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Novita ED*, As’adi AS**
*Departement of Obstetric and Gynecology, Faculty of Medicine-Universitas Indonesia, Cipto
Mangunkusumo Hospital
**Departement of Obstetric and Gynecology, Fatmawati Hospital

Androgen insensitivity syndrome (AIS) is an X-linked recessive condition due to a complete
or partial insensitivity to androgen, resulting in a failure of normal masculinisation of the
external genitalia in chromosomally male individuals. Complete Androgenic insensitivity
syndrome (CAIS), one of AIS categories, is an androgen receptor defect disorder associated
with vaginal and uterine agenesis in women with a 46,XY karyotype. Here, we describe a 20
years old female with primary amenorrhea. She was investigated and had gonadectomy. She
was confirmed of having androgen insensitivity syndrome after testing for abdominal
ultrasound, MRI exam and karyotyping. Management of androgen insensitivity syndrome
includes multidisciplinary approach and involves gonedectomy to avoid gonadal tumor in
later life. Hormone replacement therapy (HRT) and psychological support are required in
long-term basis.

Disorder of sex development (DSD) is defined as congenital condition in which the
development of chromosomal, gonadal or anatomic sex is atypical. 1 Androgenic insensitivity
syndrome (AIS) is the most common cause of disorders of sexual differentiation in 46, XY
individuals. It results from alterations in the androgen receptor gene, leading to a frame of
hormonal resistance.2,3 AIS could be divided into three different disorders depending on the
degree of androgen insensitivity: Complete AIS (CAIS), characterized by complete
feminization of the external genitalia; Partial AIS (PAIS), with a variable clinical
presentation (mainly female, mainly male or ambiguous external genitalia); and Mild AIS
(MAIS), characterized by male external genitalia and impaired pubertal virilization. 4 Patients
with complete androgen insensitivity syndrome are phenotypically females, but their genetic
composition is that of make karyotype 46, XY. The defect lies in the X- chromosome
affecting the gene responsible for the  androgen intracellular response to testosterone or

dihydrotestosterone.  The gene is located on a highly conserved region of x chromosome in
the peri-centromeric region of the log arm of Xq11-12. 2,4

Case Report

A 20 year old female, presented to us with complaint of primary amenorrhea. She had no
relevant past medical or family history.   The patient herself is the second among three
children. Patient’s mother had no problem in conception. The patient was born following a
full-term normal delivery to non-consanguineous parents, and her mother denied the use of
any sex hormone drugs or exposure to radioactive substances during pregnancy. Her weight
59 kg, height was 165 cm and body mass index was 21.6 kg/m2. The patient had no axillary
hair, Tanner stage 4 breast development, and Tanner stage 1 pubic hair growth. Inspection of
her external genitalia showed well-developed labia majora and clitoris, poorly developed
labia minora. However, a short, blind vaginal pouch was detected with a depth of 2 cm.
Urethral orifice and anus were normal. No inguinal masses were palpable on both sides.

Figure 1. Normal breast evelopment and external female genitalia

Transvaginal ultrasonography and MRI showed the absence of a uterus and ovaries. From US
exam, we also found solid mass at right iliac fossa, hypoechoic size 26x18x18 mm, suspected
from gonad. We found uterine agenesis and non visualized ovaries. Pelvic MRI also showed
the testis structure at lateral of bilateral iliac artery sized 1.92x1.77x2.69 cm for the right
testis and 1.25x1.25x1.38 cm for the left testis. Uterus and vagina structures are not seen. We
did not take laboratory evaluation of testosterone, follicle-stimulating hormone, luteinizing
hormone and estradiol serum. Chromosomal analysis confirmed a normal male 46, XY
karyotype (Fig.2). The patient was diagnosed with Complete androgen insensitivity syndrome

Figure 2. Chromosomal analysis

Gonadectomy was recommended because of the malignant transformation potential of occult

testicular elements. We performed bilateral gonadectomy in August 2019 through the
inguinal approach, which allowed easy access to the testes in both inguinal canals.  Under
laparoscope, the uterus and ovaries were not visualized. The gonads attached to bilateral
intern inguinal foramen. The right gonad measured 2x1 cm, had an ovary-like appearance
with a complete capsule, and was white, smooth and hard in texture; while the left gonad
measured 1x1 cm and had a similar appearance to the right gonad. Testicular tissue was
pulled out by coagulating and cutting it on both sides (Fig. 3). The entire procedure took 2.5 h
with  minimal blood loss. The surgery was uncomplicated, and pathological examination of
the gonads showed the immature seminiferous tubules at both sides (Fig. 4). Testosterone
post operative was  14.6 ng/dL  (normal in woman 8.40 – 48.1 ng/dL). The patient was given
Estradiol valerate 2 mg/day for hormonal therapy for the next management and vaginoplasty
when patient will get married for sexual intercourse.

Figure 3. Laparascopic procedure

Figure 4. Seminiferous tubules immature


Complete Androgen Insensitivity (CAIS) is the most frequent manifestation of AIS and was
first described by Morris in 1943. An androgen receptors (AR) gene mutation is found in
more than 95% of patients with CAIS: 70% of them result from maternally inherited
mutations.4 CAIS prevalence in 46,XY males is estimated from 1 in 20.400 to 1 in 99.100.3,4
Patients with CAIS have normal female external genitalia with a 46, XY karyotype and
undescended testes due to complete unresponsiveness towards androgen action. 4

The diagnosis of CAIS still represents a demanding challenge and is often delayed until the
evidence of primary amenorrhea during puberty, except for the cases in which bilateral
inguinal hernia appears during childhood.5 In fact, these individuals normally develop
primordial testes in the abdomen during foetal life by the seventh week after conception due
to the presence of the SRY region and start of testosterone production, whose action is not
effective because of the AR mutation in target cells. Therefore, these patients lack other male
genitalia, except for testes. Additionally, internal female genitalia are also absent because the
abdominal testes normally produce AMH, which impedes the development of the uterus,
cervix and proximal vagina. However, the distal part of the vagina can be observed because it
is not under AMH control, but it is always shorter than normal and blind-ending.  In patients
with CAIS, puberty typically appears later and has a slower advance than in the general
female population. However, breasts and female adiposity develop regularly due to the action
of oestradiol deriving from the peripheral aromatization of testosterone. In contrast, pubic and
axillary hair is absent or very rare because it mostly depends on androgen action. 4

In regard to final height, CAIS patients are typically taller than the healthy female population
due to the presence of the Y chromosome, which intervenes on statural growth independently
of hormonal status. The typical hormone profile is characterized by a high level of luteinizing
hormone (LH) above the usual reference range, while the follicle stimulating hormone (FSH)
level is usually normal, probably due to gonadal inhibin regulation. Moreover, the basal
testosterone value results are typically within the normal male range but increased relative to
the female range, while the oestradiol level is normal referring it to the male range but in the
lower range for females. 4 Unfortunately, our patient did not have hormonal examination.

Gonads can be localized and investigated by modern imaging techniques. In the first line, this
is best achieved by ultrasound (US). In CAIS, the testes-like features like size and shape as
well as the low echogenicity and vascular structure are often readily detected, whereas
müllerian structures are more difficult to identify. Further investigation by magnetic
imaging (MRI) can reveal localization of intra-abdominal gonads and genital duct anatomy.
If a gonad cannot be detected or a gonadal tumor is suspected, laparoscopy is needed for
detailed assessment and gonadal biopsy will result in gonadectomy. 6

As part of the differential diagnosis, one must consider Mayer-Rokitansky-Ku¨ster-Hauser

(MRKH) syndrome or Mullerian Agenesis, a more common cause of primary amenorrhea
with an incidence rate of 1 in 5000. The MRKH patient, who will also have primary
amenorrhea, normal breast development, and an underdeveloped vagina, typically has normal
axillary and pubic hair. In this clinical setting, a karyotype is critical to making the diagnosis.
CAIS can be differentiated from Swyer’s syndrome, XY complete gonadal dysgenesis, based
on the lack of breast development and short stature typically seen with the later. Imaging
studies, such as ultrasound and MRI, are warranted to help delineate internal anatomy,
localize testes, and rule out testicular tumors.7

The clinical management of an XY female patient generally includes prophylactic

gonadectomy to prevent malignant transformation, appropriate hormone replacement therapy
(HRT), and psychological counseling. The testes may be found in the abdomen, inguinal
canal, or labia. Abnormalities of testicular development and risk of gonad malignancy
increase after puberty. Testis tumor developing risk is thought to be 3.6% by 25 years and
33% by 50 years. In a case series of 43 patients with AIS by Rutgers and Scully, 63%

hamartomas, 23% sertoli cell adenomas and 9% malignant tumors including two seminomas,
one intratubular germ cell neoplasm with early stromal invasion and a malignant sex cord
tumor were reported. Prophylactic gonadectomy has been recommended in complete
androgen insensitivity syndrome (CAIS) because of an increased risk for the development of
malignant germ cell tumors in the intra-abdominal gonads. 6 At this time, it is mostly agreed
that gonadectomy in CAIS children prior to puberty is not warranted on a prophylactic basis.
These children should undergo their usual pubertal development with endogenous hormone
synthesis and should be informed about their condition in due course. Gonadectomy is
recommended during the postpubertal period to help the development of feminization during
puberty when the malignant changes in germ cells are relatively late and rare and to allow
involvement of the patients in important decisions affecting their body and health. The
occurrence of an inguinal hernia during childhood should not be taken as an indication for
early gonadectomy. 6 Prepubertal gonadectomy is now only considered if inguinal testes are
physically or esthetically uncomfortable, and if inguinal herniorrhaphy is necessary. 7
Laparoscopic approach togonadectomy is an excellent minimally invasive technique. It
provides good visualization of internal genitalia, and even small gonads and mullerian
structures can be removed. Postoperatively, recovery is rapid with minimal discomfort to
patient affording early mobilization. 10

After gonadectomy has been performed, exogenous HRT should be provided for XY female
patients to initiate, mature, and maintain secondary sexual characteristics. Prevention of
coronary heart disease and osteoporosis is an additional benefit of estrogen therapy. 9 The
classic HRT for CAIS patients is based on oestrogen therapy, but current data are not able to
indicate the best daily dosage. Therefore, HRT should be started at the lowest dose (i.e., oral
ethinyl oestradiol 2.5–5 mcg/day or 50–100 ng/kg/day) and then gradually increased to the
adult dosage (i.e., oral ethinyl oestradiol 20–25 mcg/day) in order to simulate physiological
secretion.2,4 Specifically in prepubertal subjects, HRT should be slowly increased every 6
months in order to complete feminization, such as breast development, changes in body
composition and reaching of female body shape, in approximately two years. After complete
breast development, therapy should be continued with a regular daily dose.4

Psychological counseling for the patient and their parents is an important element of
management for patients with 46, XY DSD. In general, most individuals with 46, XY DSD
have a completely female phenotype; therefore, female gender identity may be reinforced. 6

Sterility is the rule in CAIS and PAIS. CAIS is characterized by the absence of a uterus and
normally functioning gonads; nevertheless, the population of testicular germ cells decreases
rapidly after the first year of life.2 Gender change is very rarely described in CAIS and there
are just four cases of gender change in individuals with CAIS. Therefore, gender dysphoria in
CAIS is considered truly transgenderism. However, sexual functioning and sexual quality of
life demonstrated less-positive outcome in CAIS patients in comparison with normal
woman. 3 When patients experience difficulty with penetration due to vaginal hypoplasia, a
functional vagina may be considered for normal sexual satisfaction by progressive vaginal
dilation, the McIndoe vaginoplasty, the Williams vulvovaginoplasty, vaginal creation using
bowel, or laparoscopic Vecchietti method. 2,6 

Complete Androgenic insensitivity syndrome (CAIS) is characterized by a lack of androgen
receptor activity. Most cases are transmitted in an X-linked recessive pattern. CAIS was
diagnosed on the basis of history of primary amenorrhoea and clinical gynecologic
examination. Ultrasonography and MRI imaging of the pelvis helped in the localization of
gonads in inguinal canals. As patient was in postpubertal age group and willing for surgery,
laparoscopic approach to gonadectomy is an excellent minimally invasive technique carried
out to prevent malignant transformation of gonads. Hormone replacement therapy was
initiated and the patient is being followed up by a multidisciplinary team of doctors for
psychological and emotional support.


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