Amenorrhea

Amenorrhea remains one of the few areas of gynaecologic

endocrinology that remains a challenge to the managing
clinician. The majority of patient with amenorrhea have
relatively simple problems that can be managed easily by the
patients primary care clinician.

Definition of Amenorrhea:
• No menses by age 14 in the absence of growth or
development of secondary sexual characteristics.
• No menses by age 16 regardless of the presence of
normal growth and development with appearance of
secondary sexual characteristics.
• In a woman who has been menstruating, the absence of
periods for a length of time equivalent to a total of at
least 3 of the previous cycle intervals or 6 months of
amenorrhea.

Let it be known, that strict adherence to these criteria can

result in improper management in individual cases. There is no
reason to defer the evaluation of a young girl who presents with
obvious stigmata of Turner syndrome. Similarly, the 14-year-old
girl with an absent vagina who is otherwise completely normal
should not be told to return in 2 years. A patient deserves a
considerate evaluation whenever her anxieties, or those of her
parents, bring her to a clinician, finally, the possibility of
pregnancy should always be considered.

Basic principles of Menstrual function:

The clinical demonstration of the menstrual flow to some extent

confirms that the menstrual function is in a good condition. This
requires an intact genital outflow tract (a patent tract that
connects the endometrial cavity through the cervical canal,
vaginal canal and vaginal orifice). The presence of a menstrual
flow depends on the existence and development of the
endometrium lining the uterine cavity. This tissue is stimulated
and regulated by the proper quantity and sequence of the
oestrogen and progesterone hormones. These hormones are
secreted by the ovary, more specifically by the evolving follicles
which following ovulation becomes corpus luteum. The
development of the ovarian follicle are stimulated by the
gonadotropins (i.e FSH and LH) secreted by the anterior
pituitary, which is stimulated by the gonadotropin releasing
hormone (GnRH) which in turn is secreted from basal
hypothalamus and transferred through portal vessels to the
receptive cells within the anterior pituitary.
At 6-8 weeks of gestation, the first sign of ovarian
differentiation is shown by the rapid mitotic multiplication of the
germ cells, reaching 6-7 million oogonia by 16-20 weeks (this
represent the maximal oogonal content of the gonad), and from
this point onward there will be an irretrievable decrease in the
germ cell population for some 50 years later, the store of
oocytes will be finally exhausted. Chromosomal anomalies can
accelerate germ cell loss. Individuals with Turner syndrome
(45,X) experience normal migration and mitosis of germ cells,
but the oogonia do not undergo meiosis, and rapid loss of
oocytes leaves the gonad without follicles by birth, and it
appears as a fibrous streak.

The causes of amenorrhea can be segregated into the following

compartments:

Compartment I:
Disorders of the outflow tract or uterine target organ.

Compartment II:
Disorders of the ovary.

Compartment III:
Disorders of the anterior pituitary.

Compartment IV:
Disorders of central nervous system (hypothalamic) factors.

Evaluation of Amenorrhea:

Evaluation of the patient with amenorrhea, starts with a careful

history taking and physical examination which seeks the
following – evidence for psychological dysfunction or emotional
stress, family history of apparent genetic anomalies, signs of
nutritional deprivation (i.e. anorexia nervosa), excessive weight
loss, abnormal growth and development, the presence of a
normal reproductive tract, and evidence for CNS disease.
Thereafter, the patient is exposed to a combined therapeutic
and laboratory evaluation as depicted by the flow chart below.
Because galactorrhea (nonpuerperal breast lactation) is a
frequent problem with those who have amenorrhea – it is
always appropriate to seek for its occurrence and since there
are similarities in the evaluation of these two conditions, the
workup as described below is appropriate for patients with
amenorrhea, galactorrhea or both. Galactorrhea is an important
clinical physical sign, whether it is spontaneous or present only
with careful expression by the examiner, unilateral or bilateral,
persistent or intermittent.
Galactorrhea due to hormonal secretions usually come from
multiple duct openings in contrast to pathologic discharge that
usually comes from a single duct.

The initial step in the evaluation of galactorrhea, regardless of

the menstrual history, includes the measurement of TSH,
prolactin level and lateral view x-ray of the skull coned down to
the sella turcica.

Step 1: (initial step in the evaluation of amenorrheic patient)

First exclude pregnancy by doing a pregnancy test.
1. Begin with measurement of thyroid-stimulating hormone
(TSH), though only a few patient presenting with
amenorrhea and/or galactorrhea will have hypothyroidism
that is not clinically apparent. It is pertinent to start with
the evaluation of TSH, since the treatment for
hypothyroidism is very simple, with prompt return of
ovulatory cycles, and cessation of breast secretions for
those with galactorrhea. Elevated TSH implies that there
is hypothyroidism. The longer the duration of
hypothyroidism, the higher the incidence of galactorrhea
and the higher the prolactin levels. Therefore, the next
investigation would be serum prolactin level – it is known
that with hypothyroidism, the hypothalamic content of
dopamine is reduced resulting in the unopposed
stimulatory effect of thyrotropin-releasing hormone (TRH)
on prolactin secretion from the pituitary gland. The
constant pituitary gland stimulation with TRH can result in
hypertrophy or hyperplasia of the pituitary. Therefore,
patients with primary hypothyroidism and
hyperprolactinaemia can present with either primary or
secondary amenorrhea. The next investigation in the
evaluation of amenorrhea is to assess the level of
endogenous oestrogen and the competence of the
outflow tract. There are 3 choices of progestational
agents:
i. Parenteral progesterone in oil (200mg).
ii. Oral micronized progesterone (300mg),
usually administered at bedtime to avoid side-
effects.
iii. Oral medroxyprogesterone acetate, 10mg
daily for 5 days.

Within 2-7 days after the conclusion of progestational

medication, the patient will either bleed or not bleed. For the
patient that has a withdrawal bleeding, it can be reliably
assumed that she had anovulation. The presence of a functional
outflow tract and a uterus lined by reactive endometrium
sufficiently prepared by endogenous oestrogen is confirmed.
Therefore in the absence of galactorrhea, with normal serum
prolactin and TSH levels further evaluation is unnecessary.

Negative withdrawal bleeding (no bleeding following

progestational challenge).
- there are 2 rare situations associated with a negative
withdrawal response, despite the presence of adequate
levels of endogenous oestrogen. In both situations, the
endometrium is decidualized, and therefore, it will not be
shed following the withdrawal of exogenous progestin.
o Anovulatory state due to polycystic ovary
syndrome, where the endometrium is decidualized
in response to high androgen levels.
o Specific adrenal enzyme deficiency (17 hydroxylase
deficiency), where the endometrium is decidualized
by high progesterone levels associated with the
enzyme deficiency.

All anovulatory patients require therapeutic management,

because of the short latent period in the progression from
normal endometrial tissue to atypia to cancer (the critical
feature is the duration of exposure to constant, unopposed
oestrogen). If there is any concern, evaluation of the
endometrium with aspiration curettage is necessary.
Minimal therapy of anovulatory women requires the monthly
administration of a progestational agent: 10mg
medroxyprogesterone acetate daily for the first 10 days of each
month (this provides the needed protection against the growth-
promoting effects of constant oestrogen stimulation).

If reliable contraception is essential, the use of low-dose oral

contraceptive pills in the usual cyclic fashion is appropriate.

If, at any time, an anovulatory patient fails to have withdrawal

bleeding on a monthly progestin programme, this is a sign
(provided she is not pregnant) that she has moved to the
negative withdrawal bleed category.

The progestational challenge will occasionally trigger an

ovulation in an anovulatory patient. The tip-off will be a later
withdrawal bleed, 14 days after the progestational challenge.

Note: A positive withdrawal bleeding response to progestational

medication, the absence of galactorrhea, and a normal prolactin
level together effectively rule out the presence of a significant
pituitary tumour.

- Otherwise a negative withdrawal response implies end-

organ problem (e.g., reproductive outflow tract
 obstruction or preliminary oestrogen proliferation of the
endometrium has not occurred).

Hyperprolactinemia should draw attention to the pituitary

gland, but remember that there could be ectopic production of
prolactin (though rare) in pituitary tissue in the pharynx,
bronchogenic carcinoma, renal cell carcinoma, a
gonadoblastoma, prolactinoma in the wall of an ovarian
dermoid cyst or teratoma.

Step 2 in the management of amenorrheic patient is designed

to clarify this situation.

Step 2:
Orally active oestrogen is administered in quantity and duration
certain to stimulate endometrial proliferation and withdrawal
bleeding provided that a completely reactive uterus and patent
outflow tract exist.

Oestrogen therapy:
i. conjugated oestrogen 1.25mg daily for 21 days Or 2mg
oestradiol daily for 21 days, the above is to induce
endometrial proliferation. The addition of orally active
progestational agent terminally (medroxyprogesterone
acetate 10mg daily for the last 5 days) is to achieve
withdrawal bleeding. In the presence of a negative
withdrawal response, it is a wise precaution to have a
second course of oestrogen and if still negative, a
diagnosis of a defect in the endometrium or outflow
tract can be confidently made.
Step 3:

For those amenorrheic patient, who do not have enough

endogenous oestrogen to stimulate the endometrium. It would
be necessary to determine whether the dysfunction is in the
ovary or hypothalamo-pituitary by assaying for serum FSH and
LH.
Note: Because step 2 involved administration of exogenous
oestrogen, which can artificially and temporarily alter the true
baseline concentrations of endogenous gonadotropins, it is
necessary to delay step 3 (assay of gonadotropins) for 2 weeks
after step 2.

Normal adult female :

Serum FSH level is 5-20IU/L, with the ovulatory midcycle
peak about 2 times the baseline level.
Serum LH level is 5-20IU/L, with the ovulatory midcycle
about 3 times the baseline level.
Hypogonadotropic hypogonadism – (prepubertal, hypothalamic
or pituitary dysfunction)
Serum FSH level is less than 5IU/L and serum LH level is
also less than 5IU/L, there would be a need for lateral
view skull x-ray, coned down to the sella turcica to
exclude pituitary hypertrophy.
Hypergonadotropic hypogonadism (postmenopausal, castrate or
ovarian failure):
Serum FSH level will be greater than 20IU/L, just as serum
LH level will be greater than 40IU/L. when the result of
serum gonadotropin is elevated, there is the need to
repeat the assay several months apart.

High Gonadotropins:
Rarely tumours produce gonadotropins, as occurs in cancer of
the lung. However, due to its rarity a good history and physical
examination, precludes a routine chest x-ray for all amenorrheic
women. It is necessary to assay for both gonadotropins, so as
to be able to diagnose the rare single gonadotropin deficiency
(diagnosed by a high level of one and the baseline or
undetectable level of the other gonadotropins).
Note: an elevated FSH level is not an absolute indicator of
infertility. It is not unusual to encounter a pregnancy in a
woman after a diagnosis of premature ovarian failure.
All patients with premature ovarian failure should be tested for
complete thyroid function test including antibodies. Other rare
conditions associated with premature ovarian failure includes
myasthenia gravis, idiopathic thrombocytopenic purpura,
rheumatoid arthritis, vitiligo, and autoimmune haemolytic
anaemia. Classically, premature ovarian failure precedes
adrenal failure, hence there is the need for continued adrenal
surveillance.

Galactosemia is a rare inherited autosomal recessive disorder of

galactose metabolism due to a deficiency of galactose-1-
phosphate uridyl transferase. The problem in galactosemia is
primarily gonadal; fewer oogonia may be the result of a direct
toxic effect of galactose metabolites on germ cell migration to
the genital ridge. Premature ovarian failure is common and
usually irreversible.

A final rare clinical condition associated with high gonadotropin,

despite the presence of ovarian follicle is the enzymatic
deficiencies such as 17- hydroxylase deficiency which usually
affects ovaries and the adrenal gland. This is usually detectable
due to absence of secondary sexual development (sex steroids
cannot be produced due to the enzyme block in the adrenal
glands and the ovaries), and hypertension, hypokalemia, and
high blood levels of progesterone.
The need for chromosome evaluation:

All patients under the age of 30 diagnosed to have ovarian

failure on the basis of elevated gonadotropins must have a
karyotype determination. The presence of mosaicism with a Y-
chromosome requires the excision of the gonadal area, since
the presence of these gonad is associated with malignant
tumour (germ cell tumour such as gonadoblastomas,
dysgerminomas, yolk sac tumours, and choriocarcinoma.
Approximately 30% of patients with Y-chromosome will not
develop signs of virilization, therefore, even the normal
appearing adult woman with elevated gonadotropin levels must
be karyotyped.
Note: even if the karyotype is normal, all patients with
premature ovarian failure should have an annual pelvic
examination (a precautionary measure). Over the age of 30,
amenorrhea with high gonadotropin is best labelled premature
menopause.
Accurate diagnosis of X-chromosome deletions on karyotype
reveals there is a family history of infertility due to premature
ovarian failure, which can influence the family planning
decisions of family members.

Premature ovarian failure: (A clinical dilemma) Patients with

repeatedly elevated gonadotropin levels can be reliably
diagnosed as having ovarian failure and can be considered
sterile. However, 10-20% of patient presenting with secondary
amenorrhea and elevated gonadotropin (with normal
karyotypes), have had spontaneous recovery, with return of
normal function and have been able to achieve pregnancy.

A number of premature ovarian failure are due to autoimmune

disorders – therefore during evaluation do selected blood test
for autoimmune disease.
• Calcium
• Phosphorus
• Fasting glucose
• A.M. cortisol
• Free T4
• TSH
• Thyroid antibodies, if thyroid function is abnormal
• Complete blood count and ESR
• Total protein; albumin: globulin ratio
• Rheumatoid factor
• Antinuclear antibody
Periodic surveillance for adrenal failure is in order because
ovarian failure usually precedes adrenal failure.

Other than hypothyroidism, it is uncommon to encounter other

disorders associated with premature ovarian failure.

Normal Gonadotropins:

FSH and LH levels in the normal range in a patient with

hypoestrogen, resulting in a negative progestational withdrawal
test are consistent with pituitary-CNS failure. Extremely low or
undetectable gonadotropins are seldom found, usually only with
large pituitary tumours or in patients with anorexia nervosa.

Low Gonadotropins:

If the gonadotropins are abnormally low, or in the normal range

in a patient with amenorrhea, it would be necessary to evaluate
the sella turcica by imaging for signs of abnormal change to
distinguish between a pituitary (compartment III) or CNS-
hypothalamic (compartment IV) cause for amenorrhea.

Imaging the sella turcica:

The diagnostic modality of choice is either thin – section coronal
CT scan with intravenous contrast enhancement or MRI with
gadolinium enhancement.
MRI is more sensitive than CT-scan, but more expensive.
CT-scan is able to evaluate the contents of the sella turcica as
well as the suprasellar area. If the prolactin level is greater than
100ng/ml, or if the coned down x-ray view of the sella turcica is
abnormal then CT-scan or MRI would be necessary.
The presence of visual problems and/or headaches should also
encourage CT-scan or MRI evaluation.
Headaches are definitely correlated with the presence of a
pituitary adenoma – headaches are usually bifrontal, retro-
orbital or bitemporal.

Hypogonadotropic hypogonadism:

Patients with amenorrhea, but no galactorrhea and have normal

imaging studies are classified as hypothalamic amenorrhea.
The mechanism resulting in hypothalamic amenorrhea is
suppression of pulsatile GnRH secretion below its critical range.
It is a diagnosis by exclusion; we can identify probable causes –
anorexia and weight loss.

Specific Disorders within Compartments:

Compartment 1: disorders of the outflow tract or uterus

Asherman’s syndrome
This condition generally follows overzealous postpartum
curettage, resulting in intrauterine scarification. It may also
occur following uterine surgery, including Caesarean section,
myomectomy, or metroplasty. It as also been noted following
Sheehan’s syndrome (postpartum hypogonadism).
Patients with Asherman’s syndrome, besides amenorrhea can
present with miscarriages, dymenorrhea, or hypomenorrhea.
They can even have normal menses. Infertility can be present
with mild adhesions.
Patients with repeated miscarriages, infertility, or pregnancy
wastage should have investigation of the endometrial cavity by
hysterogram or hysteroscopy.
In Asherman’s a typical partern of multiple synechiae is seen on
a hysterogram (HSG) – filling defects. The gold standard for
diagnosis is hysteroscopy, which is more accurate and can
detect minimal adhesions that are not apparent on HSG. In the
presence of normal ovarian function, the basal body
temperature will be biphasic.

The adhesion may partially or completely obliterate the

endometrial cavity, the internal cervical os, the cervical canal or
combinations of these areas. Surprisely, despite stenosis or
atresia of the internal cervical os, haematometra does not
inevitably occur – may be perhaps, the endometrium in
response to a buildup of pressure, becomes refractory, and
simple cervical dilatation cures the problem.

Impairment of the endometrium resulting in amenorrhea can be

caused by tuberculosis, the diagnosis is made by culture of the
menstrual discharge or endometrial biopsy. Amenorrhea may
also occur in the presence of uterine schistosomiasis and
diagnosis is made by finding parasite eggs in urine, faeces,
rectal scrapings, menstrual discharge, or endometrial biopsy.

Asherman’s syndrome may also follow pelvic infection with

IUCD in-situ or severe PID.

Management: dilatation and curettage to break up adhesions,

after which an IUCD is inserted to prevent re-apposition of the
uterine wall, with consequent adhesions.
A paediatric Foley catheter appears a better option for
preventing repeat adhesion formation the balloon is filled with
3ml of fluid and removed after 7 days.
Preoperatively a broad spectrum antibiotics is started and
maintained for 10 days. An inhibitor of prostaglandin synthesis
can be used if uterine cramping becomes a problem.
The patient following adhesiolysis is treated for 2 months with
high stimulatory doses of oestrogen (e.g. conjugated
oestrogens 2.5mg daily for 21 days (i.e for 3 weeks) and
medroxyprogesterone acetate 10mg daily is added thereafter to
induce withdrawal bleeding, if the initial treatment fails to re-
establish menstrual flow, the treatment is repeated.
About 70-80% of patients with this condition have achieved
pregnancy with treatment. However, pregnancy is frequently
complicated by premature labour, placenta acreta, placenta
praevia, and/or postpartum haemorrhage.

Müllerian anomalies
In primary amenorrhea, segmental discontinuity of the
mullerian tube should be ruled out by direct observation –
imperforate hymen, obliteration of the vaginal orifice
(transverse vaginal septum). The cervix or the entire uterus
may be absent. Far less common, the uterus may be present,
but the cavity absent, or, in the presence of the cavity, the
endometrium may be congenitally absent. With the exception of
the latter abnormalities, the clinical problem of amenorrhea due
to obstruction is compounded by painful distension of
haematocolpos, haematometra, or haemoperitoneum.
In all instances, an effort must be made to incise and drain from
below at the point of closure of the mullerian tube.

Müllerian agenesis
Lack of müllerian development (Mayer-Rokitansky-Kuster-
Hauser syndrome) is the diagnosis for the individual with
primary amenorrhea and no apparent vagina. This is a relatively
common cause of primary amenorrhea (about 1 in 4000 female
births), second only to gonadal agenesis. These patients have
an absence or hypoplasia of the internal vagina, and usually an
absence of the uterus and fallopian tubes.
However, rarely, the uterus may be normal, but lacking a
conduit to the introitus, or there may be only rudimentary,
bicornuate cords present. If a partial endometrial cavity is
present, cyclic abdominal pain may be a complaint.
This condition is similar to some types of male
pseudohermaphroditism, therefore, it is necessary to
demonstrate normal female karyotype. The ovaries are not
mullerian structures and so function normally and can be
documented by normal basal body temperature or peripheral
levels of progesterone. Growth and development are normal.

The exact cause of mullerian agenesis is unknown. Likely

causes are mutation in the gene for antimullerian hormone or
the gene for the antimullerian hormone receptor. The
underlying mechanism would be unwanted exposure to
antimullerian hormone activity. Although usually sporadic,
occasional occurrence may be noted within a family.
A mutation has been noted in mothers with galactose-1-
phosphate uridyl transferase in which mothers and daughters
have mullerian agenesis.

For patient with mullerian agenesis further evaluation should

include radiologic studies. Approximately one-third of patients
have urinary tract abnormalities (ectopic kidney, renal
agenesis, horseshoe kidney and abnormal collecting ducts) and
12% or more have skeletal anomalies, most involving the spine,
although absent digits and syndactyly (webbing or fusion of
fingers or toes) can occur.
When the presence of a uterine structure is suspected on
examination, USS can be utilized to depict the size and
symmetry of the structure. When uncertain with ultrasound,
then MRI would be used for evaluation. Laparoscopy for
visualizing the pelvis may not be necessary.

Extirpation of the mullerian remnants is certainly not necessary

unless they are causing a problem such as uterine fibroid
growth, haematometra, endometriosis, or symptomatic
herniation into the inguinal canal.

Management options

Progressive dilatation
Surgical construction of the vagina

Transverse vaginal septum is a failure of canalization of the

distal third of the vagina, usually presents with symptoms of
obstruction and urinary frequency. A transverse septum can be
differentiated from an imperforate hymen by a lack of
distension at the introitus with valsalva’s manoeuvre.

Distal obstruction of the genital tract is the only condition in this

category that can be considered an emergency. Delay in
surgical treatment can lead to infertility due to inflammatory
changes and endometriosis. Definitive surgery should be
accomplished as soon as possible. Diagnostic needling should
be avoided because a haematocolpos can be converted into a
pyocolpos.

Genetic offspring can be achieved by collection of oocytes from

the genetic mother, fertilization by the genetic father, and
placement into a surrogate carrier.

Androgen insensitivity (testicular feminization):

Complete androgen insensitivity results in a blind short vaginal
canal, with absent uterus. This is the 3rd most common cause of
primary amenorrhea. The patient is a male
pseudohermaphrodite, has gonadal sex(XY), therefore the
individual has testes and an XY karyotype. The patient is a
phenotypic female, with absent or sparse pubic and axillary
hair. There is absence of virilization. This disorder is X-linked
recessive.

Clinically the diagnosis should be considered in a female child

with inguinal hernia, because the testes are frequently partially
descended, a patient with primary amenorrhea and an absent
uterus, or a patient with absent body hair.

These patients appear normal at birth except for the possible

presence of an inguinal hernia, and most patients are not seen
by a physician until puberty. Growth and development are
normal, although overall height is usually greater than average,
and there may be a eunuchoidal tendency (long arms, big
hands, and big feet). The breast, although large, are abnormal:
actual glandular tissue is not abundant, nipples are small, and
the areolae are pale. More than 50% have an inguinal hernia,
the labia minora are usually underdeveloped, and the blind
vagina is less deep than normal. There may be rudimentary
fallopian tubes composed of fibromuscular tissue with only
occasional epithelial lining. Horseshoe kidneys have been
reported.

The testis may be intra-abdominal, but often are within the

groin in the hernia. They may be nodular. After puberty testis
display an immature tubular development, and tubules are
lined by immature germ cells and Sertoli cells. There is no
spermatogenesis, and the incidence of neoplasia within these
gonads is high. Therefore, once full development is attained
after puberty, the gonads should be removed at approximately
16-18yrs, and patient placed on hormone therapy (this is the
only exception to the rule, that gonads with Y chromosome
should be removed as soon as diagnosis is made). There are 2
reasons for this exception – first, the development achieved
with hormone replacement does not seem to match the smooth
pubertal changes due to endogenous hormones, and second,
gonadal tumours in these patients have not been encountered
prior to puberty.

The removal of these gonads can be accomplished through the

laparoscope, reserving the option of laparotomy if the gonads
are inaccessible.
In testicular feminization, the urinary 17-ketosteroids are
normal, the plasma testosterone is within the range of high
normal male values, and the plasma clearance and metabolism
of testosterone are normal. Therefore, these patient do not
respond to androgens, either their own or those given locally or
systemically. Therefore, the critical steps in sexual
differentiation, which require androgens, fail to take place, and
development is totally female. Because antimullerian hormone
is present, development of the mullerian duct is inhibited,
hence the absence of uterus, tubes, and upper vagina.

This syndrome is marked by a unique combination:

1. Normal female phenotype.
2. Normal male karyotype, 46, XY.
3. Normal or slightly elevated male blood testosterone levels
and a high LH.

Incomplete androgen insensitivity: one-tenth as common as the

complete syndrome. The individuals have some androgen effect
on the end-organ. These individual may have clitoral
enlargement, or a phallus may even be present. Axillary hair
and pubic hair develop along with breast growth. Gonadectomy
should not be deferred in such cases because it will obviate
unwanted further virilization.

Patients with a deficit in testicular 17β-hydroxysteroid

dehydrogenase activity will have impaired testosterone
production and present clinically as incomplete androgen
insensitivity. Because treatment (gonadectomy) is the same,
precise diagnosis is not essential.

In the past, conventional wisdom warned against unthinking

and “needless” disclosure of the gonadal and chromosomal sex
to a patient with complete androgen insensitivity. This attitude
has changed as, more and more, patients desire and appreciate
a full understanding of themselves. Although infertile, these
patients are certainly completely female in their gender
identity, and this should be reinforced rather challenged.

What is strongly advocated is combining a truthful education

with appropriate psychological counselling of patients and
parents.

Compartment II: Disorders of the Ovary

Gonadal developmental problems can present with either

primary or secondary amenorrhea.
30-40% of cases with primary amenorrhea, are due to gonadal
streaks (resulting from abnormal development): the incidence
of the karyotypes in this group are –
• 50% - 45, X
• 25% - mosaics
• 25% - 46, XX

Women with gonadal dysgenesis can also present with

secondary amenorrhea. The karyotypes associated with this
presentation are, in order of decreasing frequency:
• 46, XX (most common).
• Mosaics (e.g., 45, X/46, XX).
• Deletions in X short and long arms.
• 47, XXX
• 45, X

Both X chromosome must be present and active in oocytes to

avoid the accelerated loss of follicles.

Perrault syndrome comprises gonadal dysgenesis, with normal

karyotype and also linked with neurosensory deafness – hence,
auditory evaluation should be considered in any patient with
gonadal dysgenesis and 46, XX.

Pure gonadal dysgenesis indicates the presences of bilateral

streak gonads, regardless of the karyotype.

Mixed gonadal dysgenesis indicates the presence of testicular

tissue on one side and a streak gonad on the other side.

Turner syndrome: 45, X

They are short statured, webbed neck, shield chest, and an
increased carrying angle at the elbow, combined with
hypergonadotropic hypoestrogenic amenorrhea. The above
finding makes the diagnosis on clinical evaluation possible. As a
result of the absent ovarian follicles, there is no gonadal sex
hormone production at puberty, and thus patient presents with
primary amenorrhea.
Always rule out autoimmune disorders, cardiovascular and renal
abnormalities. The karyotype must be performed on all patients
with elevated gonadotropins, inspite of the presence of
phenotypic trait of Turner syndrome.

Mosaicism:
Mosaicism is the presence of multiple cell lines of varying sex
chromosome composition (e.g 45, X/46, XY or 45, X/46, XX) in
an individual. This must be ruled out in patient with
amenorrhea, because of the need to exclude the presence of Y
chromosome in cases of gonadal dysgenesis; which should
necessitate gonadectomy – the presence of any testicular
component in the gonadal area predispose to tumour formation
and to heterosexual development (virilization). Only in patient
with complete androgen insensitivity is gonadectomy deferred
until after puberty, since the individual is resistant to androgens
and gonadal turmours occur late.
Approximately 30% of patients with a Y chromosome will not
develop signs of virilization. Therefore, even the normal-
appearing adult patient with elevated serum gonadotropins
must have their karyotype done, to detect a silent Y
chromosome so that prophylactic gonadectomy can be
performed before neoplastic changes occur.

The impact of mosaicism, even in the absence of a Y-

chromosome is significant. With an XX component (e.g. XX/XO),
functional ovarian tissue can be found within the gonad, leading
to a variety of responses, including some degree of female
development, and, on occasion even menses and reproduction.
These individuals may appear normal, attaining normal stature
before premature menopause is experienced.

Note: All patients with absent ovarian function and quantitative

alterations in the sex chromosomes are categorized as having
gonadal dysgenesis.

XY Gonadal dysgenesis:
A female patient with XY karyotype, who has a palpable
mullerian system, normal female testosterone levels, and lack
of sexual development has Swyer’s syndrome. Tumour
transformation in the gonadal ridge can occur at any age.
Therefore, gonadectomy should be performed as soon as the
diagnosis is made.

Gonadal agenesis:
Gonadal failure due to agenesis, does not result in any
complicated clinical problems. Hypergonadotropic
hypogonadism, in the absence of gonadal function,
development is female. Surgical removal of the gonadal streaks
is necessary to avoid the possibility of neoplasia.
Viral or metabolic influence in early gestation or undiscovered
genetic mutations may be responsible.

The Resistant Ovary syndrome:

This is a rare presentation, the patient has amenorrhea, normal
growth and development, with elevated gonadotropins despite
the presence of unstimulated ovarian follicles, there is no
evidence of autoimmune disease. Laparotomy is necessary to
arrive at a correct diagnosis by obtaining adequate histological
evaluation of the ovaries – it demonstrates not only the
presence of follicles but absence of the lymphocytic infiltration
seen with autoimmune disease. Because of the rarity of this
condition and the very low chance of achieving pregnancy even
with high doses of exogenous gonadotropins, it may not be
necessary to perform laparotomy, for the purpose of ovarian
biopsy on every patient with amenorrhea, high gonadotropins,
and a normal karyotype. These patients are excellent
candidates for oocyte donation.

Premature Ovarian failure:

This is the early depletion of ovarian follicles before the age of
40 yrs. The aetiology of premature ovarian failure is unknown is
most cases. However, the aetiological factors include
chromosomal anomalies (the most common anomalies are 45,
X and 47, XXY followed by mosaicism), autoimmune diseases,
infections (mumps oophoritis), physical assault of the ovaries
such as chemotherapy and irradiation.
Premature ovarian failure is surprisingly common,
approximately 1% of women will experience ovarian failure
before the age of 40, the incidence is higher in women with
primary amenorrhea (prevalence ranges from 10-28%).
Premature ovarian failure can present at any age: if lose of
follicles has been rapid, then primary amenorrhea and absence
of secondary sexual characteristics will be present. If loss of
follicles occurred during or after puberty, then the extent of
adult phenotypic development and the time of onset of
secondary amenorrhea will vary accordingly.
There as been reports of spontaneous resumption of normal
ovarian function, in 10-20% of patient with normal karyotype,
with premature ovarian failure. Therefore, one cannot be certain
that patient with premature ovarian failure will be sterile
forever.
Management: Laparotomy with a full thickness ovarian biopsy
may not be necessary in all cases, a survey for autoimmune
diseases (recognizing that there is no practical clinical method
to accurately diagnose autoimmune ovarian failure) and an
assessment of ovarian-pituitary activity, is sufficient.
As with other hypogonadal state, hormone therapy is
recommended. However, because of spontaneous ovulations
that can occur, an oral contraceptive is a better treatment
regimen of choice if pregnancy is not desired. The best prospect
for pregnancy in those with premature ovarian failure is oocyte
donation (note, pregnancy rates are reduced, if sibling’s
donated oocytes are used).

The effect of Radiation and Chemotherapy;

The effect of radiation on ovarian function is dependent upon
the age and the x-ray dose. Steroid levels begin to fall and
gonadotropins (FSH, LH) rise within 2 weeks after irradiation to
the ovaries. The higher number of oocytes in younger age is
responsible for the resistance to total castration in young
women exposed to intense radiation. Function can resume after
many years of amenorrhea. On the other hand, the damage
may not appear until later in the form of premature ovarian
failure. If pregnancy does occur, the risk of congenital
abnormalities is not greater than normal population. When the
irradiation field excludes the pelvis, there is no risk of
premature ovarian failure. For this reason, elective transposition
of the ovaries by laparoscopy out of the pelvis, prior to
irradiation provides a good prospect for future fertility. Gonads
are not in danger in the kitchen; microwave ovens utilize
wavelength with low tissue-penetrating power.

OVARIAN DOSE STERILIZATION EFFECT

60rads No effect
150rads Some risk over age 40
250-500rads Ages 15-40: 60% sterilized
500-800rads Ages 15-40: 60-70%
Over 800rads sterilized
100% permanently sterilized
Alkylating agents are very toxic to the gonads. There is an
inverse relationship between the dose required for ovarian
failure and the age at the start of therapy. Other
chemotherapeutic agents have the potential for ovarian
damage, have been less studied. The effect of combination
chemotherapies is similar to those of the alkylating agents.
Approximately 2/3rd of premenopausal women with breast
cancer and treated with cyclophophamide, methotrexate, and
fluorouracil lose ovarian function. Resumption of menses and
pregnancy can occur, but there is no way to predict which
patient will reacquire ovulatory function. The damage may
present late with premature ovarian failure.

The harvesting and cryopreservation of oocytes prior to

irradiation and/or chemotherapy will ultimately prove to be the
best means of preserving fertility for these patients.

Compartment III: Disorders of the Anterior Pituitary:

1. Pituitary tumours: malignant tumours of the pituitary are

very rare, most are benign and cause problem by their
growth (expansion) in a confined space. The tumour
grows upward, compressing the optic chiasma and
producing the classic findings of bitemporal hemianopsia,
 with small tumours, however, abnormal visual fields are
rarely encountered.
2. Other tumours of this region (e.g. craniopharyngioma,
usually marked by calcifications on x-ray) may be
associated with the early development of blurring of
vision and visual field defects because of their close
proximity to the optic chiasma. Other very rare tumours
include meningiomas, gliomas, metastatic tumours, and
chordomas.
• Increased melatonin secretion, probably from a cystic
pineal lesion, has been reported as a cause of delayed
puberty.
• Hypogonadism and delayed puberty deserves brain
evaluation by MRI

Situations of increased suspicion of pituitary tumours:

• Acromegaly caused by excessive secretion of
growth hormone, if suspected, growth hormone
should be measured during an oral glucose
tolerance test (a lack of suppression of growth
hormone levels is diagnostic), and the circulating
level of insulin growth factor-1 should be
measured.
• Cushing’s disease due to excessive secretion of
ACTH, if clinical criteria suggest Cushing’s
disease, ACTH levels and the 24-hr urinary level
of free cortisol should be measured, and a rapid
suppression test (dexamethasone test) for
confirmation.
• Rarely, a TSH-secreting tumour will cause
secondary hyperthyroidism.

Amenorrhea and/or galactorrhea may precede the

eventual full clinical expression of a tumour that
secretes ACTH or growth hormone.

Note: the 2 most common pituitary tumours are

prolactin-secreting adenomas and the clinically non-
functioning tumours.

Acromegaly can initially present with an elevated

prolactin level and amenorrhea, therefore, the
circulating level of IGF-1 should be measured in all
patients with a macroadenoma (> 10mm diameter).

Non-functioning pituitary tumours: (30-40% of all pituitary

tumours)
Majority of the non-functioning pituitary tumours are of
gonadotroph origin and actively secrete FSH, free α-
subunit, and rarely, LH – these hormones do not have
clinical effects. The symptoms in patient, with non-
functioning tumours are the result of space occupying
lesion.
The α-subunit can be used as a tumour marker, in
conditions of non-functioning tumour. However, in
postmenopausal women (the age at which most
gonadotroph adenomas manifest), the use of α-subunit as
tumour marker is confusing since in this menopausal
period, there is hypergonadotropins which is accompanied
with increased α-subunit.

Patients with pituitary tumour which is secreting

gonadotropins, do not down-regulate gonadotropin
secretion in response to GnRH agonist treatment, and
repeated GnRH agonist administration is associated with
persistent elevations in either FSH or α-subunit.

However, most patients with these tumours, have

reduced secretions of gonadotropins (and amenorrhea)
because of tumour compression of the pituitary stalk and
interference with the delivery of hypothalamic GnRH,
these patients also often present with modest elevation of
prolactin (due to the inability of dopamine to reach the
anterior pituitary).

Other causes of pituitary compression (non-neoplastic):

Cyst , tuberculosis, sarcoidosis, and fat deposits in
the intrasellar area are causes of pituitary
compression leading to hypogonadotropic
amenorrhea.

Lymphocytic hypophysitis is a rare autoimmune

infiltration of the pituitary gland that can mimic a
pituitary tumour, often occurring during pregnancy
or in the first 6 months postpartum. In the initial
phase of hypophysitis, hyperprolactinaemia is
common, followed by hypopituitarism.
Transsphenoidal surgery is both diagnostic and
therapeutic for this potentially lethal condition.

Nearby lesions, such as internal carotid artery

aneurysms and obstruction of the aqueduct of
Sylvius, can also cause amenorrhea.

Pituitary insufficiency can be secondary to

ischaemia and infarction, which is a late sequel of
obstetric haemorrhage – Sheehan’s syndrome.
Symptoms of hypopituitarism are usually seen early
in the postpartum period, especially failure of
lactation and loss of pubic and axillary hair.
Deficiencies in growth hormone and gonadotropins
are most common, followed by ACTH, and last, by
TSH in frequency. Diabetes insipidus is not usually
present. This condition can be life-threatening.

Other rare causes of amenorrhea are Laurence-

Moon-Biedl and Prader-Willi syndrome.

Treatment of Non-functioning Adenomas:

Asymptomatic patient with microadenoma (less
than 10mm in diameter), usually do not need
treatment, follow up imaging is recommended in a
year or two to be sure it is no growing. Usually they
are incidental finding.

If a macroadenoma (greater than 10mm in

diameter), is present in a patient and symptomatic,
surgery is necessary; these tumours are commonly
detected following the onset of symptoms
(headaches and visual disturbances). Adjunctive
irradiation may be necessary if residual tumour and
elevated gonadotropins and α-subunit are present
after surgery to reduce the risk of recurrence.
Follow-up imaging is obtained every 6 months for 1
year, and then yearly for 3-5years. The risk of
hypopituitarism increases with irradiation, therefore
ongoing surveillance of adrenal and thyroid function
is necessary.

Pituitary prolactin-secreting adenomas:

These are the most common pituitary adenomas.
Serum prolactin level of 1000ng/ml are associated
with invasive tumour, which are effectively treated
with dopamine agonist (bromocriptine).

Approximately one-third of women with

galactorrhea have normal menses. As the prolactin
concentration increases, a woman can progress
sequentially from normal ovulation to an
inadequate luteal phase to intermittent anovulation
to total anovulation to complete suppression and
amenorrhea.

The clinical symptoms do not always correlate with

the prolactin level, and patients with normal
prolactin levels can have pituitary tumours. The
highest serum prolactin levels, however, are
associated with amenorrhea, with or without
galactorrhea.

The amenorrhea associated with elevated prolactin

levels is due to prolactin inhibition of the pulsatile
secretion of GnRH.

Dopamine agonist treatment:

Bromocriptine is a lysergic acid derivative with a
bromine substitute at position 2. it is available as
2.5mg tablets. The usual average dose is 5-7.5mg
daily. This is usually achieved by starting with low
dose to gradually develop tolerance to the drug –
2.5mg daily at bed time, for about a week, before
increasing to bid (at breakfast or lunch).
This dose may need to be taken for a long time, by
the response is dramatic, with improvement in
headache, visual disturbance, menstrual cycle,
ovulation and galactorrhea.

Side effects of bromocriptine – nausea, headache,

faintness (due to orthostatic hypotension, which is
attributed to relaxation of smooth muscle in the
splanchnic and renal beds)

Route of administration:
Oral – 28% of the drugs are absorbed, 94% of the
drugs absorbed undergo extensive 1st pass effect in
the liver. Excretion is mainly biliary. The oral slow
release tablets is 5-15mg daily.

Intramuscular injections – depot-bromocriptine in a

dose of 50-75mg monthly.

Bromocriptine tablets – can be administered

through the vaginal route, it reduces the side
effects, and avoid the 1st pass effect in the liver,
with the result of longer maintenance systemic
levels, allow achievement of therapeutic results at a
lower dose. One tablet of 2.5mg is inserted high
into the vagina at bedtime. The absorption from the
vagina is nearly complete.
It is important to advise patients that the cessation
of galactorrhea is a slower and less certain
response than restoration of ovulation and menses.

Other Dopamine agonists:

 • Pergolide is more potent, longer lasting, and
better tolerated by some patient. It is given
in a single daily dose of 50-150mg, it is
effective for bromocriptine resistant patient.
• Quinagolide – given in a daily bedtime dose
of 75-300mg.
• Cabergoline given orally at doses of 0.5 to 3.0
mg once weekly.

Summary of pituitary prolactin-secreting adenomas:

Macroadenomas:
Currently, dopamine agonist treatment is advocated for
the treatment of macroadenomas, utilizing as low a dose
as possible. Shrinkage of a tumour may require 5-10 mg
of bromocriptine daily, but once shrinkage has occurred,
the daily dose should be progressively reduced until the
lowest maintenance dose is achieved. The serum
prolactin level can be used as a marker, checking every 3
months until stable.
Withdrawal of the drug is usually associated with
regrowth or reexpansion of the tumour, and, therefore,
treatment must be long-term, if not indefinite.

The failure of a tumour to shrink significantly in size

despite a normalization of prolactin levels is consistent
with a non-functioning tumour that is interrupting the
supply of dopamine to the pituitary by stalk compression.
Early surgery is indicated.
Microadenomas:
The treatment is directed to solve one of 2 problems:
infertility or breast discomfort. The treatment of choice is
dopamine agonist.

Other modalities for treating pituitary prolactin-secreting

adenomas include surgery through the transsphenoidal
approach or irradiation.

Other causes of pituitary amenorrhea includes:

• Empty sella syndrome – could be congenital,
secondary to surgery, radiotherapy, or infarction of
a pituitary tumour. This condition is benign; it does
not progress to pituitary failure.

Compartment IV: Central nervous system disorders.

Hypothalamic amenorrhea (hypogonadotropic

hypogonadism):
 Patients with hypothalamic amenorrhea have a deficiency
in GnRH pulsatile secretion.
Hypothalamic problems are usually diagnosed by
excluding pituitary lesions.
Most hypothalamic amenorrhea are associated with
stressful events. The degree of GnRH suppression
determines how these patient present clinically. Mild
suppression can be associated with a marginal effect on
reproduction, specifically an inadequate luteal phase.
Moderate suppression of GnRH secretion can yield
anovulation with menstrual irregularity, and profound
suppression is manifested by hypothalamic amenorrhea.

Patients with hypothalamic amenorrhea are categorized

by low or normal gonadotropins, normal prolactin levels, a
normal imaging evaluation of the sella turcica, and a
failure to demonstrate withdrawal bleeding.

Women with hypothalamic amenorrhea have reduced

secretion of FSH, LH, and prolactin, but increased
secretion of cortisol.

It is important to assure these patient that, at the

appropriate time, treatment for the induction of ovulation
will be available and that fertility can be achieved.
Induction of ovulation should only be performed for the
purpose of producing a pregnancy.

Causes of hypothalamic amenorrhea

• Weight loss – anorexia, Bulimia
• Exercise

Diagnosis of Anorexia nervosa

1. onset between ages 10 and 30 years.
2. weight loss of 25% or weight 15% below
normal for age and height.
3. special attitudes:
 denial,
 distorted body image,
 unusual hoarding or handling of food.
4. at least one of the following;
 lanugo hair,
 bradycardia,
 overactivity,
 episodes of overeating (bulimia),
 vomiting, which may be self-induced.
 5. amenorrhea
6. no known medical illness.
7. no other psychiatric disorder.
8. other characteristics:
 constipation,
 low blood pressure,
 hypercarotenemia,
 diabetes insipidus.

Other causes of amenorrhea acting through the CNS

• Exercise – when training starts before menarche,
menarche can be delayed as much as 3 years,
and the subsequent incidence of menstrual
irregularities is higher. Contrary to the female
situation, exercise has little effect on the timing
of puberty in boys.
• Kallmann’s syndrome – deficient secretion of
GnRH, associated with anosmia or hyposmia. In
the female, this is characterized by primary
amenorrhea, infantile sexual development, low
gonadotropins, a normal female karyotype, and
the inability to perceive odours; e.g., coffee
grounds or perfume. The gonads can respond to
gonadotropins, therefore induction of ovulation
with exogenous gonadotropins is successful.
However, clomiphene is ineffective.