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.
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.
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.