http://www.springerlink.com/content/l0776r8734j717h4/fulltext.html

Pediatric Surgery International
© Springer-Verlag 2008
10.1007/s00383-008-2232-7
Original Article

Gender assignment and hormonal treatment for disorders of sexual
differentiation

Shilpa Sharma1 and D. K. Gupta1 Contact Information
(1) Department of Pediatric Surgery, All India Institute of Medical
Sciences, New Delhi, India

Contact Information D. K. Gupta
Email: profdkgupta@...

Published online: 14 August 2008

Abstract
Purpose To study the gender assignment and hormonal treatment
advocated for disorders of sexual differentiation (DSD).
Methods A study was done on patients who were reviewed in the
Pediatric Intersex Clinic to evaluate the pattern of gender assignment
and hormonal treatment advocated.
Results and conclusion The patients included male pseudohermaphrodite
(MPH) 169; congenital adrenal hyperplasia (CAH) 91; mixed gonadal
dysgenesis (MGD) 29; true hermaphrodite (TH) 25; pure gonadal
dysgenesis (PGD) 2; persistent mullerian duct syndrome (PMDS) 2 and
others (micropenis, severe hypospadias with cryptorchidism, 46XX male)
39. Out of 91 cases of CAH, 70 (76.9%) were on steroids (prednisolone,
hydrocortisone) and/or mineralocorticoids (fluoricortisone) for
adrenal suppression. Out of 146 cases of male pseudohermaphrodite and
21 cases of true hermaphrodite and 3 cases of mixed gonadal dysgenesis
reared as males, testosterone was given for local application for
phallic growth in 101 and/or as systemic injection for mental makeup
after puberty in 41 cases. Systemic testosterone injection was also
given for 7 cases of CAH reared as males. Out of 26, 15 cases with
mixed gonadal dysgenesis and one out of 2 cases of pure gonadal
dysgenesis that attained puberty after being reared as females, after
female genitoplasty, were given conjugated oestrogen (Premarin)
supplemented with progesterone, as the uterus was preserved. For 12
post-pubertal cases of complete androgen insensitivity syndrome (AIS),
only premarin was given as there was no uterus. Growth hormone and Gn
RH analogue was given in 2 patients with CAH to tide over the early
bone maturation induced by hormones with equivocal results. Thus
judicious hormonal supplementation based upon type of DSD and gender
assigned can provide a psychological and cosmetic benefit to patients
with DSD.

Keywords Intersex disorders - DSD - Gender assignment - Hormones -
Genitoplasty

Introduction
The management of disorders of sexual differentiation (DSD) is complex
for those who do not have the exposure to a large number of cases [1,
2]. The management should have a multidisciplinary approach with
proper discussion at points of decision making giving due regard to
the patient and the family concerns. The success lies in timely
treatment and advice based on wisdom to prevent the psychological
stress associated with this disease imposed on the parents initially
and then transferred to the patients as they gain awareness. The
disease carries a social stigma that varies in different communities
and different countries.

In the most common five main groups of intersex disorders: female
pseudohermaphrodite (ovary only); male pseudohermaphrodite (MPH,
testis only); true hermaphrodite (TH, ovary + testis); mixed gonadal
dysgenesis (MGD, testis + streak gonad) and pure gonadal dysgenesis
(PGD, streak + streak gonad), the treatment involves surgery,
appropriate hormonal supplementation and psychological support. For
all practical purposes, the first four groups are the common main ones.

Purpose
The hormonal treatment given for cases with disorders of sexual
differentiation (DSD) depends upon the gender assigned. A study was
conducted to analyse the hormonal treatment advocated for DSD
depending upon the type of anomaly and the gender assigned.

Patients and method
This study is based on the treatment policy adopted at the Pediatric
Intersex Clinic at our institute, having a registry of 1,188 patients
till 2007. The study was approved by the Institutional review board
for clinical manuscripts. Patients who attended the clinic from
2005–2007 were reviewed to study the pattern of gender assignment and
hormonal treatment advocated in the different types of DSD. The
algorithm that was adopted for gender assignment is depicted in Fig.
1. The records of the hormonal treatment advocated according to the
gender assigned were studied.

MediaObjects/383_2008_2232_Fig1_HTML.gif
Fig. 1 Algorithm for gender assignment in disorders of sexual
differentiation (DSD). The four main types of DSD are MPH male
pseudohermaphrodite, CAH congenital adrenal hyperplasia, MGD mixed
gonadal dysgenesis, TH true hermaphrodite. The gender assigned was
mainly based on the phallic growth and the family desires

For male sex assignment, the required surgical procedures include male
genitoplasty, correction of penoscrotal transposition, insertion of
testicular prosthesis and the removal of all the undesired female
adenexa, if present, including seven cases of congenital adrenal
hyperplasia (CAH) with XX karyotype assigned male gender. For female
sex assignment, a female genitoplasty included clitoroplasty/clitoral
reduction, vaginoplasty and removal of the male gonad (if present).
Clitoroplasty for CAH was not done unless the hormonal status was well
under control. CAH cases reared as virilized males, received steroids
to suppress the adrenals and also testosterone supplementation.

For cases of TH, the abdominal testis was removed in all cases,
irrespective of the gender assigned. Female sex assignment was
preferred if there was ovary, fallopian tubes and uterus present.

For MGD, the streak gonad was removed irrespective of the sex
assigned. In the presence of the Y chromosome/cell line, not only the
streak but also the contra lateral testis, irrespective of its
location was removed.

For PGD, both the streak gonads were removed during surgery,
irrespective of age and chromosomal pattern.

For cases of complete androgen insensitivity syndrome (AIS) assigned a
female sex, the gonads were removed on one side and fixed high up on
the other side to avoid enlargement of the scrotal sacs. This group
formed part of the extreme spectrum of the MPH group that were totally
unvirilized or very partially virilized.

Results
During this period, 357 patients were reviewed in the Pediatric
Intersex Clinic. These included MPH 169; CAH 91: MGD 29; TH 25; PGD 2;
PMDS 2 and others (micropenis, severe hypospadias with cryptorchidism,
46XX male) 39.
The gender assigned for the various types of DSD are shown in Table 1.
The hormonal treatment advocated is given in Table 2.

Table 1 Gender assigned in the various DSDs in this series

DSD
Total
Male
Female
MPH
169
146
23

CAH
91
7
84

MGD
29
3
26

TH
25
21
4

PGD
2
–
2

PMDS
2
2
–

Others
39
39


–
MPH Male pseudohermaphrodite, CAH Congenital adrenal hyperplasia, MGD
mixed gonadal dysgenesis, TH true hermaphrodite, PGD pure gonadal
dysgenesis, PMDS persistent mullerian duct syndrome

Table 2 Hormonal treatment advocated in the various DSDs in this series

DSD
Total
Male
Received hormonal treatment
Female
Received hormonal treatment

MPH
169
146
LT–94,ST(ap)-36
23
E(ap)-12

CAH
91
7
ST-7,C-5
84
C ± M-65* GH-2

MGD
29
3
LT-3,ST(ap)-3
26
E + P(ap)-15

TH
25
21
LT-4,ST(ap)-2
4

PGD
2
–
2
E + P(ap)-1
*Noncompliant-4, Treatment stopped intermittently-15
MPH Male pseudohermaphrodite, CAH Congenital adrenal hyperplasia, MGD
mixed gonadal dysgenesis, TH true hermaphrodite, PGD pure gonadal
dysgenesis, PMDS persistent mullerian duct syndrome; LT local
testosterone, ST systemic testosterone, C corticosteroids, M
mineralocorticoids, E oestrogen (premarin), P progesterone, GH- Growth
hormone; ap after puberty

Out of 91 cases of CAH, 70 cases (76.9%) were on steroids
(prednisolone, hydrocortisone) and/or mineralocorticoids
(fluoricortisone) for adrenal suppression. Seven cases of CAH had been
reared as males and were receiving systemic testosterone injection.
Growth hormone and Gn RH analogue were given in 2 patients with CAH to
tide over the early bone maturation induced by hormones with equivocal
results.

The cases assigned a male gender included 146 cases of male
pseudohermaphrodite, 21 cases of true hermaphrodite and 3 cases of
mixed gonadal dysgenesis. Testosterone was given to them for local
application for phallic growth (101) after chordee correction had been
done and while they were awaiting urethroplasty. Twenty-one cases out
of these had also applied 5–10% testosterone before chordee
correction. There was a demonstrable increase in girth of the phallus
by more than 25% increase in the circumference in 49/101 (48.5%)
cases. There was no response in 52/101 cases.

The change in penile length was measured in 46 patients who were
applying testosterone locally at the time of the study. There was an
increase in length of the phallus by more than 1 cm in 6/46 cases less
than 8 years of age and assessed over a period of 6 months during the
time of the study.

Systemic testosterone injection was given in 41 cases for mental
makeup after puberty and for development of secondary sexual
characteristics.

Cases of DSD other than CAH assigned a female gender did not require
hormonal supplementation till they attained puberty. Most of them
developed breast tissue after the unwanted gonads with
testicular/dysgenetic components were removed even before puberty. Out
of 26, 15 children with MGD and 1 out of 2 cases of PGD had attained
puberty after being reared as females, after female genitoplasty. They
were given conjugated oestrogen (premarin) supplemented with
progesterone, as the uterus was preserved. In 12 cases of complete
androgen insensitivity syndrome reared as female who had reached
puberty, only premarin was given as there was no uterus. Ten of these
had the appearance of well-developed female sexual characteristics and
were leading a happy life.

Discussion
The management of DSD depends upon many factors and needs to be
individualised based on the type of the disorder, gonadal
differentiation, age at presentation, economical status, psychosocial
and cultural aspects [3–6]. Though the physical aspects of diagnosis
and management have become better understood, there are psychological
and social aspects that we have only begun to understand [7]. The
management is complex and constitutes many issues. Here, we will
discuss only the factors that affect the gender assignment and the
hormonal treatment.

The immediate problem when a child with DSD is brought is to take a
proper history, do a good clinical examination, reach a proper
diagnosis, consider the sex of rearing, assess the socioeconomic and
cultural background of the parents and then assign the sex of rearing,
preferably before the child is 6 months of age and before the baby is
exposed to the society. All this may take several visits and
counselling, giving the parents enough time to decide. If the child is
brought in newborn period or before 1 year, there is still a choice
that should be made taking all relevant aspects into consideration. If
the child presents late, sex of rearing is usually not changed except
if the parent desires so.

It is technically easier to construct a female genitalia rather than a
male. However, in a country with strong socio-cultural compulsions, a
considered decision is required before assigning the sex of the baby.
The chromosomal sex has no role to play in this respect. The pattern
of the internal gonads, internal and external genitalia and phallic
size mainly determine the sex to be assigned (Fig. 1).

Androgen responsiveness to a standard human chorionic gonadotropin
(hCG)-stimulation test (1,500 IU given intramuscularly for 3 days) in
neonates with ambiguous genitalia suggested by phallic growth may help
support a male sex assignment [8]. A positive hCG stimulation test in
the newborn or an LHRH stimulation test in mid-childhood might be
useful for evaluating cases of suspected AIS than the basal
gonadotrophin concentrations [9, 10]. The testosterone and
dihydrotestosterone (DHT) ratio following hCG stimulation is more
reliable than the basal testosterone:DHT ratio in identifying
5-reductase deficiency [10].

Gender assignment for patients with MGD is debatable. Some authors
feel that as no case has been reported of a tumour developing in a
fully descended testis in these patients, a male gender should be
assigned for those who are sufficiently virilized [11]. Others prefer
an elective feminine gender assignment for patients with MGD because a
uterus and vagina are always present and about half of the patients
are markedly short and have a high incidence of inadequate external
virilization [12]. The authors prefer male gender assignment only for
the most significantly virilized patients with a completely descended
testis. All the patients with bilateral dysgenetic gonads need to be
reared as females with excision of dysgenetic gonads. The authors have
seen a malignancy developing in a 17-year-old boy with MGD and a Y
cell line, and who had a scrotal testes retained.

Hormonal therapy forms part of the treatment of every intersex
condition [13]. The salt wasting type of CAH needs hormonal
replacement therapy (cortisol and aldosterone) as soon as diagnosed.
Prenatal cases with suspected CAH in families that have had an
affected baby in the past, are given dexamethasone soon after
confirmation of pregnancy even before the diagnosis of CAH is
established as by then it is too late to start treatment and
virilization would have already begun. The treatment is stopped if the
foetus is a male or an unaffected female after confirming with
amniocentesis and genetic mutation. This treatment is well tolerated
and, in general, and quite effective [13].

Almost all cases of CAH patients are reared as female, if the patient
is brought well in time. However, in this series, 7 patients were
brought late and were reared as males with a well developed phallus as
a result of uncorrected hormonal imbalance resulting in virilization
[8]. Of the seven, six have a male mental make up. There was only one
patient of CAH in this whole series who has a male mental makeup
though she is a well-developed female externally and has not yet
accepted a female gender mentally.

Out of 91 cases of CAH, 70 cases (76.9%) were on steroids
(prednisolone, hydrocortisone) and/or mineralocorticoids
(fluoricortisone) for adrenal suppression. The treatment for CAH was
stopped in one patient who got married, and developed amenorrhoea in 3
months duration and polycystic ovaries. The levels of 17 OHP were
normal but the levels of testosterone were high. The menstruation was
restored, though she is still under observation and has not conceived
as yet. Growth hormone and Gn RH analogue were given in two patients
with CAH to tide over the early bone maturation induced by hormones,
with equivocal results. These patients had stunted heights and high 17
OHP. The dose of the hormones, hydrocortisone and fluoricortisone had
to be reduced or stopped intermittently in nine patients with an
acceptable rise in 17 OHP so that bone growth could be achieved. Four
patients were non-compliant and stopped the medicines on their own.

Of the 101 patients with a small phallus who were treated with local
testosterone cream, only 48.5% showed response in the form of supple
penile skin. Most of these patients had a severe chordee. Though DHT
cream is reported to be effective in non-responders, yet the authors
did not have any experience with the use of DHT. The DHT cream in a
dose of 0.2–0.3 mg/kg per day for 3–4 months may be useful in the
management of patients with testosterone biosynthetic defects. Phallic
growth was reported, ranging from 0.5–2.0 cm, after 3–4 months in all
patients whose DHT concentrations were maintained within adult range
[14]. The testosterone/dehydrotestosterone (DHT) ratio was changed in
five patients who were diagnosed as 5-alfa reductase deficiency,
resulting in low levels of DHT.

Systemic testosterone injection was given in cases assigned a male
gender and who had attained puberty for the mental makeup and for
development of secondary sexual characteristics.

Anti-Mullerian hormone is used to facilitate the evaluation of
intersex disorders and as a marker of ovarian reserve assessment in
the infertility cases [15]. In prepubertal boys, AMH is involved in
testicular development and function [16]. When testes are non-palpable
a single measurement of serum AMH level can distinguish between
cryptorchidism and anorchia. AMH determination can help in the
diagnosis of intersex conditions [16]. AMH may be normally secreted in
intersex patients with defects restricted to androgen synthesis or
action, resulting in patients with female or ambiguous external
genitalia with no Müllerian derivatives [17].

In this series, one case of AIS that was assigned a female gender
failed to accept the same and had to be reassigned a male sex at the
age of 10 years. A phalloplasty was done using the vascularized
abdominal flap and he is now satisfied, though he still continues to
have a perineal meatus. He is still awaiting a penile implant.

Testosterone exposure during critical periods of early development
produces permanent behavioural changes including childhood play
behaviour, sexual orientation, core gender identity and other
characteristics that show sex differences [18]. There is also evidence
that testosterone works within the normal range to make some
individuals within each sex more sex-typical than others [18]. This
effect was significant in only two cases in this series, one patient
with AIS and the other with late diagnosed CAH. For decades, sex
assignment in children with intersex conditions has depended more on
surgical possibilities than on other criteria, since it was assumed
that children are psychosexually neutral at birth [19]. Adults with
intersex conditions and professionals in the field have increasingly
criticised this policy after reports suggesting that prenatal brain
exposure to sex hormones determines gender development and that the
patient may grow up feeling uncertain about his or her gender
identity, or worse still, harbour a sense of outrage about life and
treatment experiences [13, 19]. However, recent reviews on gender
dysphoria and gender change in patients with intersex conditions show
that initial gender assignment still seems to be the best predictor of
adult gender identity [19].

Three cases of MPH reared as boys and one case of CAH in this series
are married for last two years. All of them are sexually functional
and satisfied, though fertility has not yet been proved. The three
cases of MPH have oligospermia.

To conclude, the most crutial decision for management of DSD is gender
assignment. Appropriate surgical treatment should be done according to
the gender assigned [20]. The role of hormonal therapy in CAH is to
suppress the unwanted hormone excess of androgens or
mineralocorticoids by exerting negative feedback. For hypogonadism in
other disorders, sex hormone replacement therapy may be prescribed to
stimulate sexual development: growth of a hypoplastic penis, pubertal
changes, psychosexual development, adult sexual behaviour and bone
mineral density [13]. Thus, judicious hormonal supplementation based
upon type of DSD and gender assigned is the key to successful outcome
in patients with DSD.

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