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(http://www.fogsi.org/category/archives-articles/review-of-the-month-archives/) > Analysing Amenorrhea 1
Analysing Amenorrhea 1
Dr Ameya C Purandare
Member of the Managing Council of MOGS
Mumbai
E-mail: drameyacp@gmail.com (mailto:drameyacp@gmail.com)
INTRODUCTION
Menses is a cardinal event in every womans life. Hence, the absence of menses at the usual time every month
or delay in the occurrence of the first menses both cause concern which results in a gynecological referral.
The human menstrual cycle is susceptible to environmental influences and stressors. Missing a single
menstruation rarely reflects a significant pathology. However, prolonged or persistent absence of menses may
be one of the earliest signs of neuroendocrine or anatomic abnormality.
Traditionally, evaluation was usually initiated by age 16 years if normal growth and secondary sexual
characteristics were present, and at age 13 years if absent. However, because of secular trends toward earlier
menarche over the past half century, the evaluation should begin at age 15 years, the age when more than
97% of girls should have experienced menarche.
Secondary amenorrhea is clinically defined as the absence of menses for more than 3 cycle intervals, or 6
consecutive months, in a previously menstruating woman. The incidence of secondary amenorrhea can be
quite variable, from 3% in the general population to 100% under conditions of extreme physical or emotional
stress
ETIOLOGY:
Hypothalamic-pituitary abnormalities
Constitutional delay of puberty
Isolated GnRH deficiency
Eating disorder
Stress/exercise
Central lesions (tumors, hypophysitis, granulomas)
Hyperprolactinemia
Gonadal abnormalities
Chromosomal abnormalities
Euchromosomal gonadal agenesis or dysgenesis
Ovarian resistance syndrome
Abnormal gonadotropin function
Autoimmune gonadal failure
Idiopathic gonadal failure
Anatomic abnormalities
Imperforate hymen
Transverse vaginal septum
Congenital absence of the cervix
Mullerian agenesis (Mayer-Rokitansky-Kster-Hauser syndrome)
TABLE 2 : CAUSES OF SECONDARY AMENORRHEA
Common
Diabetes
Hyperthyroidism or hypothyroidism
Cushings syndrome or Addisons disease
Cirrhosis
Malnutrition
Irradiation or chemotherapy
Surgery
It is important to precisely diagnose and treat amenorrhea as the implications for future fertility; risks of
unopposed estrogen, including endometrial hyperplasia and neoplasia; risks of hypoestrogenism, including
osteoporosis and urogenital atrophy; and impact on psychosocial development significantly affect the
womans overall health and wellbeing.
PATHOGENESIS:
Pregnancy is the most common cause of amenorrhea and must be considered in every patient
presenting for evaluation of amenorrhea.
HYPOTHALAMIC DEFECTS
GnRH secreting neurons of the hypothalamus originate in the olfactory bulb and migrate along the olfactory
tract into the mediobasal hypothalamus and the arcuate nucleus. Normally, the arcuate nucleus releases
pulses of GnRH into the hypophyseal portal system every hour. Discharge of GnRH releases LH and (FSH) from
the pituitary; LH and FSH, in turn, stimulate ovarian follicular growth and ovulation. The ovarian hormones
estradiol and progesterone stimulate the development and shedding of the endometrium culminating in the
withdrawal bleeding.
These patients lack GnRH secretion, and express low, prepubertal levels of serum gonadotropins. Follicular
recruitment and ovulation do not occur. Although more than 60% of cases are sporadic, congenital GnRH
deficiency can also be inherited in an autosomal or X-linked pattern.
More common in boys with delayed puberty, constitutional delay of puberty is an uncommon etiology of
primary amenorrhea in girls. Patients demonstrate delayed adrenarche and gonadarche, but ultimately go on
to have normal, although delayed, pubertal development.
This results from abnormal hypothalamic GnRH secretion in the absence of pathologic processes. There are
decreased gonadotropin pulsations, absent follicular development and ovulation, and low estradiol secretion.
Serum FSH levels are usually in the normal range; the setting of high FSH:LH ratio is consistent with
prepubertal patterns.
It is associated with a number of environmental stressors like eating disorders and physical or psychological
stress. Weight loss, of at least 10% below ideal body weight, and excessive exercise are also associated with
hypothalamic amenorrhea. The female athlete triad syndrome is characterized by amenorrhea, eating
disorder, and osteopenia or osteoporosis.
PITUITARY DEFECTS
Pituitary causes of amenorrhea are rare; most are secondary to hypothalamic dysfunction. However, acquired
pituitary dysfunction can ensue from previous local radiation or surgery. Excess iron deposition due to
hemochromatosis or hemosiderosis may destroy gonadotropes. Congenital absence of the pituitary is a rare
and lethal condition.
Sheehans syndrome, characterized by postpartum amenorrhea, results from postpartum pituitary necrosis
secondary to severe hemorrhage and hypotension.
Surgical ablation and irradiation of the pituitary as management of pituitary tumors also can cause
amenorrhea.
Iron deposition in the pituitary may result in destruction of the cells that produce LH and FSH. This occurs only
in patients with markedly elevated serum iron levels (ie, hemosiderosis), usually resulting from extensive red
cell destruction like in Thalassemia major
Pituitary microadenomas and macroadenomas also lead to amenorrhea because of elevated prolactin levels.
Isolated hyperprolactinemia in the absence of adenoma is an uncommon cause of primary amenorrhea.
However, the diagnosis is strongly suggested by a history of galactorrhea. Diagnosis is readily made by
evaluating a serum prolactin level. Hypothyroidism may also lead to elevated prolactin levels and thereby lead
to amenorrhea.
OVARIAN AND OVULATORY DYSFUNCTION
Several gonadal disorders can cause amenorrhea. The most common cause of primary amenorrhea is
gonadal dysgenesis. This group of disorders is usually associated with sex chromosomal abnormalities,
resulting in streak gonads, premature depletion of ovarian follicles and oocytes, and absence of estradiol
secretion.
Primary ovarian failure is characterized by elevated gonadotropins and low estradiol (hypergonadotropic
hypogonadism).
Secondary ovarian failure is usually caused by hypothalamic dysfunction and is characterized by normal or
low gonadotropins and low estradiol (hypogonadotropic hypogonadism).
Gonadal dysgenesis
Turners syndrome (45,XO)
Turner variants
Pure gonadal dysgenesis (Swyers syndrome) (46,XX and 46,XY)
Idiopathic premature ovarian failure
Steroidogenic enzyme defects
Testicular regression syndrome
True hermaphroditism
Mixed gonadal dysgenesis
Ovarian resistance syndrome (Savages syndrome)
Autoimmune oophoritis
Postinfection (eg, mumps)
Postoophorectomy
Postirradiation
Postchemotherapy
TABLE 4: CAUSES OF HYPOESTROGENIC AMENORRHEA
(Hypogonadotropic Hypogonadism).
Hypothalamic dysfunction
1. Kallmanns syndrome
2. Tumors of hypothalamus (craniopharyngioma)
3. Constitutional delay of puberty
4. Anorexia nervosa
5. Severe weight loss
6. Severe stress
7. Exercise
Pituitary disorder
Sheehans syndrome
Panhypopituitarism
Isolated gonadotropin deficiency
Hemosiderosis (primarily from thalassemia major)
Ovarian Dysgenesis
If the primitive oogonia do not migrate to the genital ridge,streak gonads develop resulting in primary
amenorrhea. Two intact X chromosomes are required to maintain normal oocytes. Cytogenetic abnormalities
of the X chromosome account for the majority of abnormal ovarian development and function.Fetuses with
45,X karyotype demonstrate normal oocyte number at 2024 weeks gestation, but there is accelerated atresia
resulting in absence of oocytes at birth. Similarly, women with deletions in either the long or short arm of one
X chromosome also develop either primary or secondary amenorrhea.
Ullrich-Turner syndrome, which presents as a form of early onset vanishing testes syndrome, results from a
deletion mutation in the TDF region of Y chromosome. These patients have the 46,XY genotype but do not
secrete testosterone or AMH, resulting in feminization of internal and external genitalia. Patients present with
primary amenorrhea and gonadal failure. The syndrome is diagnosed by DNA hybridization studies showing
abnormality in the short arm of the Y chromosome.
Premature Ovarian Failure is defined as the occurrence of menopause before age 40 years of age. This is
because the ovaries fail secondary to depletion of ova. It is characterized by amenorrhea, increased
gonadotropin levels, and estrogen deficiency.
Genetic females with steroid enzyme defects have normal internal female genitalia and 46,XX karyotype.
However, they cannot produce estradiol and thus they fail to menstruate or have breast development.
Congenital adrenal hyperplasia describes one of fifteen known defects in the steroidogenic acute regulatory
(STAR) protein, which facilitates cholesterol transport from the outer to the inner mitochondrial membrane.
This enzyme catalyzes an early, rate-limiting step in tropic hormone-stimulated steroidogenesis. Patients thus
present with hyponatremia, hyperkalemia, and acidosis in infancy. Both XX and XY individuals are
phenotypically female. These patients can survive into adulthood given appropriate glucocorticoid and
mineralocorticoid supplementation. XX patients may exhibit some secondary sexual characteristics at puberty,
but present with amenorrhea and premature ovarian failure due to intraovarian accumulation of cholesterol.
Savage syndrome is characterized with elevated LH and FSH levels, and the ovaries contain primordial germ
cells. A defect in the cell receptor mechanism is the thought to be the cause.
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is one of the most common causes of secondary amenorrhea. PCOS is the
most common cause of ovulatory dysfunction in reproductive-age women.
Although the exact mechanism is unknown, it appears that insulin resistance and hyperinsulinemia play an
important role. Abnormally elevated insulin levels lead to increased androgens via decreased sex hormone-
binding globulin, and stimulation of ovarian insulin and insulinlike growth factor-I (IGF-I) receptors.
Transverse Vaginal Septum 1. Failure of fusion of the mllerian and urogenital sinus-
derived portions of the vagina.
The sexually undifferentiated male fetal testis secretes mllerian-inhibiting factor (MIF) and testosterone. MIF
promotes regression of all mllerian structures: the uterine tubes, the uterus, and the upper two-thirds of the
vagina. Testosterone and its active metabolite DHT are responsible for embryonic differentiation of the male
internal and external genitalia.
In testicular feminization, all mllerian-derived structures are absent. The external genital anlagen and
mesonephric ducts cannot respond to androgens because of androgen receptors isensitivity. Affected
individuals are therefore phenotypic females lacking a uterus and a complete vagina. They produce some
estrogen, develop breasts, and are reared as girls, and therefore present with primary amenorrhea.
If the primitive germ cells do not migrate to the genital ridge, a testis will not develop, and a streak gonad will
be present. Affected individuals have normal female internal and external genitalia, as neither MIF nor
androgens are secreted by the streaks. Because these individuals produce no estrogen, they will not develop
breasts. They are reared as girls and present clinically with either delayed puberty or primary amenorrhea.
Anorchia
If the fetal testes regress before 7 weeks gestation, neither MIF nor testosterone is secreted, and affected
individuals will present with a clinical picture identical to that of pure gonadal dysgenesis. Individuals whose
testes regress between 7 and 13 weeks gestation present with ambiguous genitalia.
A testis with defective enzymes will produce MIF but not testosterone. Affected individuals have female
external genitalia and no mllerian structures. They will be reared as girls and present clinically with either
delayed puberty or primary amenorrhea.
DIAGNOSIS
It is absolutely essential to determine which organ is dysfunctional and then to establish the precise cause so
that specific treatment can be advised
Any patient with amenorrhea who has a uterus pregnancy should be first ruled out and serum levels of
thyroid-stimulating hormone (TSH) and prolactin estimated. Galactorrhea should be identified by clinical
examination.
Pelvic examination should be done to note the presence of a vagina and uterus and no vaginal septum or
imperforate hymen that might result in the failure of appearance of menses. Because pelvic examination of an
adolescent girl may be difficult, pelvic ultrasound or examination under anesthesia may be required to
establish the presence of a uterus.
If no uterus is present, serum testosterone levels should be measured and karyotyping done to differentiate
between mllerian agenesis and testicular feminization.
The first step is the progestin challenge, which determines whether the ovary is producing estrogen but not
ovulating .hence not producing progesterone. If the endometrium has been primed with estrogen, exogenous
progestin will produce menses. Give either medroxyprogesterone acetate, 10 mg orally daily for 5 days, or
progesterone, 100200 mg intramuscularly as a single dose. If vaginal bleeding follows, the ovaries are
secreting estrogen. If it does not, it can be concluded that there is no estrogen or that the patient has
Ashermans syndrome.
Ashermans syndrome can be ruled out by the estrogen-progesterone challenge test i.e.administration of
conjugated estrogen, 2.5 mg orally daily for 25 days, plus medroxyprogesterone acetate, 10 mg orally on days
16 through 25. Patients with Ashermans syndrome do not bleed following this regimen.
Hysterosalpingography and hysteroscopy also help in diagnosing Ashermans syndrome.
In a patient who does not have Ashermans syndrome and who does not respond to the progestin challenge,
ovarian dysfunction may be of hypothalamic or ovarian origin. The distinction is based on the FSH level.
Primary ovarian dysfunction resulting in low estradiol secretion is associated with high serum FSH.
Diagnosis of Amenorrhea Caused by Primary Ovarian Failure
Karyotyping is indicated for all women who present with premature menopause, particularly if their
amenorrhea is primary. Patients with primary amenorrhea may have a steroid enzyme defect. Autoimmune
oophoritis is a reversible cause of ovarian failure that must be investigated. Table 3 lists the causes of primary
ovarian failure.
Table 4 summarizes the differential diagnosis of hypoestrogenic amenorrhea. The category includes
amenorrhea associated with athletic activity, weight loss, or stress.
Differentiation of hypothalamic from pituitary dysfunction can be achieved by giving GnRH, If there is a
significant history consistent with Sheehans syndrome, pituitary function testing is indicated in order to
determine the functional capacity of the glandparticularly the integrity of the pituitaryadrenal axis.
Patients who bleed in response to the progestin challenge (ie, whose ovaries are secreting estrogen) fit into
one of 4 categories:
(a) virilized, with or without ambiguous genitalia;
(b) hirsute, with polycystic ovaries, hyperthecosis, or mild maturity-onset adrenal hyperplasia;
(c) nonhirsute, with hypothalamic dysfunction; or
(d) amenorrheic secondary to systemic disease.
Clinical examination and transvaginal ultrasound may be helpful in making the diagnosis of PCOS. However,
25% of normal patients have polycystic ovaries; consequently, ultrasound cannot be the sole criterion for
diagnosis.
Psychological disorder
Emotional stress
Weight loss
Obesity
Exercise induced
Idiopathic
Hirsutism-virilism
PCOD
Ovarian tumor
Adrenal tumor
Cushings syndrome
Congenital and maturity-onset adrenal hyperplasia
Systemic disease
Hypothyroidism
Hyperthyroidism
Addisons disease
Chronic renal failure
Diagnosis of Amenorrhea Associated with Galactorrhea-Hyperprolactinemia
Dopamine antagonists
Phenothiazines
Thioxanthenes
Butyrophenone
Diphenylbutylpiperidine
Catecholamine-depleting agents
False transmitters (-methyldopa)
Interruption of normal hypothalamicpituitary relationship
Encephalitis
Craniopharyngioma
Pineal tumors
Hypothalamic tumors
Pseudotumor cerebri
Patients with primary hypothyroidism have elevated thyroid-releasing hormone (TRH) levels. TRH acts to
stimulate the release of prolactin and may thereby lead to galactorrhea-amenorrhea syndrome. TSH is also
elevated and as it is easier to measure ,it is the screening test for hypothyroidism.
If prolactin remains elevated or is initially higher than 50200 ng/mL, the patient should be further studied via
cone view of the sella, or computed tomography (CT) or magnetic resonance imaging (MRI) scan of the sella, to
rule out pituitary micro- or macroadenoma.
A meticulous history must be taken to ascertain whether the hyperprolactinemia is caused by ingestion of
drugs. Prolactin secretion is inhibited by dopamine and stimulated by serotonin and TRH. Any drug that blocks
the synthesis or binding of dopamine will increase the prolactin level. Prolactin is increased by serotonin
agonists and decreased by serotonin antagonists.
TREATMENT
Any patient with a Y chromosome should undergo oophorectomy to prevent tumor development.
In these patients with low estrogen levels, the pituitary does not release high quantities of LH and FSH.
If a potentially reversible cause of amenorrhea can be identified like marked weight loss, it should be
corrected.
Most of these patients respond to clomiphene citrate. The starting dose is 50 mg orally daily for 5 days. This
can be increased to a maximum of 250 mg orally daily in 50-mg increments until ovulation is induced. This
medication is FDA-approved for use up to 150 mg/d. Ovulation occurs 510 days after the last dose.
Patients with elevated androgens may not respond to clomiphene citrate may respond to combined treatment
with an oral hypoglycemic agent (metformin) and clomiphene. If clomiphene therapy with or without
metformin is ineffective, gonadotropin therapy may be attempted. Care must be taken in using FSH in these
patients, as they are likely to become hyperstimulated.
Laparoscopic ovarian drilling (LOD) is a surgical method of ovulation induction in PCOS patients. LOD involves
electrocautery or laser drilling of the ovarian cortex, with the goal of creating foci of laser or thermal damage
in the cortex and ovarian stroma. The mechanism of action may involve destruction of androgen-producing
stromal cells, a sudden drop in ovarian androgen levels, improved follicular microenvironment, or increased
gonadotropin secretion. This procedure may cause postoperative pelvic adhesions, resulting in tubal
compromise.
Dopamine agonist drugs such as cabergoline and bromocriptine are the first-line treatment of
hyperprolactinemia of any cause, including macroadenomas. These drugs can decrease prolactin secretion
and tumor size. Surgical therapy, transsphenoidal or frontal removal of the pituitary adenoma or the entire
gland, may be required if tumor size or secretion are resistant to dopamine agonists; the lesion is rapidly
enlarging or causing symptoms such as visual changes or headaches; or in women with giant adenomas (> 3
cm) who wish to discontinue agonist treatment for conception and the duration of pregnancy.
e) Ovulation Induction in Patients with Amenorrhea-Galactorrhea without Macroadenoma (Including
Patients with Microadenomas)
These patients ovulate readily in response to dopamine agonist treatment, with dose titrated until serum
prolactin is normal. Patients are maintained on the lowest dose. Once pregnancy has been achieved, the agent
can be discontinued. Patients with macroadenomas may need to continue therapy throughout pregnancy to
avoid further growth of the lesion.
Patients taking drugs that raise the prolactin level should discontinue them if possible, but continued use of
such drugs is not a contraindication to therapy.
Patients who are hypoestrogenic must be treated with a combination of estrogen and progesterone to
maintain bone density and prevent genital atrophy.
Oral contraceptives are effective replacement therapy for most women.
Combinations of 0.6251.25 mg of conjugated estrogens orally daily on days 1 through 25 of the cycle with 5
10 mg of medroxyprogesterone acetate on days 16 through 25 are an alternative. Calcium intake should be 1
1.5 g of elemental calcium daily.
Patients who respond to the progestin challenge require progestin administration to prevent the development
of endometrial hyperplasia and carcinoma.
Oral contraceptive pills may be used for regularization of the menstrual cycle.. Alternatively,
medroxyprogesterone acetate, 10 mg orally daily for 1013 days every month or every other month, is
sufficient to induce withdrawal bleeding and to prevent the development of endometrial hyperplasia.
Patients with hyperprolactinemia need periodic prolactin measurements and radiographic cone views of the
sella turcica to check for the development of macroadenoma.
SEQUELAE
The complications of amenorrhea can be numerous, ranging from infertility to psychosocial developmental
delays with lack of normal physical sexual development. Hypoestrogenic patients can develop severe
osteoporosis and fractures. The complications associated with amenorrhea in patients who respond to
progestin challenge are endometrial hyperplasia and carcinoma resulting from unopposed estrogen
stimulation.
CONCLUSION
The overall prognosis for amenorrhea is good. One must remember and reiterate to the patient and her
relatives that it is usually not a life-threatening clinical event and with proper evaluation the precise etiology
can be diagnosed and treated.
Many patients with hypothalamic amenorrhea will spontaneously recover normal menstrual cycles. Virtually all
amenorrheic women who do not have premature ovarian failure can be made to ovulate with a dopamine
agonist, clomiphene citrate, insulin-sensitizing agents, and gonadotropins.
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