergonadotropic hypogonadism. Because most of these autosomal recessive
disorders also affect adrenal steroid biosynthesis, they are more commonly
known as the congenital adrenal hyperplasia (CAH) syndromes. The CAH
syndromes associated with delayed puberty are listed in Table 29.1. All these
enzyme defects occur in the steroidogenic pathway
between cholesterol and testosterone.
