WORKUP
Lab Studies:
- A karyotype is essential
to differentiate an undermasculinized male
from a masculinized female.
- Levels of testosterone
and DHT establish the presence of normal
steroidogenesis.
- If the testosterone
level is low for age, obtain levels of
dehydroepiandrosterone (DHEA),
androstenedione, and their precursors,
17-hydroxypregnenolone and
17-hydroxyprogesterone. These levels allow
identification of errors in the steroid
biosynthetic pathways.
- An elevated ratio of
testosterone to DHT indicates a 5-alpha
reductase deficiency, a possible
differential for patients with PAIS but
usually not for CAIS. Low levels of
testosterone in the absence of evidence of
defective steroidogenesis suggest
testicular dysgenesis or Leydig cell
aplasia/hypoplasia.
- Mutation analysis of the
androgen receptor gene is now commercially
available. It detects upwards of 95% of the
mutations for CAIS and PAIS. he analysis is
performed on DNA obtained from buccal swabs.
Howoever, the testing is slow (about 6 wk
for results) and expensive (not covered by
some insurances).
Imaging Studies:
- A pelvic ultrasound
examination frequently is useful.
Identification of any müllerian structures,
such as uterus or fallopian tubes, is
inconsistent with a diagnosis of CAIS or
PAIS.
Histologic Findings:
Histologic
examination of the testes in patients with
CAIS or PAIS should show fairly normal
testicular structure, although the numbers of
spermatogonia and/or sperm may be reduced
markedly in postpubertal patients.
Given current management
recommendations (see
Treatment), a histologic examination may
be impossible to perform until the patient is
in late adolescence or early adulthood.
TREATMENT
Medical
Care:
Medical care for a patient with
AIS has 2 aspects: hormone replacement therapy
(HRT) and psychological support.
- Hormone replacement
therapy
- HRT is the first and
less complex aspect. All patients with
CAIS and most patients with all but the
mildest forms of PAIS undergo gonadectomy
at some point in their treatment (see
Surgical Care). Adolescent and adult
patients with AIS require hormone
replacement.
- For patients with CAIS,
hormone therapy almost always consists of
estrogen replacement. The general belief
is that these women do not require
progesterone because they have no uterus.
Some evidence suggests that progesterone
therapy combined with estrogen replacement
may lessen the long-term risk of breast
cancer, although this type of therapy is
debatable. More recent meta-analyses
suggest progesterone administration may
have little or no advantage for patients
without a uterus. Therapy usually is
initiated with a low dose of estrogen
alone, then is increased to routine adult
dosing. Progesterone is added, if
considered appropriate, after maintenance
therapy with estrogen is established.
- For individuals with
PAIS, traditional therapy has mirrored
therapy for individuals with CAIS.
Patients with PAIS who have a male gender
identity, however, may be treated with
testosterone and/or DHT. The advantage of
DHT is that it cannot be aromatized to
estrogen. No medical consensus has been
reached about this therapy; no dosage
schedules have been established. Therapy
may vary depending on the nature of the
gene defect.
- Psychological support
is probably the most important aspect of
medical care from the patient's point of
view. In a family with an affected infant,
the parents are the primary clients.
Parents need genetic counseling to
understand the nature of the condition and
the risk of recurrence (25% for each
subsequent pregnancy) as well as to
identify other potential carriers. In
addition, parents often benefit from the
services of a pediatric psychologist or
child and adolescent psychiatrist to help
adjust to their child's condition,
including support on how to inform the
child, over time and in an age-appropriate
manner, about the condition. Genetic
counselors do not provide this type of
ongoing family support.
- In a family with an
affected older child, the patient is the
primary client, although family members
also may require psychological services.
In these cases, too, pediatric
psychologists or child and adolescent
psychiatrists are the preferred clinicians
because of their medical background and
ability to help address medical,
emotional, and psychological issues or
questions. If at all possible, the
therapist also should have experience
dealing with patients who have intersex
conditions, even if this experience is not
specific to AIS. The patient needs to
establish a long-term relationship with
the therapist to discuss new issues that
arise as the child matures. (At times,
these visits will be infrequent.) For
adults with AIS and other intersex
conditions, lack of emotional and
psychological support has been a major
criticism of the medical care system.
- The primary care
practitioner can coordinate medical care
for a child with AIS, or coordination may
be performed by a pediatric
endocrinologist, especially as part of a
multidisciplinary team. Carefully maintain
communication and coordination among
primary care, genetic, endocrinologic, and
surgical services to avoid trauma to the
child and family.
- Contact with other
individuals who have AIS is another source
of psychological and emotional support for
the patient. The Androgen Insensitivity
Syndrome Support Group (AISSG) has
constituent organizations in the US,
United Kingdom, and Australia, as well as
contacts and/or smaller groups in many
European countries. AISSG maintains an
excellent web site at
http://www.medhelp.org/www/ais that
provides a large amount of medical
information, AISSG contact points, and
patients' accounts of their experiences
with AIS. This type of contact can
markedly decrease feelings of
"freakishness" and "being the only one,"
which patients and families frequently
experience.
Surgical Care:
For individuals with AIS, the
standard of care is an orchidectomy to prevent
possible malignant degeneration of the testes.
The timing of such surgery has been debated.
Historically, early surgery was assumed
preferable to avoid raising uncomfortable
psychosexual issues during adolescence or
young adulthood. More recently, surgery during
the late teenage years or early 20s has been
preferred. Later orchidectomy allows pubertal
development to occur spontaneously with the
production of estrogen from the aromatization
of the high levels of testosterone normally
produced.
In addition, many women with
AIS require vaginal lengthening procedures.
Orchidectomy and vaginal lengthening
procedures may be performed concurrently if
surgery is postponed until the patient
matures. Ultrasound examination of the gonads
can monitor potential tumor development.
Vaginal lengthening
procedures have stirred ongoing debate. In the
past, many vaginal lengthening procedures were
performed before or at onset of puberty. Many
patient advocates now support delaying these
procedures until the patient is sufficiently
mature to participate actively in treatment
decisions (ie, whether to undergo surgery,
what type of procedure).
Similarly, in female gender
patients with PAIS who have some degree of
masculinization of the genitalia at birth,
cosmetic reconstructive surgery traditionally
has been performed in infancy. Patient
advocates, including medical ethicists and
intersex advocates, now endorse delaying this
reconstructive surgery until children are old
enough to decide for themselves. Medical
practice and court decisions appear to be
moving in this direction as the new standard
of care.
Consultations:
Initial
consultation for the child with AIS should
include a geneticist and a pediatric
endocrinologist. These individuals order and
interpret the tests required to confirm the
diagnosis. Additionally, these clinicians can
provide appropriate information about the
child's condition. An endocrinologist helps
set the future course for medical and surgical
therapy.
Because this is a
particularly stressful diagnostic possibility
for many families, consult an appropriate
mental health professional to provide
psychological and emotional support. Part of
the mental health professional's role is to
facilitate communication between the medical
team and the family.
MEDICATION
HRT with
estrogens has been the standard of practice
for postorchidectomy patients with AIS. While
most physicians prescribe estrogen alone, some
physicians have begun adding progesterone to
the regimen, based upon a relatively small
amount of data that suggests progesterone may
lower the risk of breast cancer, have a role
in the ductal development of the breast, or
have some role in bone mineral accretion.
(These potential benefits are hypothetical.)
Administration of androgens
in more masculinized patients with PAIS has
been suggested but remains highly
controversial. Because some patients now are
assigned male gender and are identifying as
males in adulthood, this treatment probably
will be described more extensively soon. No
data currently exist regarding dosage,
administration, benefits, or adverse effects
of androgen administration to the AIS
population. Dosage and response likely depends
upon the severity of the receptor defect. DHT
or androgen analogues that cannot be
aromatized to estrogen appear to be the
treatments of choice.
Drug Category: Estrogens
-- Used as hormone replacement for women with
AIS who are postgonadectomy to support
development and maintenance of secondary
sexual characteristics and to prevent
osteoporosis.
Drug Name
|
Conjugated estrogens (Premarin)
-- Represents the average composition of
estrogens in pregnant mare urine. Composed
of estrone, equilin, 17-alpha estradiol,
equilenin, and 17-alpha dihydroequilenin
(in small amount). Rapidly biotransformed
after administration. |
| Adult
Dose |
0.3-0.625 mg PO qd
If cycling with progesterone, administer
on days 1-21 of cycle
|
|
Pediatric Dose |
In girls who are
orchidectomized prepubertally, start
estrogens at lowest available dose,
preferably when bone age is at least 13 y
Appropriate beginning dose: 0.3 mg qod;
then gradually increase dose to mimic
normal female puberty until adult levels
achieved
|
|
Contraindications |
Documented
hypersensitivity; avoid in patients
diagnosed with breast cancer, undiagnosed
abnormal genital bleeding, active
thrombophlebitis or thromboembolic
disorders, or in patients with history of
such disorders with previous estrogen use
(except when used in treatment of breast
or prostatic malignancy) |
|
Interactions |
May reduce
hypoprothrombinemic effect of
anticoagulants; coadministration of
barbiturates, rifampin, and other agents
that induce hepatic microsomal enzymes may
reduce estrogen levels; increased
pharmacologic and toxicologic effects of
corticosteroids may occur via inactivation
of hepatic P450 enzyme; loss of seizure
control has been observed when
administered concurrently with hydantoins
|
|
Pregnancy |
X - Contraindicated in
pregnancy |
|
Precautions |
May cause some degree of
fluid retention and require careful
observation; certain patients may develop
undesirable manifestations of excessive
estrogenic stimulation |
Drug Name
|
Ethinyl estradiol (Estinyl)
-- Bioequivalence of various estrogens is
quite unclear, but 5-10 mcg of ethinyl
estradiol equals approximately 300 mcg of
conjugated estrogens in terms of
quantifiable metabolic effects on sex
hormone binding globulin and gonadotropins.
|
| Adult
Dose |
20 mcg PO qd |
|
Pediatric Dose |
20 mcg PO qod |
|
Contraindications |
Documented
hypersensitivity; avoid in patients
diagnosed with breast cancer, undiagnosed
abnormal genital bleeding, active
thrombophlebitis or thromboembolic
disorders, or in patients with history of
such disorders with previous estrogen use
(except when used in treatment of breast
or prostatic malignancy) |
|
Interactions |
May reduce
hypoprothrombinemic effect of
anticoagulants; coadministration of
barbiturates, rifampin, and other agents
that induce hepatic microsomal enzymes may
reduce estrogen levels; increased
pharmacologic and toxicologic effects of
corticosteroids may occur via inactivation
of hepatic P450 enzyme; loss of seizure
control has been observed when
administered concurrently with hydantoins
|
|
Pregnancy |
X - Contraindicated in
pregnancy |
|
Precautions |
May cause some degree of
fluid retention and require careful
observation; certain patients may develop
undesirable manifestations of excessive
estrogenic stimulation |
FOLLOW-UP
Further Inpatient
Care:
- Patients with AIS require
further inpatient care only for
postoperative management.
Further Outpatient
Care:
- Outpatient follow-up
medical care for patients with AIS focuses
on HRT. Appropriate continued treatment with
estrogen is required to prevent
osteoporosis. Perform assessments of bone
mineral density every few years to ensure
treatment is adequate.
- Many patients may require
ongoing long-term psychotherapy to resolve
psychosexual identity issues raised by the
diagnosis of AIS. Therapy should be provided
on a continuing or recurrent basis for the
patient and family, beginning at the time of
diagnosis.
Deterrence/Prevention:
- AIS prevention revolves
around the identification of women who may
carry the gene. Provide appropriate
nondirective counseling, including
information about the condition and the
woman's risk of having an affected child, so
that she can make an informed decision about
whether to have children.
Complications:
- Osteoporosis and
psychological sequelae are the 2 major
complications of AIS, and their risk can be
decreased significantly by appropriate
therapeutic intervention. These
interventions involve HRT with estrogen to
prevent osteoporosis and early and
continuing involvement with an appropriate
mental health professional for psychological
and emotional support.
Prognosis:
- The medical and
psychological prognosis for a woman with AIS
is excellent if she has appropriate support
and counseling.
Patient Education:
- Educate patients and
families about the full nature of AIS.
Information for children can be provided in
an age-appropriate format, taking care to be
as accurate and understandable as possible.
As the child matures, education should
include information about issues such as
vaginal hypoplasia and osteoporosis.
Encourage patient participation in decisions
about medical and surgical alternatives.
Patient-oriented educational materials are
available through the AISSG
MISCELLANEOUS
Medical/Legal
Pitfalls:
- Legal challenges to the
management of patients with CAIS have not
been a problem to date, and such management
appears to have little likelihood of
becoming a legal problem. In PAIS cases,
however, intersex activists are pursuing the
possibility of suing physicians who perform
early genitoplasty. Legal challenges appear
likely in cases involving demonstrable loss
of sexual function or in which the adult
gender identity conflicts with the
surgically created sex. Physicians providing
care for children with PAIS and genital
ambiguity should be aware of this
possibility, although enlightened management
should lead to outcomes that make lawsuits
unlikely.
Special Concerns:
- In addition to
osteoporosis and gender identity issues,
women with AIS consistently mention a
further concern about their medical care.
These women often describe medical visits as
traumatic experiences; consequently, they
often avoid medical care, including HRT.
These issues relate to the relative rarity
of their condition as follows:
- First, these women find
that physicians and staff frequently are
unfamiliar with AIS, resulting in repeated
questioning about the nature of their
condition that start at the registration
desk. Many of these women feel frustrated
and embarrassed by being required to
explain the diagnosis to a stranger in
such a public place as the registration
desk in an office waiting room, only to
have to explain it again to the nurse and
sometimes yet again to the physician.
- Second, patients who
are seen in a teaching facility often find
multiple students or residents
participating in their visit, particularly
during the genital examination. Group
examinations become a problem for the
teaching environment because they increase
the woman's feeling of being "part of a
freak show" and create attendant
embarrassment. While students need to be
exposed to these conditions and learn
about them, the patient's feelings and
sense of privacy, even in childhood, must
be protected.
- A healthcare provider who
is an AISSG member suggests (1) involving
only a single trainee in any visit, (2)
obtaining the patient's permission for the
trainee's involvement before the start of
the visit, and (3) giving the trainee time
to get to know the patient as a person
before any examination, a process that can
be combined with obtaining the patient's
history. At all costs, avoid group showings
of the patient's genitalia, regardless of
the patient's age.
|
