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Case Report

Missing the Missing Uterus

Luke J. Hofmann, MS IV; Kathrine L. Heron, MS IV; Joey S. Rottman, DO

CASE REPORT

A 20-year-old woman, gravida 0, para 0, presented to the clinic complaining of primary amenorrhea for which she had sought care at various medical facilities over the past 5 years with no resolution. Her medical and gynecologic history included four pelvic examinations and a Papanicolaou (Pap) smear. No cervical or uterine abnormalities had been noted. The Pap specimens were prepared using liquid-based cervical cytology, and reported as nonmalignant and suitable. Surgical, family, and social histories were unremarkable, and—except for amenorrhea—the review of systems was noncontributory.

On examination, the patient had an optimal body mass index of 20, and appeared to be well-developed and well-nourished. Her vital signs were normal, as was her skull (cephalic atraumatic). No webbing of the neck was noted. Her heart rate was regular, with no murmurs, gallops, or rubs. Lung sounds were clear bilaterally. There was no organomegaly, and rectal tone was good. There was no cyanosis, clubbing, or edema of the extremities. Pulses and muscle strength were equal and bilateral in both the lower and upper extremities. All deep-tendon reflexes were intact, with a score of +2/4. Cranial nerves were grossly intact. The patient was at Tanner stage 5, with no breast masses or deformities. No cervix was visible on Pap testing, and this was confirmed on bimanual examination. No pelvic masses were palpated—including any mass that may represent a uterus.

Results of a basic metabolic panel were within normal limits. Values included estradiol 264 pg/mL (midcycle or luteal phase); follicle-stimulating hormone 21.1 mIU/mL (postmenopausal range); luteinizing hormone 91.2 mIU/mL (versus top midcycle, 76 mIU/mL); progesterone 2.5 ng/mL; prolactin 23.3 ng/mL (not pregnant < 30.0 ng/mL); thyroid-stimulating hormone 2.40 mIU/mL; and adrenocorticotropic hormone 17 pg/mL. Papanicolaou findings were reported as satisfactory for evaluation, with no endocervical/ transformation zone component, intraepithelial lesions, or malignancy. Findings for chlamydia and gonorrhea were likewise negative.

Because of the suspicion of m»llerian agenesis, pelvic magnetic resonance imaging (MRI) was performed with and without contrast. Findings were consistent with agenesis of the uterus, cervix, and upper third of the vagina (Figure 1). The left ovary was anteriorly located, near the inguinal canal (Figure 2). The genitourinary system was otherwise normal. The diagnosis was consistent with Mayer-Rokitansky-K»ster-Hauser (MRKH) syndrome.

Figure not available online

FIGURE 1. Magnetic resonance imaging demonstrates the absence of a uterus, which would typically lie above the bladder. The bladder (A), urethra (B), vagina (C), and vaginal vault (D) are all clearly visible. Courtesy of Luke J. Hofmann, MS IV; Kathrine L. Heron, MS IV; and Joey S. Rottman, DO.

Figure not available online

FIGURE 2. Magnetic resonance imaging shows the left ovary (A) and vaginal vault (B, below the line). The right ovary was found in its normal location more posterior and superior on subsequent sections of the MRI. Courtesy of Luke J. Hofmann, MS IV; Kathrine L. Heron, MS IV; and Joey S. Rottman, DO.

Karyotyping revealed a genotype of 46,XX—excluding the possibility of undescended testicles. The patient reported no difficulty with coitus, and is not currently seeking any additional treatments.

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DISCUSSION

Mayer-Rokitansky-K»ster-Hauser syndrome comprises congenital absence of the vagina, with variable uterine and fallopian tube development. It was first reported in the 1830s.1 It has also been called vaginal agenesis, m»llerian agenesis, Mayer-Rokitansky syndrome, and von Rokitansky syndrome.

In the general population, MRKH syndrome occurs at a rate of 1/5,000.2 These patients often exhibit additional extragenital anomalies, and 25% to 50% have urologic abnormalities (eg, complete/partial renal agenesis, pelvic or horseshoe kidneys).3 Skeletal malformations (10% to 15%) may involve the spine, ribs, and/or extremities. Less common features include congenital heart lesions, abnormalities of the hand, deafness, cleft palate, and inguinal or femoral hernias.4 There is no racial predilection, but a weak link exists with a loss of function deletion in the WNT4 gene.

While MRKH syndrome results from agenesis/underdevelopment of the m»llerian duct system, its exact etiology is unknown. Vaginal development normally occurs with the sinovaginal bulbs—two solid evaginations originating in the urogenital sinus at the distal aspect of the m»llerian tubercle. The bulbs proliferate into the caudal end of the uterovaginal canal, becoming a solid vaginal plate. The lumen of the lower vagina is then formed by degeneration of the central cells of this plate. Canalization of the vagina is completed by around 20 weeks¡ gestation. Vaginal agenesis is usually accompanied by cervical and uterine agenesis, but there is an obstructed or rudimentary uterus with some areas of functional endometrium in < 10% of patients.

The WNT4 gene suppresses male sexual differentiation, and is thought to repress the production of gonadal androgen in female mammals. A mutation in this gene was reported in a 46,XX woman with bilateral ovaries, m»llerian agenesis, and hyperandrogenemia,5 suggesting its absence may result in MRKH syndrome.5 It is thought that the WNT4 gene regulates m»llerian duct formation and controls ovarian steroidogenesis.

Patients who present with no menarche should be evaluated for both primary and secondary amenorrhea, as causes of secondary amenorrhea may manifest at menarche (Table, Figure 3). Causes of primary amenorrhea include imperforate hymen, androgen insensitivity (testicular feminization), and 5-α reductase deficiency. An imperforate hymen may be detected on physical examination with a bulging introitus coinciding with cyclic abdominal pain, or cyclic malodorous discharge if perforation is incomplete. Ultrasonography or MRI will demonstrate the presence of a uterus and ovaries. In cases of androgen insensitivity, serum testosterone levels will be comparable to those of a normal male in the presence of 5-α reductase deficiency. Women with imperforate hymen or MRKH syndrome will have testosterone values in the normal female range. Patients with 5-α reductase deficiency will appear phenotypically female, but without axial and pubic hair.

Table not available online

TABLE. Causes of Primary and Secondary Amenorrhea

Figure not available online

FIGURE 3. Primary amenorrhea work-up. MRI = magnetic resonance imaging.

Patients with MRKH syndrome will usually have Tanner scores of 4 or 5, depending on age of discovery. Pelvic MRI can be used to evaluate the presence of a uterus, fallopian tubes, and vaginal length. Additionally, the location of ovaries should be noted. Women with MRKH syndrome generally have two ovaries in the normal anatomic position, but if one or both of the ovaries are closer to the inguinal canal—as in this case—it is essential to ensure that these masses are not undescended testicles, indicating androgen insensitivity or 5-α reductase deficiency. It is prudent to perform DNA karyotyping to evaluate for XY or XX chromosomes.

Treatment of MRKH syndrome comprises psychological, physical, and preventive health measures. Psychologically, infertility can represent a significant burden to women with MRKH syndrome. Psychological support should be provided immediately on diagnosis and continued for as long as necessary. For women with MRKH syndrome who have functional ovaries, the eggs may be harvested, inseminated with their partner¡s sperm, and implanted in a donor carrier. Additionally, many of these patients are capable of coitus.

The two goals of physical treatment for patients with MRKH syndrome are to confirm the absence of other congenital abnormalities, and to rebuild or improve the vaginal structure. Based on the physical, history, and laboratory findings, further abnormalities should be explored with ultrasonography, intravenous pyelography, computed tomography, and/or MRI (the Àgold standard”).

There are both surgical and nonsurgical approaches to vaginal agenesis. Patients who have the lower 66% of the vagina typically require less aggressive measures. For those who are psychologically and physically ready for sexual relations, repeated sexual intercourse may be sufficient to expand the vaginal canal. The use of vaginal dilators is a mainstay of therapy for women who have the lower 33% of the vagina, but who are either too immature for sexual relations or who desire a more controlled, private approach. Dilators are used daily for several months following a warm bath. Frank6 devised the first technique for vaginal expansion with dilators; this was later refined by Ingram,7 who introduced a bicycle seat to apply more constant, controlled pressure. With proper training, dilators prove satisfactory in about 85% of patients.8

Surgical techniques are available for women with complete vaginal agenesis, and for those who do not wish to use dilators. All surgical procedures require the use of dilators during postoperative recovery. Options include sigmoid vaginoplasty, McIndoe vaginoplasty, the Davydov procedure, Williams vaginoplasty, and the Vecchietti laparoscopic procedure. The success rate for each procedure varies by patient and surgeon; outcomes are generally acceptable. In one more study, the McIndoe vaginoplasty had a success rate exceeding 90%.9 Research laboratories throughout the world are currently investigating the feasibility of uterine transplantation, which has resulted in normal offspring in mice.10,11

Patients with MRKH syndrome should be encouraged to use condoms to prevent sexually transmitted infections. While Pap smears may not be necessary to detect cervical dysplasia, all sexually active women with MRKH syndrome are susceptible to human papillomavirus, vaginal wall infections, and cancer—which are detectable using liquid-based cytology testing.

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CONCLUSION

M»llerian agenesis is a rare entity. If the cervix is not visible or palpable during Pap testing in the presence of amenorrhea, a work-up for m»llerian agenesis should ensue. Because of the higher risk of urogenital abnormalities and other congenital defects, careful physical examination is imperative to rule out other life-threatening anomalies. Reports citing inadequate Pap specimens, no cervix visible, and no transitional cells should likewise raise the suspicion of MRKH syndrome.

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Luke J. Hofmann, MS IV, and Kathrine L. Heron, MS IV, are medical students, Department of Obstetrics and Gynecology, Philadelphia College of Osteopathic Medicine, Pennsylvania. Joey S. Rottman, DO, is associate professor, Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey, Stratford.

References

1. Mayer CAJ. ûber Verdoppelungen des Uterus und ihre Arten, nebst Bemerkungen »ber Harenscharte und Wolfsrachen. Journal der Chirurgie und Augen-Heilkunde. 1829;13:525-564.
2. Evans TN, Poland ML, Boving RL. Vaginal malformations. Am J Obstet Gynecol. 1981;141(8):910-920.
3. Fore SR, Hammond CB, Parker RT, Anderson EE. Urologic and genital anomalies in patients with congenital absence of the vagina. Obstet Gynecol. 1975;46(4):410-416.
4. Griffin JE, Edwards C, Madden JD, Harrod MJ, Wilson JD. Congenital absence of the vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Ann Intern Med. 1976;85(2):224-236.
5. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signaling. Nature. 1999; 397(6718):405-409.
6. Frank RT. The formation of an artificial vagina without operation. Am J Obstet Gynecol. 1938;35: 1053-1055.
7. Ingram JM. The bicycle seat stool in the treatment of vaginal agenesis and stenosis: a preliminary report. Am J Obstet Gynecol. 1981;140(8): 867-873.
8. Roberts CP, Haber MJ, Rock JA. Vaginal creation for mullerian agenesis. Am J Obstet Gynecol. 2001;185(6):1349-1352.
9. Edmonds DK. Congenital malformations of the genital tract and their management. Best Pract Res Clin Obstet Gynaecol. 2003;17(1):19-40.
10. Brannstrom M, Racho El-Akouri R, Wranning CA. Uterine transplantation. Eur J Obstet Gynecol Reprod Biol. 2003;109(2):121-123.
11. Racho El-Akouri R, Kurlberg G, Brannstrom M. Successful uterine transplantation in the mouse: pregnancy and post-natal development of offspring. Hum Reprod. 2003;18(10): 2018-2023.

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