Amenorrhea (Primary), Müllerian Agenesis Case File

Amenorrhea (Primary), Müllerian Agenesis Case File

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

CASE 55

An 18-year-old nulliparous adolescent woman complains that she has not yet started menstruating. She denies weight loss or excessive exercise. Each of her sisters achieved menarche by 13 years of age. The patient’s mother recalls a doctor mentioning that her daughter had a missing right kidney on an abdominal x-ray film. On examination, she is 5 ft 6 in tall and weighs 140 lb. Her blood pressure is 110/60 mm Hg. Her thyroid gland is normal on palpation. She has Tanner stage IV breast development and female external genitalia. She has Tanner stage IV axillary and pubic hair. There are no skin lesions.

» What is the most likely diagnosis?

» What is the next step in diagnosis?

» What is the most likely finding on pelvic examination?

ANSWER TO CASE 55:

Amenorrhea (Primary), Müllerian Agenesis                              

Summary: An 18-year-old nulliparous adolescent woman, who may have only one kidney, presents with primary amenorrhea. She denies weight loss or excessive exercise. On examination, she is 5 ft 6 in tall and weighs 140 lb. Her blood pressure is 110/ 60 mm H g. Her thyroid gland is normal. She has appropriate Tanner stage IV breast development, axillary and pubic hair, and female external genitalia.

• Most likely diagnosis: Müllerian (or vaginal) agenesis.
• Next step in diagnosis: Serum testosterone or karyotype.
• Most likely finding on pelvic examination: Blind vaginal pouch or vaginal dimple.

ANALYSIS

Objectives

1. Know the definition of primary amenorrhea, that is, no menses by the age of 16 years.
2. Know that the two most common causes of primary amenorrhea when there is normal breast development are müllerian agenesis and androgen insensitivity.
3. Understand that a serum testosterone level or karyotype would differentiate the two conditions.

Considerations

This 18-year-old adolescent woman has never had a menstrual period; therefore, she has primary amenorrhea. She has normal Tanner stage IV breast development as well as normal axillary and pubic hair. Breast development connotes the presence of estrogen, and axillary and pubic hair suggests the presence of androgens. She also has a history of only one kidney. The most likely diagnosis is müllerian agenesis because a significant fraction of such patients will have a urinary tract abnormality. Also, with androgen insensitivity, there is typically scant axillary and pubic hair since there is a defective androgen receptor. The diagnosis can be confirmed with a serum testosterone, which would be normal in müllerian agenesis, and elevated (in the normal male range) in androgen insensitivity. In both conditions, there is no uterus, tubes, or cervix, and a blind vaginal pouch or vaginal dimple. A karyotype would also help to distinguish the two conditions. Notably, absence of breast development would point to a hypoestrogenic state such as gonadal dysgenesis (Turner syndrome).

APPROACH TO:

Primary Amenorrhea                                              

DEFINITIONS

PRIMARY AMENORRHEA: No menarche by the age of 16 years.

ANDROGEN INSENSITIVITY: An androgen receptor defect in which 46,XY individuals are phenotypically female with normal breast development.

MÜLLERIAN AGENESIS: Congenital absence of development of the uterus, cervix, and fallopian tubes in a 46,XX female, leading to primary amenorrhea.

CLINICAL APPROACH

When a young woman presents with primary amenorrhea, the differential diagnosis can be narrowed on the basis of whether or not normal breast tissue is present, and whether a uterus is present or absent. After pregnancy is excluded, the two most common etiologies that cause primary amenorrhea associated with normal breast development and an absent uterus are androgen insensitivity syndrome and müllerian agenesis (Table 55– 1).

    An individual with androgen insensitivity syndrome, also known as testicular feminization, has a 46,XY karyotype with normally functioning male gonads that produce normal male levels of testosterone. However, due to a defect in the androgen receptor synthesis or action, there is no formation of male internal or external genitalia. The external genitalia remain female, as it occurs in the absence of sex steroids. There are no internal female reproductive organs, and the vagina is short or absent. Without androgenic opposition to the small circulating levels of estrogen secreted by the gonads and adrenals, and produced by peripheral conversion of androstenedione, breast development is normal or enhanced. Pubic and axillary hair is absent or scant due to defective androgen receptors. Therefore, these individuals are genotypically male (46,XY karyotype) but phenotypically female (look like a woman). The abnormal intra-abdominal gonads are at increased risk for malignancy, but this rarely occurs before puberty. Thus, gonadectomy is not performed until after puberty is completed to allow full breast development and linear growth to occur. After these events take place, usually around the age of 16 to 18 years, the gonads should be removed. The diagnosis of androgen insensitivity syndrome should be suspected when a patient has primary amenorrhea, an absent uterus, normal breast development, and scant or absent pubic and axillary hair. The diagnosis can be confirmed with a karyotype evaluation and/ or elevated testosterone levels (male normal range).

    Women with müllerian agenesis have a 46,XX karyotype, no uterus or fallopian tubes, and a short or absent vagina. Externally, they resemble individuals with androgen insensitivity. They do, however, have normal functioning ovaries since the ovaries are not müllerian structures, and have normal breast development. They also have normal pubic and axillary hair growth because there is no defect in their androgen receptors. Congenital renal abnormalities occur in about one-third of these individuals. These women are genotypically and phenotypically female (46,XX). The diagnosis of müllerian agenesis should be suspected when a patient has primary amenorrhea, an absent uterus, normal breast development, and normal pubic and axillary hair. The presence of normal pubic and axillary hair is what differentiates them from individuals with androgen insensitivity syndrome, and laboratory confirmation can be accomplished with a karyotype examination and/ or testosterone level.

    Another type of müllerian defect is a uterine septum. In these cases, there is a midline septum that is of varying lengths due to incomplete dissolution of the fused midline portion of the müllerian ducts. Patients often have recurrent miscarriage due to the avascular nature of the septum and inability to sustain a pregnancy. Diagnosis is performed by hysterosalpingogram, saline infusion sonohysterography, or magnetic resonance imaging. Hysteroscopic resection of the septum is the treatment, and outcomes are very good.

CASE CORRELATION See also Case 54 (Delayed Puberty) to distinguish between that condition (no breast development by age 14) and müllerian agenesis (primary amenorrhea) where affected women have normal breast development but no menses by age 16.

COMPREHENSION QUESTIONS

55.1 An 18-year-old nulliparous adolescent woman complains of not having started her menses. Her breast development is Tanner stage V. She has a blind vaginal pouch and no cervix. Which of the following describes the most likely diagnosis?

A. Müllerian agenesis

B. Kallmann syndrome

C. Gonadal dysgenesis

D. Polycystic ovarian syndrome

55.2 A 20-year-old G0P0 woman is told by her doctor that there is a strong probability that her gonads will turn malignant. She has not had her menses yet. She has Tanner stage I breast development. Which of the following describes the most likely diagnosis?

A. Müllerian agenesis

B. Androgen insensitivity

C. Gonadal dysgenesis

D. Polycystic ovarian syndrome

55.3 A 19-year-old woman has primary amenorrhea, Tanner stage IV breast development, and a pelvic kidney. Which of the following describes the most likely diagnosis?

A. Müllerian agenesis

B. Androgen insensitivity

C. Gonadal dysgenesis

D. Polycystic ovarian syndrome

55.4 Which of the following is the best explanation for breast development in a patient with androgen insensitivity?

A. Gonadal production of estrogens

B. Adrenal production of estrogen

C. Breast tissue sensitivity to progesterone

D. Peripheral conversion of androgens

E. Autonomous production of breast-specific estrogen

55.5 A 15-year-old adolescent female is brought into the pediatrician due to the absence of breast development and short stature. A karyotype is performed which reveals 46,XY. Which of the following is the most likely diagnosis?

A. Androgen insensitivity

B. Gonadal dysgensis

C. Kallman syndrome

D. Testicular atrophy syndrome

ANSWERS

55.1 A. Normal breast development, no cervix, and a blind vaginal pouch may be caused by either müllerian agenesis or androgen insensitivity. The serum testosterone level will help to distinguish the two conditions. Kallmann syndrome is associated with delayed puberty (Tanner stage I breasts).

55.2 C. The Y-chromosome gonad may become malignant. This patient likely has gonadal dysgenesis since she has Tanner stage I breast development. Although usually 45,X is associated with gonadal dysgenesis, the karyotype can also be 46,XX or 46,XY. In other words, this patient has delayed puberty. This is XY gonadal dysgenesis.

55.3 A. A pelvic kidney most likely is associated with a müllerian abnormality. These women have no uterus or fallopian tubes, and have a short or absent vagina. They do, however, have normally functioning ovaries because the ovaries are not müllerian structures, and as a result, they have normal breast development.

55.4 D. Individuals with androgen insensitivity usually have full breast development due to the peripheral conversion of androgens to estrogens. Also, because of the defective androgen receptor, the high endogenous androgens do not inhibit breast development as in a normal male, but pubic and axillary hair is scant or absent. The gonads and adrenals also produce a small circulating amount of estrogen, but do not contribute as much as the peripheral androgen conversion. Progesterone sensitivity does not influence breast development, nor does a breast-specific estrogen.

55.5 B. The most common cause of delayed puberty (absent breast tissue after the age of 14 years) is gonadal dysgenesis, which can also occur with a 46,XY karyotype (along with androgen insensitivity). The most common karyotype of gonadal dysgenesis, however, is 45,XO in Turner syndrome. In androgen insensitivity, normal breast development occurs. Kallmann syndrome is an example of a hypogonadotropic hypogonadism, or hypothalamic hypogonadism, disorder caused by a deficiency in the gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus (and, therefore, decreased LH and FSH production). Gonadal dysgenesis, on the other hand, is a state of hypergonadotropic hypogonadism. Patients with Kallmann syndrome also typically have a deficiency or inability to smell. Women present with delayed puberty and lack of breast development, but have a normal karyotype (46,XX). Treatment is hormone replacement.

    CLINICAL PEARLS    

» A pregnancy test should be the first test for any woman with primary or secondary amenorrhea. » The two most common causes of primary amenorrhea in a woman with normal breast development are androgen insensitivity and müllerian agenesis. » Scant axillary and pubic hair suggest androgen insensitivity. » A karyotype and testosterone level help to differentiate between müllerian agenesis and androgen insensitivity. » Renal anomalies are common with müllerian abnormalities.

REFERENCES

Lobo RA. Primary and secondary amenorrhea and precocious puberty. In: Katz VL, Lentz GM, Lobo RA, Gersenson DM, eds. Comprehensive Gynecology. 6th ed. St. Louis, MO: Mosby-Year Book; 2012:933-960. 

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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