Pubertal Delay, Gonadal Dysgenesis Case File

Pubertal Delay, Gonadal Dysgenesis Case File

Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

CASE 54

A 16-year-old adolescent female is referred for never having menstruated. She is otherwise in good health. She has an older sister who experienced menarche at the age of 12 years. She denies excessive exercise or having an eating aversion. There is no family history of depression. On examination, she is 50 in tall and weighs 100 lb. The neck is supple and without masses. Her breasts appear to be Tanner stage I, and her pubic hair pattern is also consistent with Tanner stage I. Abdominal examination reveals no masses. The external genitalia are normal for a prepubescent female. A normal-appearing small cervix is seen on speculum examination. On bimanual examination, a small uterus and no adnexal masses are palpated.

» What is the most likely diagnosis?

» What is the next step in diagnosis?

ANSWER TO CASE 54:

Pubertal Delay, Gonadal Dysgenesis                              

Summary: A healthy 16-year-old adolescent woman is referred for never having menstruated. She denies excessive exercise or an eating aversion. On examination, she is 50 in tall and weighs 100 lb. The neck is supple and without masses. Her breasts and pubic hair are both Tanner stage I. The abdominal examination reveals no masses. The pelvic examination is consistent with a prepubescent woman.

• Most likely diagnosis: Gonadal dysgenesis (Turner syndrome).
• Next step in diagnosis: Serum follicle-stimulating hormone (FSH).

ANALYSIS

Objectives

1. Know that the absence of secondary sexual characteristics by the age of 14 years constitutes delayed puberty.
2. Know that the most common cause of sexually infantile delayed puberty, gonadal dysgenesis, is usually associated with a chromosomal abnormality.
3. Understand that the FSH level can help determine whether the delayed puberty is due to a central nervous system (CNS) problem or an ovarian problem.
4. Know that the definition of precocious puberty is the onset of secondary sexual characteristics > 2 standard deviations from the mean (age 7 years in Caucasian women and 6 years in African-American women).
5. Know that the most common cause of precocious puberty in women is idiopathic and treated with gonadotropin-releasing hormone agonist.

Considerations

This 16-year-old adolescent woman has never menstruated and, therefore, has primary amenorrhea. Furthermore, she has not yet experienced breast development (which should occur by an age of 14 years) and thus has delayed puberty. The lack of breast development means a lack of estrogen, which may be caused by either a central nervous system problem (low gonadotropin levels) or an ovarian problem (elevated gonadotropins). She is also of short stature, confirming the lack of estrogen. The absent pubic and axillary hair are consistent with delayed puberty. The most likely diagnosis without further information would be gonadal dysgenesis, such as Turner syndrome. An elevated FSH level would be confirmatory.

APPROACH TO:

Pubertal Delay                                              

DEFINITIONS

DELAYED PUBERTY: Lack of secondary sexual characteristics by the age of 14 years.

GONADAL DYSGENESIS: Failure of development of gonads (ovaries or testes), usually associated with a karyotypic abnormality (such as 45,X) and often associated with streaked gonads. Less commonly, the karyotype may be 46,XX or 46,XY.

CLINICAL APPROACH

Delayed Puberty

Maturation of the hypothalamic– pituitary– ovarian axis leads to the onset of puberty. There are four stages of pubertal development: (1) thelarche, (2) pubarche/ adrenarche, (3) growth spurt, and (4) menarche. The first sign of puberty is the appearance of breast budding (thelarche), which occurs at a mean age of 10.8 years. This is followed by the appearance of pubic and axillary hair (pubarche/ adrenarche), usually at 11 years. The growth spurt typically occurs 1 year after thelarche. The onset of menses (menarche) is the final event of puberty, occurring approximately 2.3 years after thelarche, at a mean age of 12.9 years. Normal puberty takes place between the ages of 8 and 14 years, with an average duration of 4.5 years. Delayed puberty is the absence of secondary sexual characteristics by the age of 14 years.

Thelarche → Adrenarche→ Growth spurt → Menarche

Breast bud → Axillary and pubic hair → Menses

    Delayed puberty can be subdivided on the basis of two factors: the gonadotropic and the gonadal state. The FSH level defines the gonadotropic state. The ovarian production of estrogen refers to the gonadal state. The FSH level differentiates between brain and ovarian causes of delayed puberty. Central nervous system defects result in low FSH levels secondary to disruption of the hypothalamic– pituitary axis. With ovarian failure, the negative feedback of estrogen on the properly functioning hypothalamic– pituitary axis is not present, resulting in high FSH levels.

    Hypergonadotropic hypogonadism (high FSH, low estrogen) is due to gonadal deficiency. The most common cause of this type of delayed puberty is Turner syndrome. These individuals have an abnormality in, or the absence of one of the X chromosomes leading to gonadal dysgenesis and a 45,X karyotype. They do not have true ovaries, but rather a fibrous band of tissue referred to as gonadal streaks. Thus, they lack ovarian estrogen production and, as a result, secondary sexual characteristics. The internal and external genitalia are that of a normal woman, but remain infantile even into adult life. Other characteristic physical findings are short stature, webbed neck, low set ears and posterior hairline, widely spaced nipples or “shield chest,” and increased carrying angle at the elbow. Turner syndrome should be suspected in an individual who presents with primary amenorrhea, prepubescent secondary sexual characteristics, and sexually infantile external genitalia. The definitive diagnosis can be made with an elevated FSH level and a karyotypic evaluation. Occasionally, the karyotype with gonadal dysgenesis may be 46,XX or 46,XY. When affected with 46,XY, the gonads should be removed surgically to avoid neoplastic changes. Other causes of hypergonadotropic hypogonadism are ovarian damage due to exposure to ionizing radiation, chemotherapy, inflammation, or torsion.

    Hypogonadotropic hypogonadism (low FSH and low estrogen) is usually secondary to a central defect. Hypothalamic dysfunction may occur due to poor nutrition or eating disorders (anorexia nervosa and bulimia), extremes in exercise, and chronic illness or stress. Other causes are primary hypothyroidism, Cushing syndrome, pituitary adenomas, and craniopharyngiomas (the most commonly associated neoplasm). Kallmann syndrome (absence of gonadotropin releasing hormone [GnRH]-releasing neurons in the hypothalamus) is another rare cause of hypogonadotropic hypogonadism.

    The diagnostic approach to delayed puberty begins with a meticulous history and physical examination. The history should query chronic illnesses, exercise and eating habits, and age of menarche of the patient’s sisters and mother. The physical examination should search for signs of chronic illness, such as a goiter, or neurologic deficits, such as visual field defects indicative of cranial neoplasms. Skull imaging should be obtained to look for intracranial lesions. The laboratory evaluation should include serum measurements of FSH, estradiol, prolactin, TSH, free T4, and appropriate adrenal steroids. A karyotype evaluation should be performed when the FSH level is elevated.

    The management goals for those with delayed puberty are to initiate and sustain sexual maturation, prevent osteoporosis from hypoestrogenemia, and promote the full height potential. Hormonal therapy and human growth hormone can be used to achieve these objectives. Patients with hypergonadotropic hypogonadism presenting with delayed puberty should be started on unopposed estrogen for 2 to 3 years before a progestin is added. They are started on low-dose estrogen and then gradually increased every 3 months. Estrogen will promote growth of the long bones and development of the breasts. Exposure to progestins during the first 2 to 3 years of estrogen therapy would lead to abnormal development of the breasts (tubular breast formation). Once the breasts are formed and are at Tanner stage 3 or 4, a progestin is added. Combination of oral contraceptives provides the adequate amount of estrogen needed to prevent osteoporosis, and the progestin protects against endometrial cancer.

    Patients with hypogonadotropic hypogonadism with no apparent cause need imaging of the brain to rule out a brain tumor. If a cause is identified (hyperprolactinemia, hypothyroidism, behavioral), therapy is tailored to correct the underlying cause. In non-treatable conditions such as gonadal dysgenesis, estrogen replacement is started then followed with combination estrogen/ progestin therapy.

Precocious Puberty

On the other end of the spectrum, girls who develop secondary sexual characteristics too early are said to have precocious puberty. In general, the definition is breast development prior to age 7, and in African-American women, prior to age 6. The most common cause of female precocious puberty is idiopathic, with the GnRH pulse generator initiating early without anatomical pathology. This is a diagnosis of exclusion. Serum FSH, luteinizing hormone (LH), and estradiol levels help to distinguish central (brain causes) versus peripheral causes. FSH and LH levels that are barely detectable are consistent with a peripheral cause, whereas FSH and LH levels in the reproductive range would suggest a central cause. Central causes can include brain tumors, meningitis, hydrocephalus, or head trauma. Peripheral causes can include granulosa cell tumors of the ovary, McCune-Albright syndrome, or adrenal tumors. Peripheral precocious puberty usually presents at an early age (< 4 years). If precocious puberty is untreated, the girl will be taller than her peers initially, but due to early long bone epiphyseal closure, the eventual height will be shorter. Central precocious puberty is treated with GnRH agonists.

COMPREHENSION QUESTIONS

54.1 A 15-year-old adolescent female is diagnosed with gonadal dysgenesis on the basis of delayed puberty, short stature, and elevated gonadotropin levels. Which of the following is generally present?

A. Secondary amenorrhea

B. 69,XXY karyotype

C. Tanner stage IV breast development

D. Osteoporosis

E. Polycystic ovaries

54.2 A 16-year-old adolescent female is brought into the pediatrician’s office due to no breast development. The patient’s mother notes that both of patient’s sisters had onset of breast development at age 10, and also all of her friends have already begun menstruating. Examination reveals Tanner stage I breast and pubic/ axillary hair, and is otherwise unremarkable. Which of the following is the most likely diagnosis?

A. Delayed puberty

B. Development is within normal limits and should be observed

C. Primary amenorrhea

D. Likely craniopharyngioma

54.3 A 16-year-old adolescent female is evaluated for lack of pubertal development. She is diagnosed with gonadal dysgenesis. Which of the following laboratory findings is likely to be elevated in this patient?

A. Follicle-stimulating hormone levels

B. Estrogen levels

C. Progesterone levels

D. Prolactin levels

E. Thyroxine levels

54.4 A 20-year-old individual with a 46,XY karyotype is noted to be a sexually infantile phenotypic woman and is diagnosed as having gonadal dysgenesis. Which of the following is the most important treatment for this patient?

A. Progestin therapy to reduce osteoporosis

B. Estrogen and androgen therapy to enhance height

C. Progesterone therapy to prevent endometrial cancer

D. Gonadectomy

E. Estrogen therapy to initiate breast development

54.5 A 6-year-old Caucasian girl is noted to have Tanner 3 breast development and menses. Which of the following is the probable treatment for this patient?

A. Adrenal tumor excision

B. Brain tumor excision

C. GnRH agonist therapy

D. Replacement of thyroid hormone

ANSWERS

54.1 D. Breast tissue usually is infantile (Tanner stage I) with gonadal dysgenesis because no estrogen is produced; these patients are at risk for osteoporosis. Breast tissue is a reflection of endogenous estrogen. They have primary amenorrhea, and usually a 45,X karyotype. They have streak ovaries, and not polycystic ovaries (PCOS). PCOS is a condition in which there is unopposed estrogen, high levels of circulating androgens, and normal timing of puberty onset.

54.2 A. Delayed puberty is defined as no secondary sexual characteristics by the age of 14 years. Primary amenorrhea is defined as no menarche by the age of 16 years in the presence of secondary sexual characteristics, or age 14 in the absence of secondary sexual characteristics . This patient has primary amenorrhea. Her work-up would include TSH, prolactin, FSH and estradiol levels. If estradiol is low and FSH is high, karyotype is needed. If Estradiol and FSH are both low, then a hypothalamic or pituitary cause must be considered (MRI will be needed).

54.3 A. With gonadal dysgenesis, the FSH level is elevated. This distinguishes ovarian failure from a central nervous system dysfunction (central defect). The FSH level determines the gonadotropic state, and the ovarian estradiol level dictates the gonadal state. Estrogen and progesterone levels are low; the prolactin, and thyroxin levels remain unchanged.

54.4 D. The Y chromosome predisposes intra-abdominal gonads to malignancy. Even a mosaic karyotype, such as 46,XX/ 46,XY, would predispose to gonadal malignancy. Had the patient had a karyotype similar to that in Turner syndrome (45,X), another gonadal dysgenesis disorder, a gonadectomy on the streak ovaries, would not be indicated.

54.5 C. The most common cause of female precocious puberty is idiopathic. The treatment is GnRH-agonist therapy. The patient should have an evaluation such as FSH and LH levels to determine central versus peripheral causes. If the FSH and LH are consistent with a central (brain) etiology, then the brain is imaged to assess for central nervous system etiologies. Bone age and assessment of thyroid function tests are also important. Interestingly, only hypothyroidism causes precocious puberty with delayed bone age. All other etiologies of precocious puberty are associated with accelerated bone age (bone age “older” than chronological age).

    CLINICAL PEARLS    

» The most common cause of sexually infantile primary amenorrhea is gonadal dysgenesis. » The most common karyotype associated with gonadal dysgenesis is 45,X, although 46,XX or 46,XY may be seen. » Delayed puberty is defined as no development of secondary sexual characteristics by the age of 14 years. » The FSH level distinguishes ovarian failure from central nervous system dysfunction. » The FSH level determines the gonadotropic state, and the ovarian estradiol level dictates the gonadal state. » The most important initial test for primary amenorrhea with normal breast development is a pregnancy test. » The most common cause of precocious puberty in women is idiopathic, which is a central cause, and a diagnosis of exclusion. » The treatment of central precocious puberty is GnRH-agonist therapy.

REFERENCES

De Ugarte CM, Buyalos RP, Laufer LR. Puberty and disorders of pubertal development. In: Hacker NF, Moore JG, Gambone JC, eds. Essentials of Obstetrics and Gynecology. 6th ed. Philadelphia, PA: Saunders; 2015:386-397. 

Fritz MA, Speroff L. Normal and abnormal growth and puberty. In: Fritz MA, Speroof L. Clinical Gynecology and Infertility. 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2012:391-410. 

Pisarska MD, Alexander CJ, Azziz R, Buyalos RP. Puberty and disorders of pubertal development. In: Hacker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 6th ed. Philadelphia, PA: Saunders; 2015:345-354.

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