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Dr. Mohammed AbdallaDr. Mohammed Abdalla

ASSESSMENT OF A CASE ASSESSMENT OF A CASE

OFOF AMENORRHEA AMENORRHEA

AMENORRHEAAMENORRHEA

Amenorrhea is the absence Amenorrhea is the absence or abnormal cessation of or abnormal cessation of

menstruation. menstruation.

Primary amenorrhea

is defined either as absence of menses by age 14 years with the absence of growth or development of secondary sexual characteristics .

OR as absence of menses by age 16 years with normal development of secondary sexual characteristics.

Secondary amenorrhea

is defined as the cessation of menstruation for at least 6 months or for at least 3 of the previous 3 cycle intervals.

PHYSIOLOGY

Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus luteum formed after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does not occur, this secretory endometrium breaks down and sheds as a menstrual blood.

the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.

PHYSIOLOGY

The number of primordial follicles in the human ovary peaks during the fifth

gestational month at approximately 7 million. After this initial pool is in place, no

additional primordial follicles are formed. In some cases, loss of menstrual regularity is

an early sign of declining fertility and impending premature ovarian failure

PHYSIOLOGY

by age 20 years, women have established regular and persistent patterns of menstrual cycle length with little variation .

on an individual basis Relatively stable and predictable menstrual cycle length continues until age 40 years.

PHYSIOLOGY

In the first year after menarche, the fifth percentile for menstrual cycle length is 23 days and the 95th percentile is 90 days.

By the fourth year after menarche, the 95th percentile for cycle length has declined from 90 days to approximately 50 days.

by 7 years after menarche, cycles are more stable; the fifth percentile in cycle length is 27 days, and the 95th percentile is 38 days.

PHYSIOLOGY

How common is it?

Secondary amenorrhoea (prevalence about 3%) primary amenorrhoea (prevalence about 0.3%) Between 10 and 20% of women complaining of

infertility have amenorrhoea [Franks, 1987]. Up to 50% of competitive runners (training 80 miles

per week) and up to 44% of ballet dancers have amenorrhoea [Balen, 1999a].

Etiology of Etiology of PRIMARY amenorrhoea

Secondary sexual characteristics present

Pregnancy Constitutional delay Genito-urinary malformation, e.g. imperforate hymen,

transverse vaginal septum, absent vagina with or without a functioning uterus

Androgen insensitivity: XY female or testicular feminization

Resistant ovary syndrome

Secondary sexual characteristics absent

Hypothalamic dysfunction, e.g. chronic illness, anorexia, weight loss, 'stress'

Gonadotrophin deficiency, e.g. Kallman's syndrome Hydrocephalus Tumours of the hypothalamus or pituitary Hypopituitarism Hyperprolactinaemia Gonadal failure, e.g. ovarian dysgenesis/agenesis,

premature ovarian failure Hypothyroidism

Ambiguous external genitalia

Congenital adrenal hyperplasia Androgen-secreting tumour 5-Alpha-reductase deficiency

Turner's syndrome

Turner's syndrome is caused by either a complete absence or a partial abnormality of one of the two X chromosomes. About 50% have mosaic forms such as 45X/46XX or 45X/46XY.

Features :( short stature, web neck, lymphoedema, shield chest with widely spaced nipples, scoliosis, wide carrying angle, coarctation of the aorta, and streak ovaries.)

Constitutional delay

In this condition there is no anatomical abnormality and endocrine investigations show normal results.

It is caused by immature Pulsatile release of gonadotrophin-releasing hormone; maturation eventually occurs spontaneously.

Androgen insensitivity syndrome (AIS)

formerly known as testicular feminization, 46XY failure of normal masculinization of the external genitalia

in chromosomally male individuals. This failure of virilization can be either complete (CAIS) or partial (PAIS), depending on the amount of residual receptor function.

affected individuals have normal testes with normal production of testosterone and normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5-alpha reductase deficiency.

5-alpha-reductase deficiency (5-ARD)

inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT). Because DHT is required for the normal masculinization of the external genitalia in utero,

genetic males with 5-ARD are born with ambiguous genitalia (ie, male pseudohermaphroditism).

The described clinical abnormalities range from infertility with normal male genital anatomy to underdeveloped male with hypospadias to predominantly female external genitalia, most often with mild clitoromegaly.

Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index can be determined by measuring the glans of clitoris in the anteroposterior and transverse diameter. A clitoral index greater than 35 mm2 is evidence of increased androgen effect. A clitoral index greater than 100 mm2 is evidence of virilization.

5-alpha-reductase deficiency (5-ARD)

Imperforate hymen Imperforate hymen represents the most common and

most distal form of vaginal outflow obstruction. Clinical presentations range from an incidental finding

on physical examination of an asymptomatic patient to discovery on an evaluation for primary amenorrhea or abdominal or back pain.

The differential diagnosis of uterovaginal obstruction includes disorders of vaginal development, such as transverse vaginal septum or complete vaginal agenesis, Duplication anomalies of the uterovaginal tract often involve one tract that is decompressed and one that is obstructed.

Imperforate hymen

Etiology of Etiology of secondary amenorrhoea

No features of androgen excess present

Physiological, e.g. pregnancy, lactation, menopause

Iatrogenic, e.g. depot medroxyprogesterone acetate contraceptive injection, radiotherapy, chemotherapy

Systemic disease, e.g. chronic illness, hypo- or hyperthyroidism

Uterine causes, e.g. cervical stenosis, Asherman's syndrome (intra-uterine adhesions)

Ovarian causes, e.g. premature ovarian failure, resistant ovary syndrome

Hypothalamic causes, e.g. weight loss, exercise, psychological distress, chronic illness, idiopathic

Pituitary causes, e.g. hyperprolactinaemia, hypopituitarism, Sheehan's syndrome

Causes of hypothalamic/pituitary damage, e.g. tumours, cranial irradiation, head injuries, sarcoidosis, tuberculosis

Features of androgen excess present

Polycystic ovary syndrome Cushing's syndrome Late-onset congenital adrenal hyperplasia Adrenal or ovarian androgen-producing tumour

Polycystic ovary syndrome

This condition is characterized by hirsutism, acne, alopecia, infertility, obesity, and menstrual abnormalities (amenorrhoea in 19% of cases).

Ultrasound examination of the ovaries typically shows multiple, small peripheral cysts. up to a third of women in the general population have polycystic ovaries on ultrasound examination [DTB, 2001].

Endocrine abnormalities include increased serum concentrations of testosterone, prolactin, luteinizing hormone (LH) (with normal follicle-stimulating hormone [FSH] levels), and insulin resistance with compensatory hyperinsulinaemia.

Menopause/ovarian failure occurring before the age of 40 years is considered premature.

Auto-immune disease is the most common cause; auto-antibodies to ovarian cells, gonadotrophin receptors, and oocytes have been reported in 80% of cases.

Before puberty or in adolescents, ovarian failure is usually due to a chromosomal abnormality, e.g. Turner mosaic, or previous radiotherapy, or chemotherapy

Premature ovarian failure

Ovarian failure (premature menopause)

chromosomal anomalies

autoimmune disease

If the woman is under 30, a karyotype should be

performed to rule out any mosaicism involving a Y

chromosome.

it is prudent to screen for thyroid, parathyroid, and adrenal

dysfunction

If a Y chromosome is found the gonads should be surgically excised.

Laboratory evidence of autoimmune phenomenon is much more prevalent than clinically significant disease

autoimmune related dysfunction

The most common association is with thyroid The most common association is with thyroid disease, but the parathyroids and adrenals can also disease, but the parathyroids and adrenals can also be affected. be affected.

Several studies have shown laboratory evidence of Several studies have shown laboratory evidence of immune problems in about 15-40% of women with immune problems in about 15-40% of women with premature ovarian failure. premature ovarian failure.

In general, ovarian biopsy is not indicated in In general, ovarian biopsy is not indicated in patients with premature ovarian failure since no patients with premature ovarian failure since no clinically useful information will be obtained.clinically useful information will be obtained.

Hyperprolactinaemia

A prolactinoma is the commonest cause of hyperprolactinaemia (60% of cases).

Other causes include non-functioning pituitary adenoma (disrupting the inhibitory influence of dopamine on prolactin secretion);

dopaminergic antagonist drugs (e.g. phenothiazines, haloperidol, clozapine, metoclopramide, domperidone, methyldopa, cimetidine); primary hypothyroidism (thyrotrophin-releasing hormone stimulates the secretion of prolactin), or it may be idiopathic.

Prolactin acts directly on the hypothalamus to reduce the amplitude and frequency of pulses of gonadotrophin-releasing hormone.

Weight-related amenorrhoea

A regular menstrual cycle is unlikely to occur if the body mass index (BMI) is less than 19 (normal range 20-25).

Weight loss may be due to illness, exercise, or eating disorders, among which anorexia nervosa lies at the extreme end of the spectrum.

Post-pill' amenorrhoea

This is defined as absence of menstruation for 6 months following cessation of the combined oral contraceptive pill.

It probably results from A transient inhibition of gonadotrophin-releasing hormone .

Progestogen-associated amenorrhoea

Depot medroxyprogesterone acetate inhibits the secretion of gonadotrophins and thus suppresses ovulation.

After 1 year of use, 80% of women have amenorrhoea or very scanty, infrequent vaginal bleeding.

There is partial oestrogen deficiency in women who use depot medroxyprogesterone acetate.

The progestogen-only pill leads to reversible long-term amenorrhoea in a minority of women, due to complete suppression of ovulation.

The levonorgestrel-releasing intra-uterine device commonly results in amenorrhoea after a few months. This is thought to be mainly a local effect, but suppression of ovulation can occur in some women (in some cycles).

ASSESSMENT of primary ASSESSMENT of primary amenorrheaamenorrhea

TSH elevated

hypothyroidismNormal

bone age delayed

constitutional delayNormal

LH, FSH, and prolactin levels

elevated

karyotype.

low or within

reference range

head MRI

45,XO, the cause is gonadal dysgenesis

46,XX, the primary cause is ovarian failure

•pituitary tumor or a brain lesion

•drug use, an eating disorder, athleticism, or psychosocial stress.

If puberty delayed

If the pregnancy test result is negative

TSH and prolactin levels

progestin challenge

within reference range

consider anovulatory cycles

PCO

E2/progestin challenge

outlet obstruction obtain FSH and LH levels.

low or within reference range

head MRI.

exclude chronic disease, anorexia nervosa, or psychosocial stress.

high

karyotype

Turner synd.karyotype is normal (46,XX),

the cause is ovarian failure

elevatedhypothyroidism and

hyperprolactinemia

+VE-VE

If puberty not delayed

+-

genital tract

abnormalities karyotype

If the karyotype is 46,XY If the karyotype is 46,XX

testosterone levels

male range female range

androgen insensitivity. testicular regression

or gonadal enzyme deficiency.

müllerian agenesis

(ie, Rokitansky-Kuster-Hauser syndrome).

Breast development, pubertal growth spurt,

and adrenarche are delayed or absent in persons with

hypothalamic pituitary

failure.

adrenarche occurs normally, while estrogen-dependent breast development and the

pubertal growth spurt are absent or delayed.

isolated ovarian insufficiency or failure

Secondary AmenorrheaSecondary Amenorrhea

HistoryHistory

A good history can reveal the etiologic A good history can reveal the etiologic diagnosis in up to 85% of cases of diagnosis in up to 85% of cases of

amenorrhea.amenorrhea.

If the history and physical If the history and physical exam are suggestive of a exam are suggestive of a

certain etiologycertain etiology : :

for the sake of efficiency and cost-for the sake of efficiency and cost-effectiveness, the workup can effectiveness, the workup can sometimes be more directed according sometimes be more directed according to history. to history.

( in 85% of cases)

In patients that will not demonstrate any In patients that will not demonstrate any obvious etiology for their amenorrhea obvious etiology for their amenorrhea on history and physical exam. These on history and physical exam. These

patients can be worked up in a logical patients can be worked up in a logical manner using a stepwise approach.manner using a stepwise approach.

How do I assess my patient with secondary amenorrhoea?

Risk of pregnancy

Associated symptoms, e.g. galactorrhoea, hirsutism, hot flushes, dry vagina, symptoms of thyroid disease

Recent change in body weight

Recent emotional upsets

Level of exercise

Previous menstrual and obstetric history

Previous surgery, e.g. endometrial curettage, oophorectomy

Previous abdominal, pelvic, or cranial radiotherapy

Family history, e.g. of early menopause

Drug history, e.g. progestogens, combined oral contraceptive, chemotherapy

History

Height and weight: calculate body mass index if appropriate.

Signs of excess androgens, e.g. hirsutism, acne

Signs of virilization, e.g. deep voice, clitoromegaly in addition to hirsutism, and acne

Signs of thyroid disease .

Acanthosis nigricans: this hyperpigmented thickening of the skin folds of the axilla and neck is a sign of profound insulin resistance. It is associated with polycystic ovary syndrome (PCOS) and obesity.

Breast examination for galactorrhoea.

Fundoscopy and assessment of visual fields if there is suspicion of pituitary tumour.

Pelvic examination .

How do I assess my patient with secondary amenorrhoea?

Examination

Preg.test

TSH ,PROLACTIN’, Prog.challenge test

withdrawal bleeding

without withdrawal bleeding

hypoestrogenic compromised outflow tract.

++ve.est,progest,challenge test -ve.est,progest

challenge test

FSH>30-40Normal FSH

HSG OR hysteroscopy asherman

FSH low

repeatRepeat+serum, est.

level

PROF

hypothalamic-pituitary failure

anovulation

-VE

Raised testosterone/androgen level. This group includes women with polycystic ovary syndrome (mildly raised level), and women with androgen-secreting tumours of the ovary or adrenal gland, late-onset congenital adrenal hyperplasia, or Cushing's syndrome.

Raised gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) with a low estradiol level. This group includes women with premature ovarian failure and resistant ovary syndrome.

Hyperprolactinaemia. This group includes women with prolactinomas and hypothyroidism.

Low gonadotrophins (FSH and LH) with a low estradiol level. This group includes women with amenorrhoea secondary to exercise, low weight, and stress.

Normal or mildly raised gonadotrophin levels with normal estradiol levels. This group includes women with polycystic ovary syndrome (PCOS) or other mild disorders of gonadotrophin regulation or action.

Complications and prognosis

Osteoporosis: women with amenorrhoea associated with oestrogen deficiency are at significant risk of developing osteoporosis. This increased risk persists even if normal menses are resumed. Oestrogen deficiency is of particular concern in younger women as a desirable peak bone mass may not be attained

Cardiovascular disease

Young women with amenorrhoea associated with oestrogen deficiency may be at increased risk of cardiovascular disease

Women with polycystic ovary syndrome have an increased risk of developing cardiovascular disease, hypertension, and type 2 diabetes [Hopkinson et al, 1998].

Endometrial hyperplasia: women with amenorrhoea but no associated oestrogen deficiency are at increased risk of endometrial hyperplasia and endometrial carcinoma .

Infertility: women with amenorrhoea generally do not ovulate.

Psychological distress: amenorrhoea often causes considerable anxiety, Many women have concerns about loss of fertility, loss of femininity, or worry about an unwanted pregnancy. The diagnosis of Turner's syndrome, testicular feminization, or developmental anomaly can be traumatic for both girls and their parents .

Complications and prognosis

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