BY BY MAGDY ABDELRAHMAN MOHAMEDMAGDY ABDELRAHMAN MOHAMED

20122012

AMENORRHEAAMENORRHEA

Primary Amenorrhea

is defined either as absence of menses by age 14 years with no 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

Thelarche (breast development)Thelarche (breast development)– Requires estrogenRequires estrogenPubarche/adrenarche (pubic hair development)Pubarche/adrenarche (pubic hair development)– Requires androgensRequires androgens

MenarcheMenarcheRequires:Requires:– GnRH from the hypothalamusGnRH from the hypothalamus– FSH and LH from the pituitaryFSH and LH from the pituitary– Estrogen and progesterone from the ovariesEstrogen and progesterone from the ovaries– Normal outflow tractNormal outflow tract

Events of PubertyEvents of Puberty

Magnitude of the problem Secondary amenorrhea (prevalence about 3%) Primary amenorrhea (prevalence about 0.3%) Between 10 and 20% of women complaining of

infertility have amenorrhea . Up to 50% of competitive runners (training 80 miles

per week) and up to 44% of ballet dancers have amenorrhea.

ETIOLOGY OF ETIOLOGY OF PRIMARY AMENORRHEA

Secondary sexual characteristics present

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

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

Androgen insensitivity Resistant ovary syndrome Pregnancy

Secondary sexual characteristics absent

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

Gonadotrophin deficiency, e.g. Kallman's syndrome Hypopituitarism Hyperprolactinemia Hypothyroidism Gonadal failure, e.g. ovarian dysgenesis/agenesis,

premature ovarian failure

Ambiguous external genitalia

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

CAHCAH

Sertoli-Leydig Cell TumorSertoli-Leydig Cell Tumor

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, lymphedema, shield chest with widely spaced nipples, wide carrying angle, coarctation of the aorta, and streak ovaries

Uterovaginal agenesisUterovaginal agenesis

15% of primary amenorrhea 15% of primary amenorrhea Normal secondary development & external Normal secondary development & external female genitaliafemale genitaliaNormal female range testosterone levelNormal female range testosterone level

Absent uterus and upper vagina & normal Absent uterus and upper vagina & normal ovariesovariesKaryotype 46-XXKaryotype 46-XX1515--30% associated renal, skeletal and middle 30% associated renal, skeletal and middle ear anomaliesear anomalies

Androgen insensitivity syndrome (AIS)

Formerly known as testicular feminization, 46XYFailure 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 functionAffected individuals have normal testes with normal production of testosterone and normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5-alpha reductase deficiency

Imperforate hymenImperforate hymen represents the most common and most distal form of vaginal outflow obstructionClinical 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 painThe differential diagnosis of uterovaginal obstruction includes disorders of vaginal development, such as transverse vaginal septum or complete vaginal agenesis.

Imperforate hymen

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

ASSESSMENT OF ASSESSMENT OF PRIMARY AMENORRHEAPRIMARY AMENORRHEA

TSH elevatedhypothyroidism

Normal

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

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 syndkaryotype 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

Etiology of Etiology of secondary amenorrhea

No features of androgen excess present

Physiologic, 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

Features of androgen excess present

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

Polycystic ovary syndrome

This condition is characterized by hirsutism, acne, alopecia, infertility, obesity, and menstrual abnormalities (amenorrhea 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 .

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

Asherman’s SyndromeAsherman’s Syndrome

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 necessary to screen for thyroid, parathyroid, and adrenal

dysfunction

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

Autoimmune related dysfunction The most common association is with thyroid The most common association is with thyroid disease, but the parathyroids and adrenals can disease, but the parathyroids and adrenals can also be affectedalso be affectedSeveral 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 failurepremature ovarian failureIn 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 obtainedclinically useful information will be obtained

Hyperprolactinemia A prolactinoma is the commonest cause of

hyperprolactinemia (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, 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

Progestogen-associated amenorrhea

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 estrogen 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)

ASSESMENT OF ASSESMENT OF 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

amenorrheaamenorrhea

symptoms of pregnancy Associated symptoms, e.g.

galactorrhoea, hirsutism, hot flushes, dry vagina, symptoms of thyroid disease

Recent change in body weight Recent emotional upsets 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

EXAMINATIONEXAMINATION 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 Pelvic 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

repeat

POF

hypothalamic-pituitary failure

anovulation

-VE

Complications and prognosis

Osteoporosis: women with amenorrhoea associated with estrogen deficiency are at significant risk of developing osteoporosis. This increased risk persists even if normal menses are resumed. Estrogen 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 estrogen 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: amenorrhea 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

RECENT MANAGEMENT OF RECENT MANAGEMENT OF AMENORRHEAAMENORRHEA

Ovarian cortical transplantationOvarian cortical transplantationTransplantation of ovarian cortical tissue is Transplantation of ovarian cortical tissue is performed in patients with premature ovarian performed in patients with premature ovarian failure, premature menopause due to sur5gical failure, premature menopause due to sur5gical removal of the ovary, radiotherapy & removal of the ovary, radiotherapy & chemotherapychemotherapythe ovarian cortical grafts transplanted the ovarian cortical grafts transplanted subcutaneously functioned from the 6th subcutaneously functioned from the 6th postoperative month . At the long-term follow-up postoperative month . At the long-term follow-up of the patient, cortical grafts have still been of the patient, cortical grafts have still been functioning. The patient did not have any functioning. The patient did not have any complaint requiring hormonal therapy during that complaint requiring hormonal therapy during that time periodtime period

Ultrasonographic Ultrasonographic appearance of appearance of follicles developed follicles developed from subcutaneous from subcutaneous grafts at the 6th , 9th , grafts at the 6th , 9th , and 18th monthsand 18th months

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