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% sterilized
Over 800rads 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.