Amy Brown and Nicole W. Karjane
History of present illness
A 19-year-old woman presents to the emergency department with lower abdominal pain. The pain started gradually 12 hours earlier and has progressively worsened in intensity. It is sharp in nature and localized to her left lower quadrant. She recalls that she has mild cramping pains in her lower abdomen every few weeks for years, but they have never been this intense. She denies any vaginal bleeding or discharge. She has never had a menstrual cycle and has never had vaginal intercourse.
Review of systems is negative for nausea, vomiting, diar- rhea, constipation, fever, or chills. Her only medical history consists of mild scoliosis that has never required intervention.
She takes no medications and has no known allergies. She was hospitalized at age eight for pyelonephritis, but is otherwise healthy and has never had surgery.
Physical examination
General appearance: Well-groomed, well-nourished woman in mild distress
Vital signs:
Temperature: 36.9°C Pulse: 95 beats/min
Blood pressure: 133/76 mmHg Respiratory rate: 18 breaths/min Oxygen saturation: 99% on room air BMI: 21 kg/m2
HEENT: Normal
Cardiovascular: Regular rate and rhythm, normal S1 and S2, no murmurs, no edema
Lungs: Clear bilaterally without wheezes, good respiratory effort
Breasts: Tanner stage V breast development
Abdomen: Soft, moderately tender in left lower quadrant, minimal suprapubic or right lower quadrant tenderness.
No distension, rebound or guarding. No masses palpable Genitourinary: Tanner stage V pubic hair development, external genitalia (Fig. 66.1); unable to pass speculum or perform bimanual examination
Laboratory studies:
CBC and basic metabolic panel: Normal
Urinalysis: No blood, leukocytes, nitrites, or protein.
Trace ketones present Urine beta-hCG: Negative
Imaging: Trans-abdominal ultrasound reveals no definite uterus but approximate 2 × 2 × 1 cm mass of tissue posterior to the normal bladder. No evidence of an endometrial stripe or cervical anatomy. Right ovary normal. Left ovary contains a 3 cm cyst withfluid layering consistent with hemorrhage.
Normal bloodflow visualized to the ovaries bilaterally without evidence of torsion
The patient was given 30 mg IV ketorolac (Toradol®) in the emergency department and reported great improvement of her pain.
How would you manage this patient?
The patient’s normal vital signs, laboratory evaluation, non- acute physical examination findings, and ovarian imaging suggest symptoms due to a hemorrhagic corpus luteal cyst.
More concerning, however, is the patient’s amenorrhea and findings on genital examination, which are suggestive of Mullerian agenesis.
The patient was referred for an outpatient gynecologic evaluation scheduled within 48 hours. A repeat ultrasound showed normal ovaries and a small, rudimentary uterus with- out endometrium. A karyotype was obtained confirming a 46,XX chromosome pattern. All endocrine laboratory studies were normal. The patient was diagnosed with complete Mullerian agenesis, also known as Mayer–Rokitansky–Küster– Hauser syndrome. She was ultimately started on vaginal dilator
Fig. 66.1 External genitalia.
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
therapy, received extensive counseling, and plans to consult with a fertility specialist in the future.
Primary amenorrhea and Mullerian agenesis
Primary amenorrhea is defined as either a lack of menses by age 14 without evidence of pubertal development (axillary or pubic hair growth, breast development), or a lack of menses by age 16 if other evidence of puberty is present [1]. Potential etiologies are multiple and can be classified as eitheranatomic or endocrine abnormalities. A flow-diagram of the initial workup is shown inFig. 66.2.
Anatomic causes of primary amenorrhea can be divided into abnormalities of the Mullerian organs (uterus, fallopian tubes, cervix, and superior 2/3 of the vagina) or of the distal outflow tract (inferior 1/3 of the vagina or labia). Mullerian agenesis is the most prevalent of these anatomic disorders and is second only to gonadal dysgenesis (an endocrine abnormality) as the leading cause of primary amenorrhea [1]. It encompasses a large number of potential anatomical variants depending on the degree of fusion of the Mullerian ducts in utero [2]. The patient in this scenario has Mayer–
Rokitansky–Küster–Hauser syndrome, a form of Mullerian agenesis defined by congenital aplasia of the uterus and superior 2/3 of the vagina [3]. Approximately 50% of these
patients have other congenital anomalies, the most common being renal (horseshoe kidney, unilateral renal agenesis, or ectopic kidneys) and skeletal (scoliosis or other vertebral anomalies) [2]. Multiple genes have been implicated as a potential cause for these malformations, but there is no clear consensus as to whether this is a unifactorial or multifactorial condition [3].
Patients with complete Mullerian agenesis usually present in the outpatient setting due to concerns of amenorrhea. They may, however, present earlier if any of the associated anatom- ical abnormalities are discovered as incidental finding on imaging, or if they are seeking medical attention for symptoms unrelated to the Mullerian agenesis, as in this case with the patient presenting for pain due to a functional ovarian cyst.
Additionally, 2–7% of patients with Mullerian agenesis will have rudimentary uterine horns that contain active endomet- rium. These patients will often present with symptoms of menstrual obstruction or pelvic pain due to retrograde men- struation and endometriosis formation [2]. Removal of the noncommunicating horn may be indicated for symptom relief in these cases.
Disorders of the distal outflow tract encompass any abnormality of the inferior 1/3 of the vagina or labia. The most common of these are an imperforate hymen (1 in 1000 women) and a transverse vaginal septum (1 in 80 000 women)
-
46,XY Karyotype?
- +
Mullerian agenesis
Breast development?
+
Normal external genitalia?
- -
+
- + - +
+ Elevated FSH?
- +
MRI head normal? Gonadal
dysgenesis +
- +
Idiopathic HH
Kallmann’s syndrome Hypogonadotropic
hypogonadism Anosmia present?
Androgen insensitivity
syndrome If low, consider hypothalamic
amenorrhea
If high, consider ovarian failure Check FSH levels
Anovulation Distal
outflow obstruction
Provera challenge produces withdrawal
bleed?
Bleeding with E/P challenge?
Mullerian organs present on
imaging?
-
Pituitary tumor or other CNS lesion
Fig. 66.2 Evaluation of primary amenorrhea. CNS, central nervous system; E/P, estrogen/progesterone; FSH, follicle-stimulating hormone; HH, hypogonadotropic hypogonadism.
[1]. Patients with these disorders often present with cyclic pelvic pain in the absence of menstrual bleeding due to the outflow obstruction. Because these pain symptoms most commonly prompt medical evaluation prior to concerns for primary amenorrhea, these conditions will likely be diagnosed and managed (prior to age 16) and, thus, remain less common than gonadal dysgenesis and Mullerian agenesis as an etiology of true primary amenorrhea. Surgical correction of the outflow obstruction is curative.
When primary amenorrhea is associated with an endocrine etiology, it can be divided into disorders of the hypothalamus, pituitary, or gonads. The initial laboratory evaluation is guided by the physical examinationfindings, particularly the presence or absence of pubertal development. In patients without breast development, a follicle-stimulating hormone (FSH) should be measured. Patients with absent pubertal development and low FSH levels should undergo an MRI of the brain to rule out a CNS lesion as the cause. Most of these patients will be diag- nosed with hypogonadotropic hypogonadism, a hypothalamic disorder characterized by congenital gonadotropin-releasing hormone (GnRH) deficiency. Kallmann syndrome is the most common of these disorders and is associated with anosmia, or lack of smell [1]. Rare cases of idiopathic hypogonadotropic hypogonadism without anosmia have also been reported.
Though functional hypothalamic disorders (typically due to stressors, eating disorders, or intensive exercise) are common causes ofsecondaryamenorrhea, they rarely present as primary amenorrhea except in severe cases [1].
The pituitary is responsible for approximately 5% of primary amenorrhea cases, which are typically discovered by abnormalities in pituitary hormone levels, most often prolactin. Patients presenting with primary amenorrhea and new-onset headaches or vision changes, particularly bilateral hemianopsia (temporal visualfield defects), should undergo an evaluation for a pituitary tumor, as the mass effect of a growth can produce these associated clinical symptoms.
Gonadal dysgenesis, also referred to as “primary ovarian insufficiency,”is the most frequent cause of primary amenor- rhea [1]. Just over half of these patients have Turner syndrome, which is typically characterized by the absence of all or part of one X chromosome (45,X karyotype) and streak ovaries (the ovaries are replaced by functionlessfibrous tissue). Clinically, Turner’s stigmata include short stature, neck-webbing, and primary amenorrhea. Turner’s patients may also have concur- rent congenital heart and renal defects. Up to 40% of patients with gonadal dysgenesis may have a 46,XX or XY karyotype.
Those who are XY or have the sex-determining region of the Y chromosome are recommended to undergo gonadectomy due to the risk of developing a gonadal malignancy [1].
Evaluation of primary amenorrhea should always start with a thorough history and physical examination to determine the stage of pubertal development. In patients with breast development, functional gonads can generally be assumed and, thus, the next step is to determine whether normal external genitalia, vagina, and cervical anatomy are present.
Imaging via ultrasonography may be required in patients who cannot tolerate a pelvic examination. Patients with ultrasono- graphic evidence of menstrual obstruction may need to be further evaluated by MRI to clarify their pelvic anatomy and to define the specific anomaly. In patients without a patent vagina or uterus, karyotyping should be performed to deter- mine whether the diagnosis is Mullerian agenesis or androgen insensitivity syndrome (AIS). AIS results in an apparently female phenotype at birth in a 46,XY patient due to lack of testosterone activity at the external genitalia. Unlike patients with Mullerian agenesis, however, those with AIS generally have scant pubic hair due to the insensitivity of peripheral androgen receptors to circulating testosterone. Since the karyotype is 46,XY, testicles are present (instead of ovaries) and, hence, produce anti-Mullerian hormone in utero, resulting in an absence of Mullerian organs. There is a 25% risk of developing testicular malignancy with AIS, thought to be due to the presence of intra-abdominal testes. As such, surgical removal of the testes should be prophylactically performed once puberty is complete [4].
In patients with primary amenorrhea, normal pubertal development, and normal pelvic anatomy, a progestin challenge is helpful diagnostically once pregnancy has been ruled out. If bleeding occurs in response to the progestin challenge, the etiology of the amenorrhea is anovulation, and the patient should be evaluated for etiologies of this such as thyroid dys- function, prolactinomas, and polycystic ovary syndrome. If no withdrawal bleeding follows the progestin challenge, an estro- gen plus progestin challenge should be prescribed. Bleeding in response to an estrogen/progesterone challenge confirms a patent outflow tract, but leaves concern for gonadal failure.
Patients with gonadal failure after puberty should be evaluated for Turner syndrome as well as the Fragile X premutation.
Long-term management of primary amenorrhea is dictated by the etiology of the disorder. Patients with an imperforate hymen or transverse vaginal septum (anatomic distal outflow obstructions) should undergo surgical correction, which will result in resolution of amenorrhea and cure [1]. In the case of the patient described with Mullerian agenesis, as well as those with AIS, a number of surgical techniques have been described for the creation of a neovagina. Despite surgical procedures that can create a functional vagina, vaginal dilator therapy is still considered thefirst-line intervention and in motivated patients and has a success rate of over 90% [3]. Patients with Mullerian agenesis should also be offered counseling regarding their diag- nosis and reproductive options. While they will be unable to carry a fetus due to the absence of the uterus, they are able to have their own biological children via in-vitro fertilization (IVF) technology using a gestational carrier [2]. Those with AIS do not have this ability since they have neither a uterus nor ovaries; thus, adoption and surrogacy are the only options.
Patients with primary amenorrhea from endocrine dys- function typically require hormone treatments. Patients with gonadal dysgenesis should be treated initially with low-dose estrogen therapy to initiate normal pubertal maturation and
Case 66: A 19-year-old woman with primary amenorrhea
bone growth. Once adequate breast development is present and/or the patient has breakthrough bleeding, the patient should be transitioned to estrogen/progesterone therapy for prevention of early bone loss and other estrogen deficiency symptoms while protecting against endometrial hyperplasia.
These patients may conceive using IVF with donor eggs and should likewise be offered counseling regarding fertility options. The management of pituitary lesions depends on the etiology. Prolactinomas are generally treated with dopa- mine agonists as first-line therapy, whereas more significant lesions may require referral to a neurosurgeon for manage- ment. Hypogonadotropic hypogonadism can be treated by hormone replacement therapy (similar to those with gonadal dysgenesis) once CNS lesions have been ruled out. These patients will need treatment with gonadotropins or pulsatile GnRH if pregnancy is desired [1]. Special consideration should be given to emotional and social factors for patients with primary amenorrhea and support groups may be highly beneficial.
Key teaching points
Primary amenorrhea is defined as either a lack of menses by age 14 without evidence of pubertal development, or a lack of menses by age 16 if other evidence of puberty exists.
Patients with primary amenorrhea should be evaluated to determine the etiology which can be classified as either anatomic or endocrine in origin.
Anatomic causes of primary amenorrhea include
abnormalities of Mullerian organs (uterus, fallopian tubes, cervix, superior 2/3 of the vagina), or of the distal outflow tract (inferior 1/3 of the vagina or labia).
Endocrine causes of primary amenorrhea include disorders of the hypothalamus, pituitary, or gonads.
Women with primary amenorrhea should receive
comprehensive therapy which, depending on the diagnosis, may include hormone therapy, vaginal dilator use, surgical interventions, emotional counseling, and consultation with fertility specialists.
References
1. Practice Committee of the American Society for Reproductive Medicine.
Current evaluation of amenorrhea.
Fertil Steril2008;90:S219–25.
2. American College of Obstetricians and Gynecologists. Mullerian
agenesis: Diagnosis, management, and treatment. Committee Opinion No. 562.Obstet Gynecol2013;121:
1134–7.
3. Pizzo A, Lagana AS, Sturlese E, et al.
Mayer–Rokitansky–Kuster–Hauser syndrome: Embryology, genetics, and
clinical and surgical treatment.Obstet Gynecol2013;2013:628717. DOI:
10.1155/2013/628717.
4. Hughes IA, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome.Semin Reprod Med2012;
30:432–42.