Keywords clitoromegaly - pseudoclitoromegaly - pregnancy - epidermoid cyst
Case Report
A 31-year-old gravida 2, para 1 presented at 9 weeks' gestation with concerns relating
to noticeable clitoral enlargement. A review of her gynecologic history revealed normal
menarche at age 12 and normal breast and genital development during puberty. She denied
any history of menstrual irregularities, excessive facial or body hair, acne, scalp
hair loss, change in the voice timbre, regression in breast size, or difficulty conceiving.
Patient also denied any genital trauma, dyspareunia, pruritus, or discharge. Family
history was noncontributory with no consanguinity. Two years prior, she became pregnant
with her first child and, starting at 20 weeks' gestation, noticed gradual painless
clitoral enlargement until it reached a documented size of 5 × 2 cm. The patient was
otherwise asymptomatic and did not undergo any further evaluation. Within 2 months
of delivering a healthy male infant, the patient experienced spontaneous regression
in clitoral size to its prepregnancy baseline. However, at 5 months postpartum, her
clitoris began to grow again and remained enlarged through spring 2012 when she became
pregnant for the second time.
Psychological distress relating to the persistently enlarged clitoris in her second
pregnancy finally prompted consultation to Endocrinology and Maternal-Fetal Medicine.
A transvaginal pelvic ultrasound done at 6 weeks' gestation showed unremarkable ovaries
and a normal intrauterine gestation whose crown–rump length was consistent with established
dates. On physical exam, the patient did not exhibit any systemic signs of virilization.
Her voice was normal female, the amount and pattern of body hair distribution were
gender-appropriate, and there was no evidence of acne, temporal balding, or abnormal
muscular development. Examination of her external genitalia identified a markedly
enlarged clitoris, measuring 7 × 2 cm, with the size and appearance resembling that
of a microphallus ([Fig. 1 ]). The clitoral hood was minimally retractable, and the clitoral body was firm and
demonstrated some mobility along the lateral horizontal plane. A soft fluctuance approximately
1 × 1 cm was palpated at the base. There was no erythema or tenderness. The introitus
was unremarkable, and the labia majora and minora appeared normal. A single urethral
meatus was clearly visualized in the normal anatomical location. Speculum exam revealed
a well-estrogenized vagina and a normal-appearing cervix, and bimanual exam was consistent
with early pregnancy. Notably, there was no communication between the anterior vaginal
wall and the clitoris.
Fig. 1 External genital exam.
Given the striking appearance of the clitoris, a spectrum of possible diagnoses was
considered, including acquired virilization syndromes of pregnancy, hermaphroditism,
adrenal hyperplasia, ovarian or adrenal neoplasms, exogenous androgen exposure, and
various forms of pseudoclitoromegaly, which are explored in further detail in the
Discussion section of this report. Importantly, prophylactic dexamethasone therapy
was considered early in the patient's evaluation given the possibility of late-onset
congenital adrenal hyperplasia and its associated virilizing risk for a female fetus.[1 ] This approach was deferred until further assessment, given the lack of maternal
virilization. We next performed an extensive evaluation of the pituitary-adrenal-ovarian
hormonal axes. These studies revealed gestation-appropriate levels of serum adrenocorticotropic
hormone, morning cortisol, sex hormone binding globulin, dehydroepiandrosterone sulfate,
androstenedione, total and free testosterone, 17-hydroxypregnenolone, 17-hydroxyprogestoerone,
and 11-deoxycortisol ([Table 1 ]).
Table 1
Hormonal Evaluation of Our Patient
Test
Result
Reference range
Plasma ACTH (pg/mL)
10
6–50
Morning cortisol (μg/dL)
12.2
4.3–22.4
Serum albumin (g/dL)
4.3
3.6–5.1
SHBG (nmol/L)
186
1–124 normal, likely higher in pregnancy
17-OH progesterone (ng/dL)
193
78–457 pregnancy first trimester
Androstenedione (ng/dL)
135
30–235 luteal phase, likely higher in pregnancy
11-deoxycortisol (ng/dL)
34
<51 normal, likely higher in pregnancy
Total testosterone (ng/dL)
45
2–45 normal, likely higher in pregnancy
Free testosterone (pg/mL)
1.2
0.2–5.0 normal, likely higher in pregnancy
17-OH pregnenolone (ng/dL)
46
<905 premenopausal women
DHEA sulfate (μg/dL)
203
40–325 normal, likely higher in pregnancy
Abbreviations: 17-OH, 17-hydroxyprogesterone; ACTH, adrenocorticotropic hormone; DHEA,
Dehydroepiandrosterone; SHBG, sex hormone-binding globulin.
Unfortunately, this pregnancy resulted in a spontaneous miscarriage at 11 weeks' gestation.
Pelvic magnetic resonance imaging was performed just after the miscarriage for better
elucidation of the clitoral anatomy. This revealed a 6.2 × 4.2-cm midline cystic mass
extending from the bladder base and neck into the anterior periurethral space ([Fig. 2 ]). Echotexture of the cyst contents was consistent with proteinaceous material that
demonstrated marked T1 hyperintensity and mild T2 hyperintensity ([Fig. 2B ]). Based on the magnetic resonance findings, we suspected a possible congenital urethral
duplication cyst or atypical obstructed urethral diverticulum.
Fig. 2 Magnetic resonance imaging of the pelvis. (A) Sagittal image of the pelvis showing
intense T1 hyperintensity within a large 6.2 × 4.2-cm cyst (arrow), which extends
cephalad into the anterior periurethral space. (B) Mild hyperintensity on a T2-weighted
sagittal image, corresponding to the proteinaceous fluid-filled cyst.
The patient was referred for urogynecological evaluation and subsequently underwent
resection of the clitoral mass. The mass was contained by an easily identifiable cyst
wall, which was meticulously dissected away from the underlying crura. Curiously,
the lesion was so large that it extended atop the anterior bladder wall, though intraoperative
cystogram and cystourethroscopy revealed no abnormal drainage from the structure to
surrounding lumens including the urethra and bladder. Histopathologic examination
of the patient's surgical specimen revealed a 7.5 × 2.0 × 0.4 cm deflated unilocular
cyst, containing a hemorrhagic cloudy fluid, with a wall thickness averaging 0.1 cm
and a slightly granular lining. Microscopically, the specimen was marked by a squamous
epithelium ([Fig. 3A ]), and the interior was composed of extensive histiocyte infiltrates, specifically
hemosiderin-laden macrophages amid necrotic debris. These findings were thought characteristic
of a ruptured epidermal inclusion cyst ([Fig. 3B ]). To exclude the presence of endometrial stroma or urothelial tissue,[2 ] the specimen was submitted for CD10 and CK20 staining,[3 ]
[4 ] respectively, both of which turned out negative. Postoperatively, the patient had
no difficulties from pain, infection, dysuria, or any dyspareunia—in fact, she conceived
again at 2 months after the surgery. She is currently in her second trimester, doing
well, and has not reported any changes of her clitoral size or any bladder dysfunction.
A detailed fetal anatomical survey by ultrasound revealed a female fetus, with measurements
consistent with established dates and normal-appearing urogenital structures.
Fig. 3 Histopathology of surgical specimen. (A) Characteristic features of a ruptured epithelial
inclusion cyst are shown: squamous epithelial lining (short arrow), necrotic debris
(medium arrow), and inflammatory cells (long arrow). Hematoxylin and eosin, 5× magnification.
(B) Macrophages (short arrows) consuming necrotic debris (long arrow) are characteristic
of ruptured epidermal inclusion cysts. Neovascularization (medium arrow) is consistent
with granulation tissue changes. Hematoxylin and eosin, 20× magnification.
Discussion
The differential diagnoses for adult-onset clitoromegaly are divided into hormonal
and nonhormonal etiologies ([Table 2 ]). The most pronounced cases of clitoromegaly tend to result from hormonally active
virilizing tumors, usually of ovarian origin, including Leydig-cell tumors, granulosa
cell tumors, thecomas, and sex-cord stromal tumors, which can present with markedly
elevated testosterone levels near normal-male range, are fast-growing, and correlate
with rapid development of symptoms often over the course of a few months.[5 ] Occasionally, adrenal tumors such as adrenocortical carcinomas or adenomas can also
lead to clitoromegaly.[6 ]
[7 ] More commonly, however, patients presenting with ambiguous genitalia are found to
have late-onset congenital adrenal hyperplasia, or CAH,[8 ] including deficiencies in 21-hydroxylase, 3-β-hydroxysteroid dehydrogenase, 11-β
hydroxylase, and 17-α hydroxylase. In contrast to classical CAH where virilized genitals
are present at birth, late-onset CAH is diagnosed in adulthood and tends to be milder,
presenting with hirsutism, acne, and irregular menses. However, clitoromegaly to the
degree observed in our patient would not likely be attributed to CAH, especially given
her lack of hirsutism and acne, menstrual irregularities, or infertility. Biochemically,
CAH can present as insufficient glucocorticoid production and excess synthesis of
mineralocorticoid precursors. However, our patient had no history of hypertension
or hypokalemia. Although her first child was a boy, who is healthy and well, developing
normally, and without any significant medical history, we did not know the gender
of her second fetus and therefore had to evaluate for these conditions, as maternal
hyperandrogenism can predispose a female fetus toward virilization, and empiric treatment
using dexamethasone early in pregnancy, prior to completion of development of the
fetal external genitalia, is often considered when the risk for an affected fetus
is high.[1 ]
Table 2
Differential Diagnoses of Acquired Clitoromegaly
Hormonal causes
Nonhormonal causes
Late-onset congenital adrenal hyperplasia
Neurofibromatosis
Polycystic ovary syndrome
Cysts
Virilizing ovarian or adrenal tumors
Female genital cutting, trauma
Cushing's disease or syndrome
Hypertrophy due to excess masturbation
Synthetic androgen exposure
Beckwith-Wiedemann syndrome
Pregnancy-related:
Vulvar tumors, primary or metastatic
Placental aromatase deficiency
Cavernous hemangiomas
Luteoma
Diverticuli
Hyperreactio luteinalis
Abscesses
Fistula
Clitoromegaly specifically seen during pregnancy encompasses an interesting group
of conditions including luteoma, hyperreactio luteinalis, and placental aromatase
deficiency, all of which lead to a transient maternal hyperandrogenism. Luteomas are
formed by solid proliferation of luteinized stromal cells under the influence of human
chorionic gonadotropin (hCG) during pregnancy and is typically seen at or near term.[9 ]
[10 ] In contrast, hyperreactio luteinalis can occur at any time during pregnancy and
is marked by ovarian enlargement due to theca lutein cysts.[11 ] Both of these conditions can involve either unilateral or bilateral ovaries, and
although nonneoplastic and usually self-limited, clinically they can mimic ovarian
neoplasms and cause local symptoms, therefore biopsy or surgery is sometimes performed
for diagnostic and therapeutic purposes. The development of bilateral enlarged ovaries
and high hCG levels are also thought to be linked with imbalance of angiogenic factors,
which can lead to preeclampsia.[12 ] Placental aromatase deficiency is a defect in conversion of androgen to estrogen,
which is a process that normally protects the fetus against virilizing androgens.
A deficiency in aromatase can cause hyperandrogenemia, leading to maternal virilization
in the third trimester as well as pseudohermaphroditism in affected female fetuses.[13 ] We speculated that our patient's first pregnancy could have hormonally “primed”
the patient and therefore served as a trigger for an extremely rare case of clitoromegaly,
but we ultimately abandoned this hypothesis based on the early presentation of her
clitoromegaly in relation to the pregnancy, as well as lack of systemic hyperandrogenic
cues.
The waxing and waning course of our patient's clitoromegaly and its apparent manifestation
during her first pregnancy were baffling, especially considering her normal ambient
hormone levels during the course of our evaluation. These data, along with the observation
that her virilization appeared exclusively limited to the clitoris, pointed to a local,
nonhormonal cause for the clitoromegaly. Pseudoclitoromegaly is an entity that results
from mass lesions, such as cysts, diverticuli, abscesses, tumors, or prolapsed genitourinary
organs that mimic true clitoral enlargement. Epidermoid or epithelial inclusion cysts
are a common type of cutaneous cysts that result from implantation of epidermal elements
in the dermis and can occur throughout the body. In the clitoris, it usually occurs
as the result of genital mutilation, trauma, or infection and can be painful.[14 ] Interestingly, it is thought that such cysts may be able to respond to estrogen
stimulation, thereby providing a plausible mechanism for the cyclical nature of the
mass.[15 ]
[16 ] Alternatively, the increased blood flow and pelvic pressure associated with an enlarging
gravid uterus provides a conceivable explanation for the pregnancy-related recurrence
of clitoromegaly in our patient.
Surgery is the treatment of choice for symptomatic epidermoid cysts and usually involves
marsupialization or enucleation of the mass. These procedures are usually well tolerated
and curative.[8 ] Complete excision of the cyst wall is desired, as any remnant epithelial tissue
may lead to cyst recurrence later.
Conclusion
Evaluation of adult-onset clitoromegaly requires careful assessment by detailed physical
exam, hormonal testing, and, when possible, imaging studies. An urgency in unraveling
the underlying diagnosis is of the essence when this phenomenon is identified in pregnancy,
as fetal implications of maternal hyperandrogenemia can be devastating. In this case,
our patient underwent an expeditious and extensive evaluation to find that this was
a nonhormonal process, and she was able to achieve a satisfactory surgical cure of
her condition with no detriment to future fertility and reproductive health.
