Gonadal Dysgenesis

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Chapter 167 Gonadal Dysgenesis

INTRODUCTION

Description: Gonadal dysgenesis is a developmental abnormality of patients who do not carry the stigmata of Turner’s syndrome but still have absent menarche because of chromosomal abnormalities. These patients generally are tall (>150 cm), are more normal in appearance, and are a chromosomally heterogeneous group (46,XX, 46,XY, or mosaic X/XY karyotypes).
Prevalence: Appears in 1 of 2500 female births.
Predominant Age: Present at birth, may not be detected until puberty is delayed.
Genetics: Sporadic, loss of part or all of one X chromosome (amenorrhea more common with long arm loss; short stature with short arm loss).

ETIOLOGY AND PATHOGENESIS

Causes: Pure gonadal dysgenesis—45,XO (Turner’s syndrome); 46,XY gonadal dysgenesis (Swyer syndrome); 46,XX q5 X chromosome long-arm deletion, mixed or mosaic.
Risk Factors: Translocations involving the X chromosome (rare).

CLINICAL CHARACTERISTICS

Signs and Symptoms

(Based on the amount of chromatin lost.)

• Primary amenorrhea and infertility (the most common cause of failure to begin menstruation is gonadal dysgenesis; in approximately 60% of women with primary amenorrhea, an abnormality of gonadal differentiation or function has occurred during the fetal or neonatal period)
• Absent or grossly abnormal gonad development

DIAGNOSTIC APPROACH

Differential Diagnosis

• Polycystic ovary syndrome
• Hypothyroidism
• Growth hormone deficiency or glucocorticoid excess
• Androgen insensitivity syndrome (male pseudohermaphroditism, testicular feminization)
• Intersex abnormality
• Enzymatic defects (such as 17α-hydroxylase deficiency)
• Structural genital tract abnormalities (uterine and/or vaginal agenesis or an imperforate hymen)
• Ovarian insensitivity syndrome (resistant ovary [Savage’s] syndrome)
• Follicular depletion (autoimmune disease, infection [mumps], infiltrative disease processes [tuberculosis, galactosemia])

Associated Conditions: Amenorrhea, infertility, incomplete or abnormal external genitalia, and premature menopause.

Workup and Evaluation

Laboratory: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are high (nonspecific). (Follicle-stimulating hormone is usually elevated in gonadal dysgenesis.) Assessment of thyroid function, prolactin, or growth hormone if indicated by the differential diagnosis being considered.
Imaging: Pelvic ultrasound studies to evaluate the presence and condition of upper genital tract organs.
Special Tests: Karyotype.
Diagnostic Procedures: History, physical examination, karyotyping.

Pathologic Findings

Abnormal karyotype. Germ cell involution occurs soon after they migrate into the undifferentiated gonad. This results in fibrous streak gonads that are hormonally inactive.

MANAGEMENT AND THERAPY

Nonpharmacologic

General Measures: Evaluation, screening for associated defects, counseling about menstrual and fertility issues.
Specific Measures: Hormone replacement therapy. When there is a mosaicism involving a Y chromosome, surgical extirpation of the gonads must be performed because of a 25% to 30% risk of malignant gonadal tumors. Timing of gonadal removal in patients with a Y chromosome is controversial: removal as soon as the diagnosis is made versus delaying removal until pubertal changes are complete.
Diet: No specific dietary changes indicated.
Activity: No restriction.
Patient Education: Extensive counseling about sexual maturation and fertility.

Drug(s) of Choice

Adolescents are much more sensitive to the effects of estrogen than are postmenopausal women, allowing doses in the range of 0.3 mg of conjugated estrogen, 0.5 mg of estradiol, or their equivalent, daily. After 6 to 12 months of therapy at this level, the dose should be doubled and a progestin (e.g., medroxyprogesterone acetate, 10 mg for the first 12 days of the month) should be added, or the patient’s treatment should be switched to combination oral contraceptives. This generally results in regular menstruation, and normal pubertal development proceeds on its own when the patient reaches a bone age of 13.
Contraindications: Undiagnosed amenorrhea.

FOLLOW-UP

Patient Monitoring: Normal health maintenance.
Prevention/Avoidance: Prenatal chromosomal analysis for those known to carry translocations (detection only, not prevention, although the couple may choose not to continue the pregnancy based on the findings).
Possible Complications: Gonadal malignancy or virilization in those with Y chromatin present. Others based on cause.

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Expected Outcome: Reasonably normal lives with the exception of fertility.

MISCELLANEOUS

Pregnancy Considerations: These patients may be infertile. In pure gonadal dysgenesis and XX/XY mosaicism, a uterus is present. Consequently, some patients may achieve pregnancy. Pregnancy is associated with a 50% chance of aneuploidy.
ICD-9-CM Codes: 752.0.

REFERENCES

Level II

Gravholt CH, Fedder J, Naeraa RW, Muller J. Occurrence of gonado-blastoma in females with Turner syndrome and Y chromosome material: a population study. J Clin Endocrinol Metab. 2000;85:3199.

Ogata T, Muroya K, Matsuo N, et al. Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. J Clin Endocrinol Metab. 2001;86:5498.

Level III

American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. ACOG Committee Opinion 349. Obstet Gynecol. 2006;108:1323.

American College of Obstetricians and Gynecologists. Vaginal agenesis: diagnosis, management, and routine care. ACOG Committee Opinion 355. Obstet Gynecol. 2006;108:1605.

Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92:10. Epub 2006 Oct 17

Federman DD. Disorders of sexual development. N Engl J Med. 1967;277:351.

Hall JG, Gilchrist DM. Turner syndrome and its variants. Pediatr Clin North Am. 1990;37:1421.

Lobo RA. Primary and secondary amenorrhea and precocious puberty. In: Katz VL, Lentz GM, Lobo RA, Gershenson DM, editors. Comprehensive Gynecology. 5th ed. Philadelphia: Mosby/Elsevier; 2007:937.

Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73:1374.

Park SY, Jameson JL. Minireview: transcriptional regulation of gonadal development and differentiation. Endocrinology. 2005;146:1035. Epub 2004 Dec 16

Pletcher JR, Slap GB. Menstrual disorders. Amenorrhea. Pediatr Clin North Am. 1999;46:505.

Ranke MB, Saenger P. Turner’s syndrome. Lancet. 2001;358:309.

Saenger P. Turner’s syndrome. N Engl J Med. 1996;335:1749.

Styne DM, Kaplan SL. Normal and abnormal puberty in the female. Pediatr Clin North Am. 1979;26:123.

Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med. 2004;351:1227.

van Niekerk WA. Chromosomes and the gynecologist. Am J Obstet Gynecol. 1978;130:862.

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