10th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology
Puberty : Pathology
Jean-Michel Dubuis
Division d'Endocrinologie et Diabétologie Pédiatriques Hôpital des Enfants H.U.G. Genève
- Constitutional Delay in Growth and Puberty
- Hypogonadotropic Hypogonadism
- Hypergonadotropic Hypogonadism
- Differential Diagnosis of Delayed Puberty
- Treatment of Delayed Puberty
- Idiopathic Precocious Puberty
- Incomplete GnRH-Independent or Pseudoprecocious Puberty
- Evaluation of Sexual Precocity
- Treatment of Sexual Precocity
A number of intrinsic and environmental factors may influence the timing of puberty. Chronic illness, psychological deprivation, sustained child abuse, and prolonged psychosocial and physical stress including intensive competitive training and exercise may all delay puberty. In contrast, central nervous system disease may accelerate its onset.
Puberty is delayed when there is no sign of pubertal development by the age 13 years in girls and 14 years in boys.
Patients who have a delayed bone age but who have always grown at the normal rate for their bone age would be expected to have a delayed onset of pubertal development. This is a variation of normal and is often familial. Puberty usually begins by the time the bone age reaches 12 years of age in boys and 11 years in girls.
HYPOGONADOTROPIC HYPOGONADISM
Patients with hypogonadotropic hypogonadism have eunuchoid proportions because their long bones grow for a longer than normal period of time, producing an upper-to-lower ratio below 0.9.
If there is an inability to release gonadotropins, but no other pituitary abnormality, the patient has isolated gonadotropin deficiency. Patients grow normally until the time of the pubertal growth spurt, when they do not accelerate growth. Patients may have associated midline defects, such as cleft palate or optic hypoplasia.
Kallmann Syndrome combines isolated gonadotropin deficiency with abnormal olfaction. There is genetic heterogeneity ; some patients have a decreased sense of smell, others have abnormal reproduction, and some have both.
Central nervous system (CNS) tumors are a serious cause of gonadotropin deficiency (craniopharyngiomas, germinomas,...) Craniopharyngiomas, tumors of Rathke pouch, have a peak incidence in the teenage years and may lead to any type of anterior or posterior hormone deficiency. These tumors may descend into the sella turcica, causing erosion ans calcification and destroying pituitary and hypothalamic cells.
Congenital absence of various combinations of pituitary hormones may produce idiopathic hypopituitarism. Inheritance may be X-linked or autosomal recessive ; sporadic types of congenital idiopathic hypopituitarism are more common. Congenital hypopituitarism may be manifested in a male with GH deficiency and/or associated gonadotropin deficiency with a microphallus. The current absence of GH and ACTH may lead to hypoglycemia from decreased gluconeogenesis.
Weight loss resulting from voluntary dieting, malnutrition, or chronic disease will lead to decreased gonadotropin function when weight falls below 80% of ideal weight. Anorexia nervosa is characterized by striking weight loss. Primary or secondary amenorrhea is frequently found in affected girls, and pubertal development is absent or minimal, depending on the level of weight loss. Regaining weight reverses the condition. Increased physical activity even without weight loss can lead to decreased menstrual frequency and gonadotropin deficiency. When physical activity is interrupted, menstrual function may return. Hypothyroidism inhibits the onset of puberty and delays menstrual periods.
Patients with hypergonadotropic hypogonadism have elevated gonadotropins resulting from primary gonadal failure.
Klinefelter Syndrome (seminiferous tubular dysgenesis) is the most common cause of testicular failure. The incidence is approximately 1/1000 in live male infants. The typical karyotype is 47,XXY but Klinefelter syndrome has occured with multiple X chromosomes and one (or two) Y chromosomes. Infants and prepubertal boys are not identified owing to the absence of recognizable clinical features. Testosterone levels may be close to normal because Leydig cell function may be spared, but seminiferous tubular function is characteristically lost, causing infertility. The age of the onset of puberty is usually normal but secondary sexual changes may not progress because of inadequate Leydig cell function.
Patients with variants of Turner syndrome, gonadal dysgenesis, galactosemia, or following radiation therapy may have ovarian failure.
Turner syndrome is a common cause of ovarian failure. The incidence of this syndrome is 1/2000-5000 births. This syndrome is associated with functional monosomy for the short arm (p) of the X chromosome. The most common karyotype in Turner syndrome is 45,X with the second sex chromosome missing, but many affected females are mosaics. 45,X/46,XX is the most common mosaic, but 45,X/47,XXX and 45,X/46,XY also have been observed. Some females with Turner syndrome do have two X chromosomes, but in these instances one X has a missing p arm.
The gonads are present at birth and appropriately infantile ; during childhood they often regress and may be absent at puberty. The main clinical manifestations of Turner syndrome are short stature, sexual infantilism, and the consequences of congenital anomalies (increased incidence of bicuspid aortic valve and coarctation of the aorta ; horseshoe kidney). Additional features include a low hairline, webbed neck, widely spaced hypoplastic nipples, and cubitus valgus of the elbow.
Once it is determined that no secondary sexual development is present after the upper age limits of normal pubertal development, gonadotropin determinations should be obtained to determine whether the patient has hypogonadotropic or hypergonadotropic hypogonadism. Differentiation between constitutional delay in growth and hypogonadotropic hypogonadism is difficult if no family history for the former or no CNS abnormalities for the latter have been identified. Sometimes, a period of observation for months or years is necessary before the diagnosis is confirmed.
If a permanent condition is apparent, replacement with sex steroids is indicated. Girls are given ethinyl estradiol in daily doses until breakthrough bleeding occurs, at which time cycling is started with a dose being given on the first 21 days of the month ; on days 12-21, a progestational agent is added to mimic a normal menstrual period.
In boys, testosterone enanthate given once every 4 weeks may be started. This regimen is appropriate for patients with hypo- or hypergonadotropic hypogonadism. Boys with hypogonadotropic hypogonadism may receive better virilization if hCG is added to their androgen dose.
Patiens with hypogonadotropic hypogonadism may be able to achieve fertility by the administration of gonadotropin therapy or hypothalamic-releasing hormone therapy.
Precocious puberty is secondary sexual development occuring before the age of 9 years in boys or 8 years in girls. The condition is true precocious puberty or central precocious puberty if it emanates from premature reactivation of the hypothalamic-pituitary-gonadal axis (GnRH dependent), or incomplete precocious puberty or pseudoprecocious puberty if the hypothalamic-pituitary-gonadal axis is not involved (GnRH independent).
Members of some families enter puberty prior to the lower limits of normal (constitutional or familial precocious puberty). In these cases, every aspect of pubertal development is normal but early.
The endocrine changes of puberty, such as increased pulsatile gonadotropin secretion or increase response of LH to GnRH, are the same as in normal puberty. Idiopathic precocious puberty occurs approximately 9 times more often in girls than in boys. Boys have a much higher incidence of CNS disorders such as tumors or hamartomas precipitating precocious puberty.
Optic or hypothalamic gliomas (with or without neurofibromatosis), astrocytomas, and ependymomas also can cause precocious puberty by exerting mass effects on those areas of the CNS that characteristically inhibit pubertal development. Almost any condition that affects the CNS, including hydrocephalus, meningitis, encephalitis, suprasellar cysts, head trauma, and irradiation, has been reported to precipitate central precocious puberty.
Boys may have incomplete precocious puberty as a result of autonomous production of testosterone or other androgens by adrenal glands or testes, or of a tumor that produces hCG, stimulating the production of androgens.
Girls might have precocious puberty as a result of autonomous production of estrogens from the ovaries or adrenal glands.
In boys and girls, pseudoprecocious puberty can be due to an abnormality in the G-protein system, inducing an autonomous function of several endocrine organs, creating the McCune-Albright syndrome. Characteristically these patients have café-au-lait spots, polyostotic fibrous dysplasia of the long bones, and precocious puberty. Other patients may have hyperthyroidism, hyperadrenalism, or acromegaly in addition.
On physical examination, it should be noted whether characteristics of normal puberty are apparent.
In boys it is important to note whether the testes are enlarged over 2.5 cm, suggesting an ectopic production of hCG or central (GnRH-dependent) precocious puberty. If the testes are not enlarged but virilization is progressing, the source of the androgens may be the adrenal glands.
Laboratory examinations include sex steroid and gonadotropin levels, usually in the GnRH-stimulated state. Thyroid hormone determination is useful. If there is a possibility of a CNS anomaly or a tumor (CNS, hepatic, adrenal, ovarian, testis), a CT scan or MRI of the appropriate location is indicated.
Long-acting analogues of GnRH are the treatment of choice for central precocious puberty as they suppress gonadotropin secretion. The early sexual development and height of the patient with precocious puberty requires psychologic counseling for the children and families. In many cases of pseudoprecocious puberty, the removal of the hormone-secreting tumor will be curative.
Boys with GnRH-independent premature Leydig cell and germinal cell maturation cannot be treated with GnRH analogues but require treatment with ketoconazole, spironolactone, or testolactone (all inhibitors of testosterone synthesis or effect).
In girls, medroxyprogesterone acetate, that inhibits the ovarian steroidogenesis and induces regression of cyst by inhibition of FSH relase, and testolactone, that blocks the estrogen synthesis, can be used.
VARIATIONS IN PUBERTAL DEVELOPMENT
This term is used to describe the isolated appearance of unilateral or bilateral breast in girls aged 6 months to 3 years. There are no other signs of puberty and no evidence of excessive estrogen effect (thickening of the vaginal secretions or bone age acceleration). Ingestion or application of estrogen-containing compounds must be excluded as etiology. Laboratory investigations are not usually necessary, but pelvic ultrasound study may be performed to exclude ovarian pathology.
Girls with this condition should be re-evaluated at intervals of 6-12 months to ensure that premaure thelarche is not the beginning of isosexual precocious puberty. The prognosis is excellent, and no treatment other than reassurance is necessary.
Breast enlargement in the male is usually a benign, self-limited condition, noted in 50-60% of boys during early adolescence.
Gynecomastia may be associated with Klinefelter or other syndromes and with certain medications (amphetamines, digitalis, estrogens, opiates, ketoconazole, spironolactone, tricyclic antidepressants, ...). Other etiologies are hormone-secreting tumors, cirrhosis, hypo- and hyperthyroidism. Most of the time reassurance that the condition is self-limited is the only treatment required. If the condition worsens and is associated with psychologic morbidity, pharmacologic treatment with bromocriptine may be used.. Surgical treatment with reduction mammoplasty is rarely indicated.
In girls, the appearance of pubic hair before the age of 8 years is relatively common. The critical issue is whether the pubic hair is associated with any other features of virilization, such as clitoral enlargement, advanced bone age, or other signs of virilization, such as acne, rapid growth, and voice change. With rapid progression of pubic hair, a detailed investigation for the virilizing cause must be undertaken. Measurements of testosterone, 17-OH progesterone and DHEA are indicated. An ultrasound study may reveal a virilizing adrenal or ovarian tumor, whereas the presence of excessive 17-OH progesterone or DHEA will indicate an enzyme defect consistent with congenital adrenal hyperplasia. Most cases of isolated pubic hair, however, do not have these abnormal signs of progressive virilization and reflect a condition known as benign premature pubarche. Premature activation of DHEA-S secretion from the adrenal gland is postulated.
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