2. Definition
• Secondary amenorrhoea is defined as the
absence of menstruation for 6 months or more
in a woman with previous spontaneous regular
cycles
• OR
• a period equal to the duration of three
cycles if previous cycles are irregular.
4. Causes of secondary
amenorrhoea
• Physiological conditions
Secondary amenorrhoea can be physiological in
the following situations:
•
Pregnancy
Lactation
Menopause
5. Pathological conditions
• Normal menstrual cycle indicates normal functioning
of the complex hypothalamic–pituitary–
ovarian axis and normal uterus
• Abnormality at any level in this axis or uterus can cause amenorrhoea
• Causes of secondary amenorrhoea
are listed in Box 19.2 and diagrammatically
represented in Fig. 19.1.
6. Hypothalamic causes
• Hypothalamic conditions account for nearly 30%
of all causes of secondary amenorrhoea. These
are listed in Box 19.3.
7. Functional hypothalamic amenorrhoea
• In this disorder, there is a decrease in gonadotropin-releasing
hormone (GnRH) secretion, leading
to decreased pulsatile secretion of luteinizing
hormone (LH), absence of midcycle surge and anovulation
• Serum follicle-stimulating hormone
(FSH) levels are low or normal
• This can be caused by emotional stress, weight
loss and vigorous exercise. Chronic illnesses
8. • Vigorous exercise causes release of catechol oestrogens and endogenous opioids,
which
act on the hypothalamus to suppress GnRH production
• Weight loss > 10–15% of ideal body weight is associated with amenorrhoea
• anorexia nervosa, which is usually seen in teenage girls. It is an extreme form of
eating disorder and leads to severe weight loss and amenorrhoea
• Obesity is a common cause of secondary
amenorrhoea. Obese women convert the
androgens to oestrone, and this causes a
chronic hyperoestrogenic state inhibit GnRH
secretion by the hypothalamus lchronic anovulation
amenorrhoea. The condition can be mistaken
for polycystic ovarian syndrome (PCOS).
Features of hypothalamic amenorrhoea are
summarized in Box 19.4.
9. Pituitary causes
• Disorders of the pituitary contribute to about
15–20% cases of secondary amenorrhoea
(Box 19.5).
10. Pituitary necrosis—Sheehan syndrome
• Pituitary necrosis occurs most often following
postpartum haemorrhage (PPH) and the resulting
hypotension. This condition is known as
Sheehan syndrome.
These patients can have panhypopituitarism involving thyroid and
adrenal glands as well
• Clinical picture:patients present several years after
PPH with recurrent episodes of vomiting and
hypotension requiring hospitalization and
intravenous (IV) fluids and unless specifically
questioned may not even mention the PPH
that occurred years ago.
11. • There is a history of failure to lactate, weight
loss, breast atrophy, depigmentation of the
areolae, hypotension and symptoms of hypothyroidism.
r Levels of thyroid-stimulating hormone (TSH),
plasma cortisol, prolactin, FSH and LH are
low, and there is no response to progesterone
challenge.
12. Hyperprolactinaemia
• Hyperprolactinaemia usually presents with amenorrhoea
and galactorrhoea, although galactorrhoea
may be absent in some
• Prolactin secretion is under the inhibitory control by the hypothalamus
through dopamine
• Hyperprolactinaemia is associated with reduction in GnRH and
gonadotropin production through direct effect on the hypothalamus and
pituitary. Secondary to gonadotropin deficiency,
oestrogen levels are low and patients generally do
not have withdrawal bleeding with progesterone.
It should be remembered that values up to 25 ng/
mL are normal in women of reproductive age.
13. • Hyperprolactinaemia can be caused by physiological,
pharmacological and pathological
conditions (Box 19.6).
r History of drugs that cause hyperprolactinaemia
and serum TSH to exclude hypothyroidism
are the first steps in evaluation of hyperprolactinaemia.
r If TSH is elevated and primary hypothyroidism
is diagnosed, no further tests are necessary
and thyroxine therapy can be instituted.
r If hypothyroidism has been excluded, a serum
prolactin level of >200 ng/mL is indicative of
prolactinomas. Prolactin levels between 25 and
75 ng/mL indicate functional hyperprolactinaemia
or drug-induced hyperprolactinaemia.
Levels between 75 and 200 ng/mL may be due
to microprolactinoma, stalk compression by
nonfunctional pituitary tumours or drugs.
14. • If visual fields are normal, a patient with prolactin
>200 ng/mL can be started on treatment
with dopamine agonists without any
further tests. If visual field defects are present
on perimetry, imaging of the pituitary with CT
scan/MRI is required to determine the size
and extent of the tumour (Fig. 19.2).
r If prolactin levels are between 75 and 200 ng/
mL and the patient is on drugs that cause the
increase, the patient may be reassured. If pituitary
microprolactinoma or other tumours are
suspected, further imaging and treatment are
warranted.
The characteristic features of pituitary amenorrhoea
are listed in Box 19.7.
15. • Primary ovarian insufficiency
This condition was formerly known as premature
ovarian failure and premature menopause.
Primary ovarian insufficiency (POI) is defined
as ovarian failure with high FSH levels, occurring
before 40 years of age.
In this condition, the patient presents with
secondary amenorrhoea and the ovaries have
no oocytes; there is no folliculogenesis or ovarian
hormone production. Serum FSH levels rise
due to lack of negative feedback by oestrogens.
Some women may have intermittent LH surges
and ovulation.
16. • There are two major categories of POI:
r POI associated with follicle depletion
r POI with no follicle depletion
17. • POI with follicle depletion
Causes of POI with follicle depletion are given as
follows:
r Chromosomal disorders such as fragile X syndrome
or partial deletion of X chromosome or
other somatic chromosomal defects.
18. • Autoimmune ovarian destruction associated
with lymphocytic infiltration of ovaries.
Autoimmune failure can also be part of polyglandular
failure, involving the pancreatic
islets, thyroid, parathyroid and adrenal glands.
r Following chemotherapy with ovariotoxic
drugs, especially alkylating agents such as
cyclophosphamide, or following radiotherapy
to the abdomen and pelvis.
Women with POI present with symptoms
of hypo-oestrogenism and are prone to all the
long-term problems of menopause such as osteoporosis
and coronary heart disease. The endometrium
is atrophic and does not bleed with
administration of progesterone.
Diagnosis is by elevated levels of serum FSH
(>40 mIU/L) in a woman with secondary amenorrhoea
or infrequent menstruation. Evaluation
should include tests for other endocrine deficiencies
and karyotyping.
Occasional ovulation can occur; pregnancies
have been reported. This must be borne in mind
while counselling these women.
19. • POI without follicular depletion
Formerly known as resistant ovary, this condition
is characterized by amenorrhoea and ovaries with
follicles that do not develop under FSH stimulation.
The defect may be in FSH receptors, oestradiol
precursor production or aromatase function.
Clinical presentation is similar to POI with follicular
depletion; FSH levels are high. Ovarian biopsy
is diagnostic but is not recommended as a routine
since it does not contribute to the management.
The salient features of amenorrhoea due to
ovarian causes are summarized in Box 19.14.
20. terine causes
Secondary amenorrhoea can be due to damage
to the endometrium (Box 19.15).
• Intrauterine adhesion (Asherman syndrome)
is caused by vigorous curettage postpartum
or after an abortion. The basal layer of the
endometrium is scraped off, and adhesions form
in the uterine cavity.
Genital tuberculosis can also cause amenorrhoea.
This is dealt with in Chapter 14, Tuberculosis
of the female genital tract.
Cervical stenosis that occurs following operations
such as cone biopsy, cervical amputation
and Fothergill surgery can cause obstruction to
the menstrual flow and amenorrhoea associated
with abdominal pain. The hormone levels are
normal, but there is no withdrawal bleeding with
progesterone.
Salient features of amenorrhoea due to uterine
causes are listed in Box 19.16.
21. • hyroid and adrenal
endocrinopathies
Endocrinopathies involving thyroid, adrenal
and other glands can cause amenorrhoea
(Box 19.17).
22. • Hypothyroidism with elevated TSH causes
hyperprolactinaemia and amenorrhoea. Dry
skin, puffiness of face, pedal oedema, pallor and
slow-relaxing ankle jerks are important clues to
the diagnosis.
23. • Cushing disease can be secondary to overproduction
of adrenocorticotropic hormone
(ACTH) by the pituitary or primary abnormality
in the adrenal gland. In pituitary ACTHdependent
Cushing disease, the elevated ACTH
causes hyperpigmentation of skin and stimulates
adrenal androgen production as well and
causes hirsutism. The excess cortisol production
from the adrenal causes suppression of GnRH
and gonadotropins causing secondary amenorrhoea.
Other clinical features of Cushing disease
such as truncal obesity, nuchal fat pads, purple
abdominal striae, hypertension, proximal muscle
weakness and osteoporosis are usually seen
(Fig. 19.9). In early stages, Cushing disease can
closely resemble PCOS and is, therefore, an
important differential diagnosis for PCOS.
Congenital adrenal hyperplasia (CAH) due to
21-hydroxylase deficiency occurs in the classic
form in the neonate and nonclassic or milder
form in the adult. The classic form presents with
ambiguous genitalia and electrolyte imbalance.
The nonclassic congenital adrenal hyperplasia
(NCCAH) manifests at puberty. Clinical spectrum
is varied and hyperandrogenism can cause
hirsutism alone or mild virilization in addition.
Serum levels of 17D-hydroxyprogesterone and
dehydroepiandrosterone (DHEA) are elevated.
This is discussed further in Chapter 20, Hirsutism
and virilization.
24. • Clinical evaluation
istory
Thorough history and clinical examination
are mandatory before ordering investigations.
Important details in history are listed in Box
19.18.
26. • urther evaluation
Further evaluation should be performed in a
stepwise manner.
r The possibility of pregnancy must be kept in
mind in all women presenting with secondary
amenorrhoea. This has to be ruled out by a
urine pregnancy test or serum E-human chorionic
gonadotropin (hCG) test.
r If the pregnancy test is negative, the next step
is measurement of serum FSH, LH, prolactin
and TSH.
r Assessment of oestrogen status may be by estimation
of serum oestradiol levels or progesterone
challenge test.
r Progesterone challenge test is performed
using any of the preparations given in Box
19.20. This helps to detect endogenous oestrogen
production, which primes the endometrium
and makes it respond to progesterone
by withdrawal bleeding. Withdrawal bleeding
can occur 2–10 days after completing the dose.
The test is especially useful in low-resource
settings where hormonal evaluation is expensive
and/or unavailable. Positive test indicates
the presence of oestrogen.
27. • Normal FSH, TSH and prolactin levels and
positive progesterone challenge test are indicative
of PCOS, or late-onset 21-OH deficiency.
LH may be moderately elevated in PCOS.
r Normal TSH, prolactin and normal or lownormal
FSH and LH and negative progesterone
challenge test indicate hypothalamic
28. • disorder. They should be evaluated further by
magnetic resonance imaging and other tests.
r Low FSH, LH, prolactin and TSH and negative
response to progesterone challenge indicate
pituitary failure, most often due to necrosis.
r High serum FSH indicates POI. Progesterone
challenge test is usually negative. Karyotyping
and tests to exclude polyglandular failure
should be performed.
r High serum prolactin indicates hyperprolactinaemia.
If levels are >200 ng/mL (tumour
range), MRI of the pituitary is the next step. If
levels are lower, other causes such as drugs,
thyroid dysfunction and microprolactinomas
must be excluded.
r Elevated TSH occurs in hypothyroidism.
r If all hormonal levels are normal, progesterone
challenge test is negative and there is a history
of uterine curettage, tuberculosis or surgery,
uterine causes must be suspected. Oestrogen–
progesterone challenge test can be performed
in these women.
29. • Oestrogen–progesterone challenge test The
endometrium is primed with oestrogen (ethinyl
oestradiol 10 μg daily or conjugated equine oestrogen
1.25 mg daily) for 2 weeks and progesterone
added during the third week. Bleeding is
expected to occur within a week after stopping
the hormones. Failure to bleed indicates endometrial
pathology such as Asherman syndrome
or tuberculosis.
Endocrine workup is required to make a diagnosis
at this stage (Fig. 19.10)
30. Management
• Management consists of
r Counselling
r Treatment of the underlying cause
r Achieving fertility
r Prevention of long-term complications
r Counselling is the first and most important step
in the management. Some of the pathological
conditions cannot be cured and resumption of
spontaneous menstruation or achieving fertility
is not possible. Some conditions such as
PCOS and hypo-oestrogenic amenorrhoea are
associated with long-term complications and
require long-term preventive therapy. These
should be discussed in detail with the patient.
r Treatment is mostly medical, although surgical
intervention is occasionally required. Medical
31. • treatment of hirsutism and infertility associated
with PCOS is dealt with in Chapter 20, Hirsutism
and virilization, and Chapter 22, Infertility.
r Women with hypothalamic amenorrhoea
need psychotherapy, weight optimization and
lifestyle modification. Oral contraceptive (OC)
pills can be tried for re-establishing menstrual
cycles but may not be effective. These women
are prone to osteoporosis: therefore, calcium
and vitamin D supplementation is required.
r Pituitary necrosis results in deficiency of
gonadotropins, TSH and ACTH. The patients
require thyroxin and steroid replacement in
addition to OC pills. Calcium and vitamin D
supplementation is mandatory.
r The first step in management of hyperprolactinaemia
is to discontinue drugs that increase
prolactin levels and treat hypothyroidism, if
present. Both macroprolactinoma and microadenoma
are treated initially with dopamine
agonists—Bromocriptine or cabergoline.
Bromocriptine is used in doses of 1.25–2.5 mg
daily and is less effective in decreasing prolactin
levels. Dose of cabergoline is 0.25–0.5 mg
once a week. Transsphenoidal surgery is indicated
only when there is no response to treatment
or in giant macroadenomas
32. • Management of PCOS is complex. Treatment
depends on the patient’s age, clinical features
and desire for pregnancy. Lifestyle modification
and weight optimization are mandatory
for all women with PCOS to prevent long-term
complications.
– Adolescents with menstrual irregularity
are treated with OC pills or progestin
alone, given for 7–10 days every month.
Management of hirsutism is discussed
in Chapter 20, Hirsutism and virilization.
Insulin resistance and abnormal glucose
tolerance are indications for metformin.
– Women in the reproductive years may, in
addition, require treatment for infertility.
Ovulation induction by clomiphene with
or without metformin is required. This is
discussed further in Chapter 22, Infertility.
Even after completion of family, progestins
for 7–10 days once a month or alternate
months is advisable to prevent endometrial
hyperplasia and carcinoma.
r Treatment of POI is with OC pills that should
be continued till age 50. Polyglandular failure
requires replacement of other hormones as
well. Calcium and vitamin D supplementation
is essential.
33. • r Intrauterine adhesions (Asherman syndrome)
are diagnosed by hysteroscopy or hysterosalpingography.
The adhesions can be broken
down by hysteroscopic resection. An intrauterine
device can be inserted following this
and OC pills administered for three to six
cycles to prevent reformation of adhesions.
r Cervical stenosis should be managed by dilatation
of cervix.
Management of secondary amenorrhoea is
summarized in Table 19.2.
