Normal and abnormal sexual

development and puberty

‫شيماء عبد حسن‬.‫د‬

Sexual differentiation and development are
highly complex processes which start at
conception. A thorough understanding of
these mechanisms is fundamental in
understanding how the normal fetus
develops. It is also key to understanding the
complex group of conditions known as
‘disorders of sex development’ (DSD).
:Sexual differentiation

 Differentiation of the fertilized embryo into a male or female fetus is

controlled by the sex chromosomes. All normal fetuses have an
undifferentiated gonad which has the potential to become either a
testis or an ovary.

 In addition, all fetuses have both Mullerian and Wolffian ducts and
the potential to develop male or female internal and external genitalia.
of the zygote determines whether the indifferent gonad becomes a
testis or an ovary.

 The first step in this pathway is dependent on the SRY gene (sex
determining region of the Y chromosome). This gene, helped by other
testes-determining genes, causes the gonad to begin development into
a testis.
As the gonad develops into a testis, it
differentiates into two cell types. The Sertoli
cells produce anti- Mullerian hormone (AMH)
and the Leydig cells produce testosterone.
Anti-Mullerian hormone suppresses
development of the Mullerian ducts. Where
the gonad becomes an ovary, the absence of
AMH allows the Mullerian structures to
develop.
 The proximal two thirds of the vagina develops from the paired
Mullerian ducts which grow in a caudal and medial direction and
fuse in the midline. These ducts form bilateral Fallopian tubes,
and midline fusion of these structures produces the uterus, cervix
and upper vagina. The rudimentary distal vagina fuses with the
posterior urethra at week 7 to Mullerian tubercles and the
urogenital sinus. Cells proliferate from the upper portion of the
urogenital sinus to form structures called the ‘sinovaginal bulbs’.
These fuse to form the vaginal plate which extends from the
Mullerian ducts to the urogenital sinus. This plate begins to
canalize, starting at the hymen and proceeds upwards to the
cervix. The external genitalia do not virilize and, in the absence of
testosterone, the genital tubercle becomes the clitoris and the
labioscrotal swellings form the labia. The lower part of the vagina
is formed from the urogenital folds.
Chromosomal abnormalities

 If an embryo loses one of its sex chromosomes, then the total

complement of chromosomes is 45. This is usually incompatible with
life, except in the case of Turner syndrome which results from a
complete or partial absence on one X chromosome (45XO).

 Turner syndrome is the most common chromosomal in females,

occurring in 1 in 2500 live female births. Although there can be
variation among affected women, most have typical clinical features
including short stature, webbing of the neck and a wide carrying
angle. Associated medical conditions include coarctation of the aorta,
inflammatory bowel disease, sensorineural and conduction deafness,
renal anomalies and endocrine dysfunction, such as autoimmune
thyroid disease. In this condition, the ovary does not complete its
normal development and only the stroma is present at birth. The
gonads are called ‘streak gonads’ and do not function to produce
oestrogen or oocytes.
Diagnosis is usually made at birth or in early
childhood from the clinical appearance of the
baby or due to short stature during childhood.
However, in about 10 per cent of women, the
diagnosis is not made until adolescence with
delayed puberty. The ovaries do not produce
oestrogen, so the normal physical changes of
puberty cannot happen. In childhood, treatment is
focused on growth, but in adolescence it focuses
on induction of puberty. Pregnancy is possible, but
ovum donation is usually required. Psychological
input and support is important.
 XY gonadal dysgenesis

 In this situation, the gonads do not develop into a testis, despite the presence of
an XY karyotype. In about 10 per cent of cases, this is due to an absent SRY
gene, but in most cases the cause is unknown.
 In complete gonadal dysgenesis (Swyer syndrome), the gonad remains as a
streak gonad and does not produce any hormones.
 In the absence of AMH, the Mullerian structures do not regress and the uterus,
vaginal and Fallopian tubes develop normally. The absence of testosterone mean
the fetus does not virilize. The baby is phenotypically female, although has an
XY chromosome. The gonads do not function and presentation is usually at
adolescence with failure to go into spontaneous puberty. The dysgenetic gonad
has a high malignancy risk and should be removed when the diagnosis is made.
This is usually performed laparoscopically. Puberty must be induced with
oestrogen and pregnancies have been reported with a donor oocyte. Full
disclosure of the diagnosis including the XY karytoype is essential, although can
be devastating and psychological input is crucial.
46XY DSD
Complete androgen insensitivity syndrome (CAIS) occurs in
individuals where virilization of the external genitalia does
not occur due to a partial or complete inability of the
androgen receptor to respond to androgen stimulation. In
the fetus with CAIS, testes form normally due to the action of
the SRY gene.
At the appropriate time, these testes secrete AMH leading to
the regression of the Mullerian ducts. Hence, CAIS women
do not have a uterus. Testosterone is also produced at the
appropriate time, however, due to the inability of the
androgen receptor to respond, the external genitalia do not
virilize and instead undergo female development. A female
fetus is born with normal female external genitalia, .
uterus and testes found at some point in their line of
descent through the abdomen from the pelvis to the
inguinal canal. During puberty, breast development will
be normal, however, the effects of androgens are not
seen, so pubic and axillary hair growth will be minimal.
Presentation is usually at puberty with primary
amenorrhoea, although if the testes are in the inguinal
canal they can cause a hernia in a younger girl. Once the
diagnosis is made, initially management is psychological
with full disclosure of the XY karyotype and the
information that the patient will be infertile.
Gonadectomy is recommended because of the small long-
term risk of testicular malignancy, although this can be
deferred until after puberty.
5-Alpha-reductase deficiency

In this condition, the fetus has an XY karytype and a

normal functioning testes which produce both testosterone
and AMH. However, the fetus is unable to convert
testosterone to dihydrotestosterone in the peripheral
tissues and so cannot virilize normally. Presentation is
usually with ambiguous genitalia at birth, but can also be
with increasing virilization at puberty of a female child due
to the large increase in circulating testosterone with the
onset of puberty. In the Western world, the child is usually
assigned to a female sex of rearing.
 Congenital adrenal hyperplasia

 This condition leads to virilization of a female fetus. It is due to an

enzyme deficiency in the corticosteroid production pathway in the
adrenal gland with over 90 per cent being a deficiency in 21-
hydroxylase, which converts progesterone to deoxycorticosterone,
and 17-hydroxyprogesterone (17-OHP) to deoxycortisol.

 The reduced levels of cortisol being produced drive the negative

feedback loop, resulting in hyperplasia of the adrenal glands and
increased levels of progesterone production. This leads to an excess
of androgen precursors and then to elevated testosterone production.
Raised androgen levels in a female fetus will lead to virilization of the
etxternal genitalia. The clitoris is enlarged and the labia are fused
and scrotal in appearance. The upper vagina joins the urethra and
opens as one common channel onto the perineum.
 Traditionally, all female infants with CAH underwent
feminizing genital surgery within the first year of life.
This management is now controversial as adult patients
with CAH are very dissatisfied with the outcome of
their surgery and argue that surgery should have been
deferred until they were old enough to have a choice.
Surgery certainly leaves scarring and may reduce
sexual sensitivity, but the alternative of leaving the
genitalia virilized throughout childhood can be difficult
for parents to consider. At present, cases are managed
individually by a multidisciplinary team involving
surgeons, endocrinologists and psychologists.
Mullerian anomalies

 These are common, occurring in up to 6 per cent of the female population,

and may be asymptomatic. The aetiology is unknown, although associated
renal anomalies are present in up to 30 per cent.

 Mullerian obstruction
 Failure of complete canalization of the Mullerian structures can lead to
menstrual obstruction. The obstruction most commonly occurs at the junction
of the lower third of the vagina at the level of the hymen, although more
proximal obstruction can occur. Presentation with an imperforate hymen is
usually with increasing abdominal pain in a girl in early adolescence. The
retained menstrual blood stretches the vagina causing a haematocolpus. This
can cause a large pelvic mass and in addition can usually be seen as a
bulging membrane at the vaginal entrance. Treatment is simple with a
surgical incision of the hymen and drainage of the retained blood.
Mullerian duplication
Duplication of the Mullerian system can occur resulting in a
wide range of anomalies. It may be a complete duplication of the
uterus, cervix and vagina, but may be simply a midline uterine
septum in otherwise normal internal genitalia. Second uterine
horns may also occur and can be rudimentary or functional.

Mullerian agenesis
In approximately 1 in 5000 to 1 in 40 000 girls, the Mullerian
system does not develop resulting in an absent or rudimentary
uterus and upper vagina. This condition is known as Rokitansky
syndrome or Mayer–Rokitansky–Kuster–Hauser (MRKH)
syndrome.
Normal puberty

 Puberty is the process of reproductive and sexual development and

maturation which changes a child into an adult. During childhood,
the hypothalamic– pituitary–ovarian axis is suppressed and levels
of GnRH, FSH and LH are very low. However, from the age of eight
to nine years, GnRH is secreted in pulsations of increasing
amplitude and frequency. These are initially sleep-related, but as
puberty progresses, these extend throughout the day.
 The physical changes occurring in puberty are:
 • breast development (thelarche);
 • pubic and axillary hair growth (adrenarche);
 • growth spurt;
 • onset of menstruation (menarche).
 The first physical signs of puberty are breast budding and this
occurs two or three years before menarche.
The appearance of pubic hair is dependent on
the secretion of adrenal androgens and is
usually after thelarche. In addition to
increasing levels of adrenal and gonadal
hormones, growth hormone secretion also
increases leading to a pubertal growth spurt.
The mean age of menarche is 12.8 years and
it may take over three years before the
menstrual cycle establishes a regular pattern.
Initial cycles are usually anovulatory and can
be unpredictable and irregular.
 Precocious puberty
 This is defined as the onset of puberty before the age of eight in a
girl or nine in a boy. It is classified as either central or peripheral.
Central precocious puberty is gonadotrophin-dependent. The
aetiology is often unknown, although up to 25 per cent are due to
central nervous system malformation or brain tumours. Peripheral
precocious puberty is always pathological and can be caused by
oestrogen secretion, such as exogenous ingestion or a hormone-
producing tumour.

 Delayed puberty
 This occurs when there are no signs of secondary sexual
characteristics by the age of 14 years. It is due to either a central
defect – hypogonadotrophic hypogonadism or to a failure of
gonadal function – hypergonadotrophic hypogonadism.
 Hypogonadotrophic hypogonadism
 This may be constitutional, but other causes must be
excluded. These include anorexia nervosa, excessive exercise
and chronic illness, such as diabetes or renal failure. Rarer
causes include a pituitary tumour and Kalmans syndrome.

 Hypergonadotrphic hypogonadism
 In this situation, the gonad does not function despite a high
FSH. Both Turner syndrome and XX gonadal dysgenesis will
cause this. Premature ovarian failure can occur at any age
and may be idiopathic, but can also be part of an
autoimmune disorder or following chemo- or radiotherapy
for childhood cancer.
Good luck