This chapter deals primarily with APGO Educational Topic Area:
TOPIC 42 PUBERTY
Students should be able to describe the normal endocrinologic changes and normal sequence of events in puberty and identify any deviations. They should be able to outline a basic approach to evaluating the patient with precocious puberty and delayed puberty. They should discuss the complex psychological issues associated with puberty and abnormal puberty.
Clinical Case
A 15-year-old girl is brought in by her mother because she has not yet started to menstruate. She is tall for her age but otherwise of normal body habitus. She had a growth spurt that began when she was about age 12 years and began breast development at age 13 years. Physical examination finds Tanner stage 3 breast development and stage 3–4 pubic hair. She shaves her underarms.
Puberty is an endocrine process that involves the physical, emotional, and sexual transition from childhood to adulthood. It occurs gradually in a series of well-defined events and milestones. When puberty is early or delayed, an understanding of the hormonal events of puberty and the sequence of physical changes is essential to diagnosis of a potential problem. Knowledge of the events of puberty is also key to understanding the process of reproduction.
NORMAL PUBERTAL DEVELOPMENT
A series of endocrine events initiate the onset of sexual maturation. The hypothalamic–pituitary–gonadal axis begins to function during fetal life and remains active during the first few weeks following birth, after which time the axis becomes quiescent secondary to enhanced negative feedback of estrogen. The hypothalamic–pituitary– gonadal axis again becomes active during puberty, triggering the production of gonadotropin-releasing hormone (GnRH). The gonadotropins control the production of sex steroids from the ovary, and higher levels cause the physical changes of puberty. At approximately age 6 to 8 years, adrenarche, the increase in production of androgens, occurs in the adrenal glands. Adrenarche involves the increased production of dehydroepiandrosterone, which can be converted to more potent androgens (testosterone and dihydrotestosterone).
The process of sexual maturation requires approximately 4 years. It takes place in an orderly, predictable sequence that includes growth acceleration, breast development (thelarche), pubic hair development (pubarche), maximum growth rate, menarche, and ovulation. The initial event is accelerated growth; however, this may be subtle, and breast budding is easier to detect as the first event. The sequence of breast development and pubic hair growth is quantified by the Tanner classification of sexual maturity (Fig. 38.1).
The ages at which some of these events occur are presented in Table 38.1. There is a strong relationship between body fat content and the onset of puberty. Mild to moderate obesity results in earlier puberty, whereas thinness results in later puberty. The onset of puberty is also marked by significant ethnic differences. Puberty usually begins earlier in African American and Mexican American girls than in white girls, and much of this difference may result from differences in body mass index (BMI; Table 38.1). In contrast, puberty tends to begin in Asian American girls later than in white girls. BMI may account for most of this difference, although as yet undefined genetic or environmental factors may also be important.
ABNORMALITIES OF PUBERTAL DEVELOPMENT
The abnormalities of puberty include precocious puberty, primary amenorrhea, delayed sexual maturation, and incomplete sexual maturation.
The presence of any of these disorders requires investigation of both the hypothalamic–pituitary–gonadal axis and the reproductive outflow tract. The initial evaluation should begin with the measurement of pituitary gonadotropin (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) levels, which helps distinguish a hypothalamic–pituitary etiology from a gonadal etiology.
FIGURE 38.1. Tanner staging of breast and pubic hair development, which includes five stages. (From the American College of Obstetricians and Gynecologists. Precis: An Update in Obstetrics and Gynecology: Reproductive Endocrinology. 3rd ed. Washington, DC: American College of Obstetricians and Gynecologists; 2007; modified from Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.)
Precocious Puberty
Precocious puberty is the onset of secondary sexual characteristics prior to the age of 6 years in African American girls and 7 years in white girls. Precocious puberty is caused by either GnRH-dependent or GnRH-independent sex hormone production (Box 38.1). GnRH-dependent or true (central) precocious puberty develops secondary to the early activation of the hypothalamic–pituitary–gonadal axis. The most common causes are idiopathic; other causes include infection, inflammation, and injury of the central nervous system. In idiopathic precocious puberty, the arcuate nucleus in the hypothalamus is prematurely activated. This causes early sexual maturation with early reproductive capability. The elevated estrogen levels produced affect the skeleton, resulting in short stature in adulthood secondary to premature closure of the epiphyseal plates. These individuals are at risk for early sexual activity and potential sexual abuse and may have psychosocial problems related to their early sexual development. Occasionally, GnRH-dependent precocious puberty results from neoplasms of the hypothalamic–pituitary stalk. In this situation, although sexual development begins early, the rate of sexual development is slower than usual. Transient inflammatory conditions of the hypothalamus may also result in GnRH-dependent precocious puberty; however, sexual development may begin and end abruptly. Laboratory studies show either an appropriate rise in gonadotropins or a steady gonadotropin level in the prepubertal range.
GnRH-independent sex hormone production, or precocious pseudopuberty (peripheral), results from sex hormone production (androgens or estrogens) independent of hypothalamic–pituitary stimulation. Ovarian cysts and tumors, McCune-Albright syndrome, adrenal tumors, and iatrogenic causes including hormone and alternative medicine ingestion can cause this condition. Some tumors, such as granulosa cell tumors, teratoma, and dysgerminomas, directly secrete sex hormones. Physical examination usually reveals a palpable pelvic mass and leads to further evaluation/imaging studies.
BOX 38.1 Causes of Precocious Sexual Development
Gonadotropin-Releasing Hormone–Dependent (Central) Causes
Idiopathic Origin
• Central nervous system tumors
• Hypothalamic hamartoma
• Craniopharyngiomata
• Gliomata
• Metastatic
• Arachnoid or suprasellar cysts
Central Nervous System Infection/Inflammation
• Encephalitis
• Meningitis
• Granulomata
Central Nervous System Injury
• Irradiation
• Trauma
• Hydrocephalus
Gonadotropin-Releasing Hormone–Independent (Peripheral) Causes
Exogenous Sex Steroid Administration
Primary Hypothyroidism
Ovarian Tumors
• Granulosa–theca cell
• Lipoid cell
• Gonadoblastoma
• Cystadenoma
• Germ cell
Simple Ovarian Cyst
Mccune-Albright Syndrome
Incomplete Precocious Sexual Development Premature Thelarche
• Nonprogressive, idiopathic
• Progresses to precocious puberty
Premature Adrenarche
• Idiopathic
• Congenital adrenal hyperplasia
• Precursor to polycystic ovary syndrome
• Adrenal or ovarian tumor (rare)
McCune-Albright syndrome (polyostotic fibrous dysplasia) is characterized by multiple bone fractures, café-au-lait spots, and precocious puberty. Premature menarche can be the first sign of the syndrome. The syndrome is thought to result from a defect in cellular regulation with a mutation in the α-subunit of the G protein that stimulates cyclic adenosine triphosphate formation, which causes affected tissues to function autonomously. This mutation causes the ovary to produce estrogen without the need for FSH stimulation, resulting in sexual precocity independent of the pituitary and hypothalamus.
Adrenal causes of precocious puberty include adrenal tumors and enzyme-secreting defects such as congenital adrenal hyperplasia (CAH). Tumors are very rare and must secrete estrogen to cause early sexual maturation. The most common form of CAH, 21-hydroxylase deficiency, presents at birth with the finding of ambiguous genitalia. However, the nonclassical form, previously known as late-onset CAH, tends to present at adolescence. In this disorder, the adrenal glands are unable to produce adequate amounts of cortisol as a result of a partial block in the conversion of 17-hydroxyprogesterone to deoxycortisol. Deficiency of the 21-hydroxylase enzyme leads to a shunting away from aldosterone and cortisol production in cholesterol biosynthesis toward the production of sex hormones, which results in precocious adrenarche. A pathognomonic finding for 21-hydroxylase deficiency is an elevated 17-hydroxyprogesterone level. Plasma renin is also measured to determine the amount of mineralocorticoid deficiency. Medical therapy is instituted as early as possible and is aimed at steroid/mineralocorticoid replacement, depending on the severity of the deficiency. In the nonclassical form of CAH, patients present with premature adrenarche, anovulation, and hyperandrogenism, appearing somewhat like patients with polycystic ovarian syndrome.
Iatrogenic causes, such as drug ingestion, must be considered in all children who present with precocious puberty. These children may exhibit increased pigmentation of the nipples and areola of the breast secondary to ingestion of oral contraceptives, anabolic steroids, and hair or facial creams. Many herbal or alternative medications carry unanticipated estrogenic effects.
Treatment
The main goals of treatment of precocious puberty are to arrest and diminish sexual maturation until a normal pubertal age as well as to maximize adult height. Therapy for GnRH-dependent precocious puberty involves administration of a GnRH agonist. Results occur rapidly and continue during the first year of treatment. Treatment for GnRH-independent precocious puberty attempts to suppress gonadal steroidogenesis.
Delayed Puberty
There is wide variation in normal pubertal development. However, puberty is considered delayed when secondary sex characteristics have not appeared by the age of 13 years, there is no evidence of menarche by age 15 to 16 years, or when menses have not begun 5 years after the onset of thelarche. These findings should prompt the physician to initiate a workup to determine the cause of the delay. The most common causes of delayed puberty are shown in Box 38.2.
BOX 38.2 Causes of Delayed Puberty
Hypergonadotropic Hypogonadism (follicle-stimulating hormone [FSH] > 30 miU/mL)
• Gonadal dysgenesis (Turner syndrome)
Hypogonadotropic Hypogonadism (FSH + luteinizing hormone < 10 miU/mL)
• Constitutional (physiologic) delay
• Kallmann syndrome
• Anorexia/extreme exercise
• Pituitary tumors/pituitary disorders
• Hyperprolactinemia
• Drug use
Anatomic causes
• Müllerian agenesis
• Imperforate hymen
• Transverse vaginal septum
FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Hypergonadotropic Hypogonadism
The most common cause of delayed puberty with an elevated FSH is gonadal dysgenesis, or Turner syndrome. In this condition, there is an abnormality in, or absence of, one of the X chromosomes in all cell lines (45X,O). Patients have streak gonads, with an absence of ovarian follicles; therefore, gonadal sex hormone production does not occur at puberty. These patients typically have primary amenorrhea, short stature, webbed neck (pterygium colli), shield chest with widely spaced nipples, high-arched palate, and an increased carrying angle of the elbow (cubitus valgus) as shown in Figure 38.2.
FIGURE 38.2. Clinical features of Turner syndrome. In Turner syndrome, there is an abnormality or absence of one of the X chromosomes in all cell lines. Patients have streak gonads with an absence of ovarian follicles and, therefore, no gonadal sex hormone production at puberty. These patients typically present with primary amenorrhea, short stature, webbed neck (pterygium colli), shield chest with widely spaced nipples, high-arched palate, and an increased carrying angle of the elbow (cubitus valgus). (Modified from Rubin R, Strayer DS. Rubin’s Pathology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2008:195.)
Estrogen administration should be initiated at the normal time of initiation of puberty, and growth hormone should be initiated very early (often prior to estrogen therapy) and aggressively to normalize adult height. Estrogen is necessary to stimulate breast development, genital tract maturation, and the beginning of menstruation. Low-dose estrogen is used to initiate secondary sexual maturation, and the dose is increased once breast budding and menarche occur. If an excessive amount of estrogen is administered initially, epiphyseal closure may begin, and long bone growth is truncated and adult height compromised. A delay in estrogen administration can lead to the development of osteoporosis in the teenage years. Progestins should not be given until the patient has reached Tanner stage IV, because premature progestin therapy may prevent the breast from developing completely, thus resulting in an abnormal contour (a more tubular breast).
Hypogonadotropic Hypogonadism
The arcuate nucleus of the hypothalamus secretes GnRH in cyclic bursts (or a pulsatile fashion), which stimulates the release of gonadotropins from the anterior pituitary gland. Dysfunction of the arcuate nucleus disrupts the short hormonal loop between the hypothalamus and pituitary. As a result, FSH and LH secretion does not occur. Consequently, the ovaries are not stimulated to secrete estradiol, and secondary sexual maturation is delayed. The most common cause of this type of delayed puberty is constitutional (physiologic) delay. Other causes include Kallmann syndrome; anorexia, exercise, or stress; pituitary tumors/pituitary disorders; hyperprolactinemia; and drug use.
Constitutional delay of puberty represents approximately 20% of all cases of delayed puberty. It is thought to be a normal variant of the development process and trends can be seen within families. Children with constitutional delay usually have not only delay of secondary sexual maturation but also short stature with an appropriate delay of bone maturation.
Kallmann Syndrome
In Kallmann syndrome, the olfactory tracts are hypoplastic, and the arcuate nucleus does not secrete GnRH. Young women with Kallmann syndrome have little or no sense of smell and do not have breast development. This condition can be diagnosed on initial physical examination by challenging the olfactory function with known odors, such as coffee or rubbing alcohol. Once the condition is recognized and treated, the prognosis for successful secondary sexual maturation and reproduction is excellent. Secondary sexual maturation can be stimulated by the administration of exogenous hormones or by the administration of pulsatile GnRH. Patients typically can have normal reproductive function. Ovulation is induced by the administration of exogenous gonadotropin, and progesterone is given in the luteal phase to allow implantation of the embryo.
Other Causes
Other causes of hypothalamic amenorrhea include weight loss, strenuous exercise (such as vigorous dancing or long-distance running), anorexia nervosa, and bulimia. These conditions all result in suppressed gonadotropin levels with low estrogen levels. The correction of the underlying abnormality (such as weight gain in patients with weight loss) restores normal gonadotropin levels, stimulating ovarian steroidogenesis and the resumption of pubertal development.
Craniopharyngioma is the most common tumor associated with delayed puberty. This tumor develops in the pituitary stalk with suprasellar extension from nests of epithelium derived from Rathke pouch. Magnetic resonance imaging is the recommended modality to locate a (supra) sellar calcified cyst. Calcifications are present in approximately 70% of craniopharyngiomas.
Anatomic Causes
During fetal life, müllerian ducts develop and fuse in the female fetus to form the upper reproductive tract (i.e., the fallopian tubes, uterus, and upper vagina). The lower and midportion of the vagina develop from the canalization of the genital plate (see Chapter 4).
Müllerian Agenesis
Müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome, is the most common cause of primary amenorrhea in women with normal breast development. In this syndrome, there is congenital absence of the vagina and, usually, an absence of the uterus and fallopian tubes. Ovarian function is normal, because the ovaries are not derived from müllerian structures; therefore, all the secondary sexual characteristics of puberty occur at the appropriate time. Physical examination leads to the diagnosis of müllerian agenesis. Renal anomalies (e.g., reduplication of the ureters, horseshoe kidney, and unilateral renal agenesis) occur in 40% to 50% of cases. Skeletal anomalies such as scoliosis occur in 10% to 15% of cases. Mayer-Rokitansky-Küster-Hauser syndrome is generally sporadic in expression, although occasional occurrences in families can be seen.
There are several therapeutic approaches to this condition. Nonsurgical approaches should be tried first, using dilators and pressure on the dimple between the urethra and the rectum, twice a day. This tissue is quite pliable and, with increasing dilator size, a normal length vagina can be achieved. An artificial vagina may be created by repetitive pressure by vaginal dilators on the perineum or by surgical construction followed by a split thickness skin graft. After creation of a vagina, these women are able to have sexual intercourse. With the advances in assisted reproductive technologies, including in vitro fertilization and use of a surrogate mother (gestational carrier), it is possible for a woman with this condition to have a genetic child by using her oocytes.
Imperforate Hymen
The simplest genital tract anomaly is imperforate hymen. In this condition, the genital plate canalization is incomplete, and the hymen is, therefore, closed. Menarche occurs at the appropriate time, but, because there is obstruction to the passage of menstrual blood, it is not apparent. This condition presents with pain in the area of the uterus and a bulging, bluish-appearing vaginal introitus. Hymenotomy is the definitive therapy. This condition may be confused with a transverse vaginal septum. Transverse vaginal septa can occur along the vagina at any level and result in obstruction to outflow of menses. A vaginal septum can be resected and primarily repaired via a procedure called a Z-vaginoplasty. Prolonged obstruction to menstruation can be associated with an increased incidence of endometriosis.
Clinical Follow-Up
Although this girl is behind her peers in pubertal development, her sequence and stage seem appropriate, and menses should be anticipated at any time. A diagnosis of delayed puberty would not normally be assigned unless she fails to menstruate 5 years after the onset of thelarche.
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