Normal and abnormal sexual development ppt

gonad iJTDF Testis Un differentiated gonad Testosterone 5a- reductase Wolffian Dihydro- development testosterone V No No Mullerian testosterone inhibitor Mullerian regression Vas deferen

The means by which the embryo differentiates is

con-trolled by the sex chromosomes This is known as

fenetic sex The normal chromosome complement is

46, including 22 autosomes derived from each parent

An embryo that contains 46 chromosomes and has

tr.e sex chromosomes XY will develop as a mate If the

M chromosomes are XX, the embryo will

differenti-Jie into a female The resulting development of the

gonad will create either a teslis or an ovary This is

known as gonaclal sex Subsequent development of

*e internal and external genitalia gives phenotypic

^- i>r the sex ol appearance Cerebral

differen-•arion to a male or female orientation is known as

hi the developing embryo with a genetic complement

of 46 XY, it is the presence of the Y chromosome thatdetermines that the undifferentiated gonadwill become

a testis (Fig 3.1) Absence of the Y chromosome willresult in the development of an ovary On the short arm

of the Y chromosome is a region known as the SRI'gene, which is responsible for the determination of tes-

ticular development as it produces a protein known

as testicular determining factor (TDF) TDF dircc influences the undifferentiated gonad to become ;

testis When this process occurs, the testis abtMiillerian inhibitor

The imdifferentiated embryo contains b

and Miillerian ducts The Wolffian du

gonad iJTDF

Testis

Un differentiated gonad

Testosterone 5a- reductase Wolffian Dihydro- development testosterone

V

No No Mullerian testosterone inhibitor

Mullerian

regression

Vas deferens Epididymis Seminal vesicles

Penis Scrotum

Figure 3.1 Male differentiation (TDF testicular determining

factor.)

potential to develop into the internal organs of the

male, and the Mullerian ducts into the internal organs

of the female If the testis produces Mullerian inhibitor,

the Miillerian ducts regress

The testis differentiates into two cell types, Leydig

cells and Sertoli cells The Sertoli cells are responsible

for the production of Mullerian inhibitor, which leads

to Mullerian regression The Leydig cells produce

testosterone, which promotes the development of

the Wolffian duct, leading to the development of

vas deferens, the epididymis and the seminal vesicles

Testosterone by itself does not have a different effect

on the cloaca; in order to exert its androgenic effects,

it needs to be converted by the cloacal cells through

the enzyme 5<*-reductase to dihydrotestosterone These

androgenic effects lead to the development of the penis

and the scrotum

The absence of a Y chromosome and the presence

of two X chromosomes mean that Mullerian inhibitor

is not created, and the Mullerian ducts persist in the

female (Fig 3.2) The absence of testosterone means

that the Wolffian ducts regress, and the failure of

andro-gen to affect the cloaca leads to an external female

phenol ype

Miillerian Wolffian development regression Uterus

Fallopian tubes Cervix Vagina Figure 3.2 Female differertialion (TOP, testicular determining factor.)

Abnormal development

Any aberration in development that results in anunexpected developmental sequence of events may bemediated in a number of ways

to complete their development and at birth only thesiroma of the ovary is present (streak ovaries) Thus,

in Turner's syndrome, the absence of a functional ovarymeans that there is no oestrogen production at puberty,and secondary sexual characteristics cannot develop

;.' Only one X

§ chromosome

No Mullerian inhibitor

: : • - •

As the genes involved in achieving final height are

shared by the sex chromosomes, the absence of one

« chromosome will also lead to short stature

In females who have an XY karyotype, a mutation at

~<; site on the short arm of the Y chromosome

result-•igin failure of production of TDF will mean there is

K> testicular development (XY gonadal agenesis) The

lefault phenotypic state is female (Fig 3.4) In these

»cumstances, the absence of a testis means that the

•Krnal genitalia will persist as a result of the

develop-•mt of Mullerian structures, and the Wolffian ducts

_ rtsress The external genitalia will be female

Sonadal abnormalities

iMalei, a number of gonadal abnormalities may exist

• of these is known as the vanishing testis syndrome:

XY fetus develops testes that then undergo atrophy,

rreason for this remains speculative, although

tor-thrombosis and viral infections have been

sug-However, the failure of the development of the

; leads to a female default state, as above (similar

B- 3.4)

Leydig cell hypoplasia, the Leydig cells

respon-: tor the production of testosterone either completely

Gonadal development failure

No gonad

No testosterone

No Mullerian inhibitor

4

Wolffian regression

Mullerian development Figure 3.4 XV gonadal agenesis (TDF testicular determiningfactor.)

fail to produce this or produce it in only small tities A range of abnormalities may result, dependent

quan-on the level of androgen produced, and therefore thephenotype may range from female through to thehypospadiac male

In XY gonadal dysgenesis, a genetic abnormalityleads to an abnormal testicular development The testisfails to secrete androgen or Mullerian inhibitor, result-ing in an XY female If the genetic abnormality leads

to an enzyme deficiency in the biosynthetic pathway

to androgen, testosterone will fail to be secreted bythe testis However, some androgen maybe produced,depending on which enzyme is absent in the pathway.Therefore some effect on the external genitalia may

be possible and a varying degree of virilism will occur

If the biosynthetic production of Mullerian inhibitor

is deficient, ils absence will, of course, mean the ence of the Mullerian duct This is an extremely raresyndrome

persist-In the female, gonadal dysgenesis may occur, and inthis situation (similar to Turner's syndrome) the gonad

is present only as a streak These individuals have beenfound to have small fragments of a Y chromosome and,

as a result of this, the gonad may undergo rnitoticchange, which leads to the development of a gonadal

tumour, e.g a gona do blastema The Mtillt-rian

struc-tures remain and the Wolffian strucstruc-tures regress,

because of the absence of testes At puberty, the failure

of development of the ovary will mean that there is no

possibility for the production of ocstradiol, and a failure

of secondary sexual characteristic growth will occur

In the rare condition known as mixed gonadal

dys-genesis, there is a testis and a streak gonad in the same

individual The chromosome complement is typically

46 XX or a mosaic with a Y component Here, strangely,

the Wblffian structures develop only on the side of the

testis, but all Mullerian structures regress The

exter-nal genitalia in this rare condition may be ambiguous,

depending on the functional capacity of the testis

In true hermaphrodites, the gonad may develop into

either a testis or an ovary, or a combination of the two

known as an ovotestis Here, a number of permutations

may occur, with either a testis and an ovary, or an

ovoteslis with a testis, an ovary or another ovotestis

(Fig 3.5) This usually results from a mosaic XX:XY

karyotype, and the predominance of either ovarian or

testicular tissue in the gonad depends on the

percent-age of cell lines in the mosaic As can be seen from

Figure 3.5, the combination of gonads will determine

the degree of virilizatiori; the greater the testicular

com-ponent, the more virilized the resulting development

and the more likely the presence of Mulleriari inhibitor

Thus, in the true hermaphrodite, it is possible to get

co-existent Wiillerian and Wolffian structures in terms

of internal development, and varying degrees of

masculinization of the external genitalia, depending

on the combination of gonads

Testis and ovary

Ovotestis and ovary

si of

Internal genitalia abnormalities

In males there are three fundamental changes thatmay lead to abnormalities of the internal genitalia.The first of these is androgen insensitivity (Fig 3.6)

In this condition the fetus fails to develop androgenreceptors due lo mutations in the androgen receptorgene Failure to possess the receptor means thatalthough the testis will be producing testosterone,the androgenic effect cannot be translated intothe end organ as it is not recogni/ed by the cell wall.The result here is that the fetus develops in thedefault female state, as it is unable to recognize theandrogenic impact This is the commonest type of

XV female and the Wolffian ducts regress, as theyalso have no androgen receptor However, theMullerian ducts also regress because the testis is nor-mal and produces Mullerian inhibitor Girls with thisabnormality present with primary amenorrhoea atpuberty

A further aberration in XY females also exists with

a condition known as 5«-rcductase deficiency (Fig 3.7)

As outlined above, this enzyme is responsible for theconversion of testosterone to di hydro testosteroneresulting in virilization of the cloaca If this enzyme isabsent, the external genitalia will be female but theinternal genitalia will be male The Mullerian ductswill regress Here again, this female will present withprimary amenorrhoea

Testis ci

Mullerian inhibitor

Mullerian regression

."; - Testosterone

No receptor

Ovotestis

1 Failure of development of Wolf(ian structures

2 No masculinization of cloaca Figure 3.5 True hermaphrodite Figure 3.6 XY female - anrJrorjeii in sensitivity.

No reductase

5a-No testoslerorie

dihydro-No virilization

of cloaca

External developmentfemaleFigure 3.7 XV female - So-recfiictase deficiency

an^HB^^^^^^fe Testosterone

No Miillenan

inhibitor

Wolffian development

Male external gen Italia

Mullerian

development

Figure 3.8 XV female-absence of Miillerian inhibitor.

Finally, a rare condition known as Mullerian

inhibitory deficiency may mean that an XY male may

have persistent Mullerian structures, due to the absence

of Miillerian inhibitory factor, and co-existent male

and female internal structures (Fig 3.8)

In 46 XX females, a genetic defect that results in

fail-ure of development of the uterus, cervix and vagina is

known as the Rokitansky syndrome This is the

sec-ond most common cause of primary amenorrhoea in

women, the first being Turner's syndrome Here the

ovaries are normal, and the external genitalia are

nor-mally female The internal genitalia are either absent

or rudimentary Variations on this may lead to

devel-opment of the vagina without develdevel-opment of the

uterus, or development of the uterus without

subse-quent development of the cervix or vagina, and a

functional uterus may result The aetiology of thisdevelopmental abnormality remains to be clarified It

is probably, however, a defect in the genes responsiblefor the development of the internal female genitalia.These genes, known as the homeobox genes, are likely

to possess either deletions, which may be partial orcomplete, or point mutations and, as a consequence

of these variations, the resulting structures of the nal genitalia will vary in their development However,the overall effect of this developmental abnormality is

inter-a finter-ailure of uterine inter-and vinter-agininter-al development, leinter-ading

to infertility These patients will present at puberty witheither primary amenorrhoea or, in circumstances when

a small portion ot uterus may be functional, with lical abdominal pain due to retained menstrual blood.Two other developmental abnormalities may occur.The first of these is ma [development of the uterus, inwhich fusion defects occur from the extreme of a dou-ble uterus with a double cervix through to the normallyfused uniform uterus These abnormalities have beenclassified and result from the failure of fusion of theparamesonephric ducts at their lower border A mal-devcloped uterus may be associated with some degree

cyc-of reproductive failure

The development of the vagina involves a growth of the vaginal plate and subsequent union ofthis with the cloaca and thereafter canalization Thisprocess can also fail, leading to the second developmen-tal abnormality, transverse vaginal septae, in which thepassage of the vagina is interrupted and therefore atpuberty menstrual blood is trapped in an upper vaginathat does not connect to the lower vagina In theunusual condition of a double uterus, a double vaginacan also exist, and failure to develop the full doublevaginal system may result in a blind hemivagina, againleading to a collection of menstrual blood at puberty

down-External genitalia abnormalities

In males, the external genitalia may fail to develop for anumber of the above reasons, and the phallus may beunderdeveloped, leading to hypospadias In hypospa-dias, the urethra often fails to reach the end of the phal-lus or penis, and urine exits from the base of the penis

In females, the external genitalia may be virilized, ing a masculine appearance This is most commonlyseen in a condition known as congenital adrenal hyper -plasia In this condition, an enzyme defect in the adrenalgland- usually 21 -hydroxylase deficiency- prevents the

giv-fetal adrenal gland from producing cortisol Failure of

the production of cortisol means that the feedback

mechanism on the hypothalamus leads to an elevation

of adrenocortkolrophic hormone (ACTH) This in

turn stimulates the adrenal gland to undergo a form of

hyperplasia, and the excessive production of steroid

precursors (17-hydroxyprogestcrone) means that the

adrenal gland produces excessive amounls of androgen

This androgen enters the fetal circulation and impacts

on the developing cloaca, thereby leading to

virili/a-tion The female child is then born with a degree of

phallic enlargement, and the lower part of the vagina

maybe obliterated by the development of a mate-type

perineum and hence a vaginal orifice is not apparent

Virili/ation of the cloaca can also occur if the fetus

is exposed to androgen in an androgeuic drug ingested

by the mother or, in many cases, the virilization is

idio-pathic The end result in both of these circumstances

is known as the intersex state At birth, investigation

of the chromosomes, the endocrine status of the infant

and ultrasound of the internal organs will lead to a

rapid diagnosis, revealing whether the child is a female

with a virilrzalion state, which is most likely to be

con-genital adrenal hyperplasia, or a male who has been

tinder-masculinized

Brain sex

The sex of orientation of a human is influenced by

many factors Theories exist that this is genetically

predetermined and it is most likely that our sexual

orientation is in fact determined by our sexual make up

However, this may be influenced by androgen

expos-ure in utero or by other genetic and environmental

factors that impact on this function Enormous care

has to be Taken before a final decision is made on the

sex of rearing of those individuals who are uncertain

about their sexual orientation

Puberty

The hy pot h alamo-pituitary-ovarian axis is

function-ally complete during the latter half of fetal life

Follicle-stimulating hormone (FSH) levels are suppressed

from 20 weeks' gestation by the production of

oestro-gen by the placenta and by the fetus itself At birth,

the fetus is separated from its placenta and therefore

the major source of oestrogen is removed The FSH

level then rises in response to the hypo-oestrogeniestate of the fetus and remains elevated for some 6-18months after birth During this time it is suppresseddue to the ceiitral inhibition of the production ofgona do troph in-releasing hormone (GnRH), whichcontrols the pituitary production of FSH The mech-anism by which this is achieved remains speculative,but almost certainly is controlled by a gene in theGnRH ceil nucleus in the hypothalamus ft is possiblethat there is a relationship between the production ofleptin, a peptide produced by fat cells, and the sub-sequent control of this gene

During childhood, FSH pulses are almost able, and at around the age of 8 or 9 years a changegradually occurs in the function of the GnRH cell

undetecl-This change begins with the production of singlenocturnal spikes of GnRH and subsequently FSH

These spikes of FSH increase in frequency during thenigh t-time hours over a period ol 1-2 years Eventually,the frequency of the FSH pulses increases such thatthey are detectable in the daylight hours, and there-after, after a period of 4-5 years, a fully functional pro-duction of GnRH with normal adull frequency andpulse amplitude leads to the establishment of the ovu-latory menstrual cycle Puberty therefore occurs over

a total of 5-10 years, and involves five types of opment (see box below)

devel-The physiology of puberty

The sequence of events that occur in the physicalchange resulting in the adult fertile female is usuallythe growth spurt, followed by breast development,pubic hair growth, menarche, and finally axillary hairgrowth Although this is the sequence of events in 70per cent of girls, variations often occur The descrip-tion of pubertal development is credited to Tanner

He has classified the stages of development into fivestages tor breast growth and pubic hair growth

Five stages of puberty

• Growth spurt

• Breast development

• Pubic hair growth

• Menstruation

• Axillary hair growth

The breast bud rrsj oestradiol by the ovai

•yons, It is perfectly ™ the midline up tc misconstrued b The growth spurt bef

•• nris-and the rate at i

*«= about 6 to 10cm fiMflv- the effect of oes fc^nr causes fusion, an

15 •ml girls have achi Menarche (the first

-

: arrcs

.-.

Common clinical presentations and problems 27

ID the hypo-oestrogenie

& devated for some 6-18

this time it is suppressed

m of the production of

jrmone (GnRH), which

crion of FSH The

mech->ed remains specLilative,

trolled by a gene in the

pothalarnus It is possible

rtween the production of

by fat cells, and the

sub-ilses are almost

ulses increases such that

ijdight hours, and

there-irs, a fully functional

pro-mal adult frequency and

establishment of the

ovu-rty therefore occurs over

rakves five types of

devel-ty

it occur in the physical

I fertile female is usually

of development into five

pubic hair growth

The breast bud responds to the production ofoestradiol by the ovary, which is itself reliant onGnRH production, as outlined above The breastgrows in phases Initially the body of the breast grows;

this is then superseded by areolar development,which leads to a pronounced a re o la in comparisonwith the rest of the breast, and at this stage the breasthas reached Tanner stage 4 Finally, the breast tissuegrows to become confluent with the areola and thebreast has then completed its development

Pubic hair growth begins on the labia and extendsgradually up onto the mons and then into the inguinalregions It is perfectly normal for pubic hair to extendalong the midlinc up towards the umbilicus, but this

is often misconstrued by women as being abnormal

The growth spurt begins around the age of 11 years

in girls, and the rate at which growth occurs increasesfrom about 6 to 10cm per year for around 2 years

Finally, the effect of oestrogen on the end-plate of thefemur causes fusion, and growth ceases; by the age of

15, most girls have achieved their final height

Menarche (the first menstrual period) occurs atany age between 9 and 17 years As one would imagine,the hypo thai a mo-pituitary-ovarian axis is not fullymature at the time of menarche, and subsequent

menstrual cycles are commonly irregular Menstrualloss may also vary enormously, as a result of the imma-turity of the axis It takes between 5 and 8 years fromthe time of menarche for women to develop ovulatorycycles 101) per cent of the time In understanding themenstrual difficulties that might arise during adoles-cent life, this piece of physiology is important to bear

in mind

Common clinical presentations and problems nabicd n

Turner's syndrome

Patients with this condition may present at two ages

in their life: either soon after birth or, more rarely, at

a time of delayed puberty The manner of tion in infancy is variable In the first few months oflife there may be unexplained oedema of the handsand feet, loose folds of skin at the neck and occasion-ally unusual facies In older children, the oedemausually disappears, although it can persist, but themain feature of the growing child is shortness of

presenta-Table 3.1 Common clinical presentations and problems

Turner's syndrome

XY females

IntersexVaginal atresia

Oedema of hands and feetShort stature

Webbed neckWide carrying angleBroad chestPrimary amenorrhoeaUsually normal breast developmentScanty/absent pubic and axillary hairAbsent uterus and tubes

Undescended/maldescended testesAmbiguous genitalia at birthPrimary amenorrhoeaNormal secondary sexual characteristicsAbsent vagina and uterus

Normal ovaries

FSH and LHKaryotype 45 XO

Karyotype 46 XY

Karyotype 46 XX

FSH, Follicle-stimulating hormone; LH, luteinizing hormone

typically 45 XO and measurement of gonadoLrophinswill show markedly elevated FSH and LH.

The treatment of this condition falls into two phases.

The first phase is the induction of puberty, whichinvolves the administration of hormone replacementtherapy In order to ensure that secondary sexual char-acteristics appear normally, oestrogen is administeredorally, beginning at an extremely low dose and grad-ually increasing over a number of years As puberty" itselftakes 5 years to complete, the same time frame should

be anticipated when puberty is induced by exogenousoestrogen The introduction of progesterone to theregime usually occurs after 18 months to 2 years, whenwithdrawal bleeds from the patient's functioning uteruswill occur

The second phase of treatment is at a time when thepatient desires a pregnancy As she is deficient ofoocytes, pregnancy can only be achieved w i t h the aid

of a donor egg, which, with a sperm from the patient'spartner, is used to create an embryo, which is thentransferred to the recipient's uterus Pregnancy pro-gresses normally thereafter, although childbirth may

be difficult because of the short stature

If investigations reveal a diagnosis of 46 XX gonadaldysgenesis, the gonads have a 30 per cent risk ofdeveloping a gonadohlastoma (a malignant tumour

of the ovary) and therefore patients should be advised

to have their gonads removed Again, these womenrequire induction of puberty in the same way asTurner's syndrome patients

XY females

Figure 3.9 Turner's syndrome.

stature It is this that suggests to the clinician the

pos-sibility of a sex chromosome anomaly As the child

grows, a wide carrying angle of the arms may become

apparent, the neck may become webbed in its

appear-ance, and the chest becomes broad with widely

spaced nipples Individuals occasionally have

associ-ated features such as colour blindness, coarctation of

the aorta and short melatarsals (Fig 3.9) As these

girls approach puberty, they have streak ovaries and

are, therefore, incapable of producing oestradiol The

hypothalarnus and pituitary function normally and

therefore FSH levels and luteinizing hormone (LH)

levels are elevated due to ovarian failure As mentioned

previously, the internal genitalia are otherwise

nor-mal, and investigation will reveal a karyotype that is

These patients present at puberty with primary orrhoea Patients with androgen insensitivity arephenotypically normal females with breast develop-ment because their testes have produced androgen atpuberty, which is converted peripherally to oestrogen

amen-by aromatase activity in fat cells This oestrogen thenenters the circulation and induces breast growth It iscommon for breast growth to be complete at the time

of presentation

However, the absence of an androgen receptor meansthat pubic and axillary hair is either very scanty orabsent The vagina is short and, of course, the uterusand tubes are absent The testes may be found in thelower abdomen, groins or, rarely, in the labia rnajora.1'hese girls may well have presented in childhoodwith inguinal herniae, which have been operated on,

Common clinical presentations and problems 29

ment of gonadotrophins

FSHandLII

Ooa tails into two phases.

tion of puberly, which

f hormone replacement

a secondary sexual

char-•estrogen is administered

mdy low dose and

grad-r of yeagrad-rs As pubegrad-rty itself

• same time frame should

is induced by exogenous

i of progesterone to the

i months to 2 years, when

dent's functioning uterus

mit is at a time when the

: As she is deficient of

be achieved with the aid

sperm from the patient's

i embryo, which is then

uterus Pregnancy

pro-dthough childbirth may

art stature

ignosis of 46 XX gonadal

i a 30 per cent risk of

B (a malignant tumour

itients should be advised

xL Again, these women

j in the same way as

crty with primary

amen-Irogen insensitivity are

les with breasl

dcvciop-« produced androgen at

"eripherally to oestrogen

rfls This oestrogen then

hices breast growth It is

i be complete at the time

mdrogen receptor means

is either very scanty or

od, of course, the uterus

Ms may be found in the

rely, in the labia majora

presented in childhood

have been operated on,

and the gonads will have been discovered at that stageand removed If this has not been the case and the testesare still present, advice that they should be removedbecause of the risk of malignancy should be given Theclinical appearance of these patients makes the diagno-sis straightforward, and only confirmation by karyo-typing is necessary

Oestrogen will need to be administered to thesewomen in order to maintain their female body habitus,but the failure of the development of the Mullerianstructures means pregnancy is impossible, except inthose cases of XY gonadal agenesis or the XY femalewith absent Mullerian inhibitor only

Intersex

Ambiguous genitalia are usually diagnosed at birth

when the infant is clearly neither male nor female In

these circumstances, gender assignment should be

withheld until the infant can be fully evaluated A

very sensitive approach to the clinical situation must

t>e taken The parents will obviously be anxious to

learn as swiftly as possible whether their child is male

or female Initially the most important investigation

ii karyotyping and, with the facilities that now exist,

tr,e karyotype can be determined within 24 hours on

white blood cells taken from the infant

The most common cause of ambiguous genitalia isj^ngenital adrenal hyperplasia Therefore, as we know

•' affected individuals are females with a

masculin-tted vulva, ultrasound of the pelvis will reveal a

•ormal uterus and ovaries This, in conjunction with

i karyotype of 46 XX, will almost always clinch the

dfagnosis These children fail to produce cortisol and

17-hydroxyproges-none, another investigative test that should be formed The infants require cortisol supplementation

per-i order to avoid an adrenal crisis Further

investiga-ion may be required if the karyotype is 46 XY, and the

possibilities for this are outlined earlier in the chapter

Vaginal atresia

• presentation of an adolescent with primary and normal secondary sexual characteristicsraise the possibility of congenital absenceihe vagina as the primary concern until proven

amen-otherwise Here, the clinical story is a simple one,with absence of the establishment of menses Clinicalexamination of the vulva will reveal a normal externalappearance However, parting the labia will reveal anabsent vagina An ultrasound examination of the pelviswill then confirm the absence of the development ofthe internal genitalia, but the presence of normalovaries The management of these patients is extremelysensitive, as their diagnosis will cause them great dis-tress Teenage girls are emotionally labile duringpuberty and adolescent development, and the newsthat they have no vagina and no uterus is very dis-tressing to them and to their parents

It is impossible currently to offer any help for theabsence of ihe uterus However, it is possible to create

a vagina so that sexual intercourse may occur mally This may be created in one of two ways, eithernon-surgically or surgically Trie non-surgical tech-nique involves the use of graduated glass dilators,which will stretch the small vagina into a fully func-tional vagina This may be achieved over a period of6-8 weeks of gradual dilatation, which is performed

nor-by the patient herself In order for this technique to besuccessful, which it is in some 85 per cent of girls,motivation must be appropriate and it usually helps ifthe patient is in an established relationship andwishes to have sexual intercourse For those patientslor whom this cannot be successfully achieved, a sur-gical approach may be necessary to create a vagina.Several techniques have been described, involvingvarious materials, including skin grafts, amnion orbowel Again, subsequent to the surgery, dilators arerequired in order to maintain the surgically createdneovagina

Obstructive outflow tract problems

Two varieties of outflow tract problems exist in thedevelopmental abnormalities observed by gynaeco-logists in their female patients The first of these isknown as transverse vaginal septae The simplest andmost common is the imperforate hymen, where men-strual blood is trapped behind a thin hymenal mem-brane This situation is easily resolved by a cruciateincision, which releases the menstrual blood; subse-quent sexual activity is normal and there are nosequelae

In cases where a transverse vaginal septum resultsfrom failure of canalization of the vagina, septae may

Figure 3.10 A haematocolpos seen in the theatre just before

incision.

occur at three levels: the lower third, middle third or

upper third of the vagina In all these cases, women

present with cyclical abdominal pain, and the

devel-opment of a pelvic mass as menstrual blood

accumu-lates in the vagina, thereby distending it In some

cases the vagina may distend to give a mass, which

may extend to the umbilicus Investigation of these

circumstances demands an ultrasound scan that will

demonstrate the presence of a haematocolpos (blood

in the vagina) (Pig 3.10) Having established the

anatomical defect, corrective surgery is required to

excise and reconstruct the vagina, thereby creating a

normal vagina, with normal menstrual drainage and

normal function, both for sexual intercourse and

subsequent conception

Where there is a vertical septal defect, a midline

septum persists between two hemi-vaginas, one of

which has successfully developed and the other has

failed to reach the perineum In these cireumstances

the hemi-uterus on [he blind side bleeds into the

blind hemi-vagina, creating a haematocolpos Cyclical

abdominal pain occurs with increasing severity, but

this time the patient does have periods because the

other hemi-uterus and hemi-vagina function normally

Excision of the midline septum results in proper

drainage of the menstrual flow, thereby resolving the

problem

Menorrhagia in adolescence

•Menstrual problems in adolescence are very common,

and may manifest themselves in a number of ways

The periods may be irregular and very heavy and

occasionally result in marked anaemia, or they may

be very light and infrequent and cause equal concern

As outlined above, an understanding of the ogy of the onset of the menstrual cycle and its subse-quent normal development is imperative for theclinician to manage these patients correctly

physiol-In the former group of heavy menstrual loss, if thepatient is not anaemic, it is unnecessary to offer anytreatment other than reassurance If the patient doesbecome anaemic, some control ot menstrual loss must

be undertaken This is best achieved either by gens or by the oral contraceptive pill Control of thecycle will result until such time as the hypothalamo-pituitary-ovarian axis has matured

progesto-In the group of patients who have very infrequentperiods, a further investigation may be required, andthis is best carried out by assessing several levels ofgonadotrophins and by ultrasound of the ovary Insome circumstances, a diagnosis of polycystic ovarysyndrome may be made, and these patients may requiremenstrual cycle control in [he form of the oral contra-ceptive pill They also may develop oligomenorrhoealater in life, which may contribute towards an infertilityproblem (hat may require attention However, it isimportant to remember that the vast majority ofthese teenage girls will eventually establish a normalmenstrual cycle and be fertile The clinician is welladvised to be cautious in giving advice about fertilitypotential, as incorrect advice may invoke unnecessaryanxiety

Precocious puberty

Occasionally, pubertal changes may occur earlierthan normal, and they have been known to occur asearly as 3 or 4 years of age Most cases of precociouspuberty are idiopathic, but result from prematureactivation ot the gene in the Gn RH cell The sequence

of events that occur subsequently mimics normalpuberty, and therefore ovulatory cycles may result

in very young children if they are not treated

In fact, pregnancy has been known to occur in 5 and6-year-olds in whom sexual maturity has beenreached Precocious puberty may, however, also resultfrom abnormal situations, e.g a granulosa celltumour that produces oestradiol, and this will lead

to pLibertal development, or from pituitary or

hypo-thalamic tumours, which lead to FSH production,e.g craniopharyngioma

Common clinical presentations and problems 31

aJ anaemia, or they may

and cause equal concern

[standing of the physio

1-irual cycle and its

subse-t is imperasubse-tive for subse-the

Bents correctly

avy menstrual loss, if the

unnecessary to offer any

ranee If the patient does

rol of menstrual loss must

hieved either by

progesto-iptive pill Control of the

ime as the

hypolhalamo-latured

who have very infrequent

Ion may be required, and

assessing several levels of

rasound of the ovary In

nosis of polycystic ovary

these patients may require

ic form of the oral

contra-develop oligornenorrhoea

tute towards an infertility

attention However, it is

:at the vast majority of

itually establish a normal

tOe The clinician is well

sing advice about fertility

t may invoke unnecessary

When investigating these children, the exclusion

of a serious tumour is of primary importance, andimaging techniques can be used to achieve this As themajority of cases are idiopathic, treatment is targeted

at down-regulation of the pituitary using GnRHanalogues

Genetic sex is determined by tne presence of the sex chromosomes X a n d Y.

The presence of a Y chromosome determines maledevelopment; the absence of a ¥ chromosome leads to afemale phenotype

In Turner's syndrome, the absence of a second Xchromosome leads to streak ovaries

If the testis fails to develop or cannot f unction, the defaultstate is female

True hermaphrodites have bolh ovarian and testicular tissue

The effect is determined by the dominant cell line

New developments

Laparoscopic techniques have been developed to help form a neovagina in cases of vaginal atresia Although more invasive than using dilaiors, they allow a functional vagina to be formed more quickly.

Congenital absence of the uterus and vagina is the second most common cause of primary amenorrhoea.

Uterine maldevelopment does not usually result in reproductive failure.

External genitalia in girls may be virihzed by excessiveandrogen exposure in utero.

Puberty is genetically determined and controlled from thehypothalamus

Additional reading

Edmonds DK Normal and abnormal development of the genital tract Gynaecological disorders of childhood and

adolescence In: Edmonds DK (ed.), Dewhurst's textbook of

obstetrics and gynaecology tor postgraduates, 6th edn.

Oxford: Blackwell Science, 1999,1-11 and 12-16.

Moore KL, Persaud TVIM The developing human: clinically

orientated embryology, 6th edn Philadelphia;

WB Saunders, 1998.

Sanfilippo JS (ed ) Pediatnc and adolescent gynecology.

2nd edn Philadelphia: WB Saunders, 2D01.

irtges may occur earlier

: been known to occur as

Most cases of precocious

it result from premature

GnRH cell The sequence

equently mimics normal

jlatory cycles may result

f they are not treated,

known to occur in 5 and

cual maturity has been

Y may, however, also result

i, e.g a granulosa cell

ladiol, and this will lead

* from pituitary or

hypo-lead to FSH production,