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Mohammad Gharaybeh

on 16 April 2013

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Transcript of Amenorrhea

Amenorrhea Dr. Jihan Hamadneh Done By:
- Mohammad Gharaybeh
- Raneem Ashour
- Rana Owais
- Omar Abughanimeh
- Noémi Al Momani
- Talal Kayyali
- Aseel Alhader Introduction Normal Menstrual Cycle Definitions and Causes Hypothalamic-Pituitary-Ovarian axis Oligomenorrhoea when menstrual periods occurs at intervals of greater than 35 days, with only four to nine periods in a year Amenorrhea absence of menstrual bleeding There are some physiological situations where the woman is amenorrhoeic:
Prior to the onset of puberty
Otherwise; we are talking about abnormal cessation of menses, which could be:
Secondary Sexual characteristics anatomical and psychological characteristics that are strongly associated with one sex relative to the other Primary sexual characteristics any of the body structures directly concerned in reproduction, as the testes, ovaries, and external genitalia Secondary sexual characteristics any of a number of manifestations which is specific to each sex and incipient at puberty but not essential to reproduction, as development of breasts or beard, muscularity, distribution of fat tissue, and change of pitch in voice. Normally appears with puberty Primary amenorrhea when the female has never had menses before absence of menses at age 16
+ normal growth
+ normal secondary sexual characteristics
absence of menses at age 14
+ absence of secondary sexual characteristic Secondary Amenorrhea when the female was having menses in the past but now she in not previously regular menses
>>> absence of menses for >3 cycle intervals
previously irregular menses
>>> absence of menses for >6 months Causes of Amenorrhea Causes result in primary amenorrhea only.
Causes result in secondary amenorrhea only.
Mutually exclusive causes (can result in Primary amenorrhea and can result in secondary amenorrhea depending on the age of the patient). Causes of
primary amenorrhea Clinical Approach Preliminary Evaluation 1. Are Breasts Present Or Absent?
An indicator of secondary sexual characteristics
Presence of breasts - adequate estrogen
Absence of breasts - inadequate estrogen

2. Is a Uterus Present Or Absent:
Assessed by pelvic U/S Diagnosis & Management Diagnostic Evaluation Primary amenorrhea is evaluated most efficiently by:
The function of the ovary (estrogen action) - presence or absence of breast development
The presence or absence of the uterus
(by ultrasound, or in more complex cases by MRI)
FSH level (function of hypothalamus and pituitary)
Causes of outflow obstruction (imperforate hymen) Secondary Amenorrhea Definition No menses for ≥ 3 months in a woman who previously had normal menses.


No menses for > 6 months if previously has irregular cycle.( some references say 9 months) BREASTS ABSENT, UTERUS PRESENT



BREASTS PRESENT, UTERUS PRESENT Breasts Absent / Uterus Present Patients without breasts and with a uterus have No Ovarian Estrogen
Mostly The external female genitalia are normal Gonadal Dysgenesis (HYPERgonadotropic Hypogonadism) Pathogenesis During embryogenesis, without any external influences for or against, the human reproductive system is intrinsically conditioned to give rise to a female reproductive system
In Gonadal Dysgenesis; the affected person, no matter whether genetically male or female, will develop external female genitalia. Internal female genitalia, primarily the uterus, may or may not be present depending on the etiology of the disorder Failure of gonadal development leading to dysfunctioning gonads (gonadal streak)
Most common cause of primary amenorrhea
Most commonly due to chromosomal defects

Low estrogen > no breast development
High FSH & LH, due to negative feedback Types of gonadal dysgenesis:
1. Turner Syndrome and its variations
2. Pure gonadal dysgenesis (46,XX and 46,XY) Turner Syndrome 1. 45,XO
Gonadal streak, no breast
The external female genitalia, uterus, and fallopian tubes develop normally until puberty

2. 46XX
Partial deletions and structural rearrangement

3. Mosaic (46,XX and 45,XO)
Spontaneous menstruation and pregnancy may occur Turner Syndrome (45,XO) Primary amenorrhea and absent breasts
Somatic abnormalities:
Short stature (most prevalent), webbing of the neck, short fourth metacarpal, cubitus valgus, cardiac abnormality, renal abnormalities, and hypothyroidism

How to manage?
Estrogen, progesterone and growth hormone
For fertility: egg donar Turner Syndrome Pure Gonadal Dysgenesis (46,XY) Swyer syndrome; a type of hypogonadism in which no functional gonads are present to induce puberty in an XY female

Externally female with streak gonads

How to manage?
Remove gonads (risk of cancer) and give HRT 17 alpha-hydroxylase Deficiency (EUgonadotrpic hypogonadism) Causes congenital adrenal hyperplasia; a rare genetic disorder of steroid biosynthesis that causes:
Decreased production of glucocorticoids and sex steroids
Reduced or absent levels of both gonadal and adrenal sex hormones
Increased synthesis of mineralocorticoid
Hypertension, hypernatremia and hypokalemia

For fertility: IVF / Embryo Transfer Hypothalamic-Pituitary Disorders (HYPOhgonadotrpic hypogonadism) Causes:
Anatomic lesions of the hypothalamus or pituitary
Inadequate (GnRH) release
Isolated gonadotropin deficiency (pituitary disease)
Constitutional delay of puberty Anatomic lesions of the hypothalamus or pituitary Congenital:
Stenosis of aqueduct
Absence of sellar floor.

Prolactinoma Prolactinoma
The most common cause of hyperprolactinemia
Prolactin inhibits gonadotropin activity
Causes galactorrhea 

Other causes of hyperprolactinemia: stress, sleep, exercise, intercourse, drugs and meals Inadequate (GnRH) Release Functional Hypothalamic Amenorrhea:
Due to significant weight loss, exercise, nutritional deficiencies (ex. Celiac) and stress
Risk of osteoporosis

Congenital GnRH deficiency:
Kallmann's syndrome (if assosiated with anosmia) Isolated gonadotropin deficiency
(pituitary disease) Associated with:
Thalassemia major: iron deposits in the pituitary
Mumps encephalitis
Prepubertal hypothyroidism
Retinitis pigmentosa Breasts Present, Uterus Absent Androgen Insensitivity Syndrome
(testicularfeminization) XY karyotype; defect in the androgen receptors
Have functioning male gonads (testicles) that produce normal male levels of testosterone
High levels of FSH & LH Normal level of antimullerian hormone leads to mullerian ducts regression, so: no female internal genitalia (no uterus)
Testes produce estrogen, so:
normal breasts (small nipples)
a short or absent vagina
normal female external genitalia
scant or absent axillary and pubic hair The gonads should be removed after puberty (risk of neoplasia)
Psychological counseling; raised as females Mullerian agenesis Mayer-Rokitansky-Kuster-Hauser syndrome 46, XX with testosterone levels appropriate for females
Failure of mullerian ducts to fuse distally and to form the upper genital tract
Ovaries are fallopian tubes are present, but uterus is absent
Shortened Vagina
Normal breast development and normal axillary and pubic hair
Associated with renal abnormalities and should be screened with an ultrasound or pyelogram
Neovagina can be done Breasts Present, Uterus Present Vaginal disorders are the second largest category of individuals with primary amenorrhea after chromosomal/gonadal dysgenesis Imperforate Hymen & Transverse Vaginal Septum Presentation:
Dysmenorrhea without vaginal bleeding
Physical exam:
Septa or hymen
Perirectal or abdominal mass
Treatment: hymenectomy Breasts Absent, Uterus Absent 17 alpha-hydroxylase deficiency:
46,XY karyotype, have testes
Low testosterone
Low estrogen (no breast)
Female external genitalia
Antimullerian hormone causes the regression of the mullerian ducts (no female internal genetalia) 1-


4- Step 1: History The following questions should be asked to a woman with primary amenorrhea: 1- Has she completed other stages of puberty?
A growth spurt
Development of axillary and pubic hair
Apocrine sweat glands
Breast development Note : Lack of pubertal development suggests ovarian or pituitary failure, or a chromosomal abnormality 2- Is there a family history of delayed or absent puberty?
suggests a possible familial disorder (constitutional growth delay)
3- What is the woman's height relative to family members?
Short stature may indicate Turner syndrome or hypothalamic-pituitary disease
4- Was neonatal and childhood health normal?
Neonatal crisis suggests congenital adrenal hyperplasia.
Poor health may be a manifestation of hypothalamic-pituitary disease.
5- Are there any symptoms of virilization?
The presence of virilization suggests:
Polycystic ovary syndrome.
Androgen-secreting ovarian or adrenal tumor.
Presence of Y chromosome material. 6- Lately, has there been stress, change in weight, diet,
exercise habits, or illness?
Might result in functional hypothalamic amenorrhea.

7- Is she taking any drugs that might cause or be associated
with amenorrhea?
Medication for a systemic illness
(e.g. medication for Sarcoidosis).
Heroin and methadone can alter hypothalamic gonadotropin secretion. 8- Is there galactorrhea (suggestive of excess prolactin)?
Some drugs cause amenorrhea by increasing serum
prolactin concentrations.
( i.e. metoclopramide and antipsychotic drugs.)
9- Are there symptoms of other hypothalamic-pituitary disease?
- Headaches
- Visual field defects
- Fatigue
- Polyuria
- Polydipsia Step 2: Physical Examination 1) Evaluation of pubertal development, including:

Current height, weight, and arm span (normal arm span for adults is within 5 cm of height).
Evaluation of the woman's growth chart. 2) An assessment of breast development:

Tanner staging 3) A careful genital examination should be performed for:

Clitoral size
Pubertal hair development
Intactness of the hymen
Depth of the vagina
Presence of a cervix, uterus, and ovaries 4) Examination of the skin for:

Increased pigmentation
Vitiligo 5) Evaluation for the classic physical features of
Turner syndrome such as:

Low hair line
Web neck
Shield chest
Widely spaced nipples should be noted. Note: the blood pressure should be measured in both arms if Turner syndrome is suspected, because it is associated with an increased incidence of coarctation of the aorta. Step 3: Basic Investigation Ultrasonography If a normal vagina or uterus is not obviously present on physical examination, looking for any anatomic abnormalities of the vagina, cervix, or uterus. 1- No uterus >>> do karyotyping and serum testosterone level. 2- Uterus present: Normal müllerian structures , no evidence of an imperforate hymen, vaginal septum, or congenital absence of the vagina.
An endocrine evaluation should be performed:
Measure Serum Beta Human Chorionic Gonadotropin: to exclude pregnancy
Serum FSH FSH Results of serum FSH can help as follows:
1- FSH level suggests:
primary ovarian failure (i.e. Turner’s syndrome) karyotype should be obtained.
swyer syndrome
2- FSH or normal concentration suggests:
Functional hypothalamic amenorrhea
Congenital GnRH deficiency (e.g.. kallmann syndrome)
Other disorders of the hypothalamic-pituitary axis. Other important endocrine values Serum prolactin and thyrotropin:
should be measured if FSH is low or normal, especially if galactorrhea is present.

If there are signs or symptoms of hyperandrogenism, serum testosterone and dehydroepiandrosterone sulfate (DHEA-S) should be measured to assess for an androgen-secreting tumor. Treatment Includes 3 aspects:

Correcting the underlying pathology (if possible)
Helping the woman to achieve fertility (if desired)
Prevention of complications of the disease process (eg: estrogen replacement to prevent osteoporosis) A brief summary for methods of treatment may include:

1- Psychological counseling :
Is particularly important in patients with absent müllerian structures or a Y chromosome.

2- Surgery :
May be required in patients with either congenital anatomic lesions or Y chromosome material.
(As an example, surgical correction of a vaginal outlet obstruction) 3- Symptomatic treatement:
As in women with PCOS, treatment of hyperandrogenism is directed toward achieving the woman's goal
(eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS.

4- Functional hypothalamic amenorrhea
can be reversed by:
Weight gain
Reduction in the intensity of exercise
Resolution of illness or emotional stress. 5- Assisted reproductive technologies
now make it possible for many women with primary amenorrhea to participate in reproduction:
For women with gonadal dysgenesis, the use of donor oocytes and their partners' sperm with IVF allow the women to carry a pregnancy in their own uterus.
For women with an absent uterus, use of their own oocytes in IVF and transfer of their embryos to a gestational carrier can allow these women to have genetically related children. Pathophysiology hypogonadotropic (suggesting hypothalamic or pituitary dysfunction)
hyper gonadotropic (suggesting ovarian follicular failure)
eugonadotropic (suggesting pregnancy, anovulation, or uterine or outflow tract pathology) often caused by hormonal disturbances from the hypothalamus and the pituitary gland, from premature menopause or intrauterine scar formation Etiology Pregnancy (most common)
Ovarian (40%)
Polycystic ovary syndrome (40%)
Ovarian failure
Autoimmune oophoritis
Hypothalamic (35%)
Functional GnRH deficiency (same reasons as under 1o amenorrhea)
eating disorders and weight loss (obesity, anorexia nervosa, or bulimia)
Pituitary (20%)
Hyperprolactinemia (90%) > decreased GnRH
Uterine (5%)
Asherman’s (>90%).
Others ( 1%) e.g. cervical & endocrine
hypothyroidism, hyperthyroidism, arrhenoblastoma Etiologies
According to Clinical Importance Pregnancy (MC)
Anovulation: (polycystic ovary syndrome, hypothyroidism, pituitary adenoma, elevated prolactin, and medications (e.g., antipsychotics, antidepressants)) first patient present with amenorrhea then irregular bleeding.
Estrogen Deficiency (absence of functional ovarian follicles or hypothalamic-pituitary insufficiency).
Outflow Tract Obstruction (Asherman's syndrome) Hypothalamic causes Functional hypothalamic amenorrhea: GnRH secretion, without other causes.
Weight loss/anorexia nervosa: malnourishment will reproductive ability. Tx : Weight gain.
Stress and exercise. E.g. athletes.
Drugs: OCPs act at the level of the hypothalamus and pituitary. Postpill amenorrhea can occur up to 6 months after stopping the pill.
Lesions: Craniopharyngiomas, granulomatous disease, encephalitis sequelae. Pituitary causes (HYPOESTROGENIC AMENORRHEA) Neoplasms: e.g. Prolactinomas, nonprolactin- secreting pituitary tumors.
Lesions: caused by anoxia, thrombosis, or hemorrhage. postpartum hypopituitarism or postpartum pituitary necrosis caused by ischemic necrosis due to blood loss and hypovolemic shock during and after childbirth.
rare complication , The presence of DIC (amniotic fluid embolism or HELLP syndrome) appears to be a factor in its development
Symptoms : Most common initial symptoms of Sheehan's syndrome are agalactorrhea or difficulties with lactation , others like amenorrhea or oligomenorrhea after delivery , features of hypopituitarism , may be asymptomatic
Treatment includes replacement of pituitary hormones. Sheehan syndrome Pituitary damage unrelated to pregnancy Simmonds disease Ovary 1- Premature ovarian failure (POF):
Aka Primary ovarian insufficiency , premature menopause
the loss of function of the ovaries before age 40
It leads to estrogen deficiency, endometrial atrophy, and cessation of menstruation.
triad for the diagnosis is amenorrhea, hypergonadotropinism, and hypoestrogenism
Causes : autoimmune ovarian destruction,  Radiation therapy, chemotherapy, genetic or infection
2- Polycystic ovaries.
3- Anovulation:
no corpus luteum → no progesterone →no progesterone withdrawal bleeding.
Cause endometrial hyperplasia (unopposed estrogen stimulation of endometrium)
Causes include : PCOS , hypothyroidism , hyperprolactenemia , drugs (antipsychotics and antidepressants).
4- Surgical: Bilateral salpingo-oophorectomy. Uterus 1- Asherman syndrome:
Intrauterine adhesions can obliterate the endometrial cavity and cause amenorrhea.
Most frequent cause is endometrial curettage associated with pregnancy.
Adhesions may form after myomectomy, metroplasty, or cesarean delivery.
Confirm the diagnosis with hysterosalpingogram (HSG) or hysteroscopy.
Treat via hysteroscopic resection of adhesions. Estrogens administered to stimulate regrowth of endometrium. 2- Endometrial ablation:
This procedure may have been performed for menorrhagia.
3- Infection:
Endometritis or tuberculosis. Cervical: Stenosis due to loop electrosurgical excision procedure (LEEP) or cold-knife cone. Treat with cervical dilation.
Endocrine disease: can cause secondary amenorrhea.
Diabetes mellitus.
Hyperandrogenism (neoplasm, exogenous androgens). Approach Once pregnancy and Asherman's syndrome have been excluded, all of the remaining causes of amenorrhea are associated with anovulation due to hypothalamic, pituitary, or ovarian disorders.

Step 1: Confirm the case By Hx and P/E
Step 2: Rule out pregnancy.
Step 3: Hormonal assay.
Step 4: Progestin challenge
Step 5: Depend on progestin challenge Test result Approach to Secondary Amenorrhea Step 1: Confirm Definition
(Hx, P/E) History Questions 6-9 of the primary amenorrhea history + the following: (refer to previous slides):

- Are there any symptoms of estrogen deficiency?
hot flashes
vaginal dryness
poor sleep
decreased libido
> These symptoms may be prominent in the early stages of ovarian insufficiency. In contrast, women with hypothalamic amenorrhea do not usually have these symptoms.

- Is there a history of obstetrical catastrophe?
severe bleeding
dilatation and curettage
endometritis or other infection that might have caused scarring of the endometrial lining (Asherman's syndrome) Physical Examination 1- Measurements of height and weight.
A body mass index greater than 30 kg/m2 is observed in approximately 50 percent of women with PCOS.
Women with a BMI less than 18.5 kg/m2 may have functional hypothalamic amenorrhea due to an eating disorder, strenuous exercise, or a systemic illness associated with weight loss
2- The patient should be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, and easy bruisability.
3- Breasts should be examined for evidence of galactorrhea.
4- Vulvovaginal exam should look for signs of estrogen deficiency Step 2: Rule out pregnancy A pregnancy test is recommended as a first step. Measurement of serum beta subunit of hCG is the most sensitive test. Step 3: Hormonal assay Minimal laboratory testing should include:
Serum prolactin.
Serum Androgens ( testosterone, DHEA) . Step 4: Progestin challenge The test is performed by administering progesterone orally in the form of medroxyprogesterone acetate (Provera), or intramuscularly.

If the patient has sufficient serum estradiol (greater than 50 pg/mL) then withdrawal bleeding should occur 2-7 days after the progestin is finished, indicating that the patient's amenorrhea is due to anovulation. Progestin challenge, or progesterone withdrawal test if no bleeding occurs after progesterone withdrawal, then the patient's amenorrhea is likely to be due to either:
Low serum estradiol.
a problem with the uterine outflow tract, such as cervical stenosis or uterine synechiae (Asherman's syndrome).
In order to distinguish between hypoestrogenism or a uterine outflow tract problem, estrogen may be administered followed by a course of progestin in order to induce withdrawal bleeding. If the patient experiences withdrawal bleeding with the combined estrogen/progestin therapy, then the amenorrhea is likely due to low estrogen. Follow-up testing 1- Assessment of estrogen status:
in some cases to help with interpreting the FSH values, and in others to help guide therapy. 2- High serum prolactin concentration:
Prolactin secretion can be transiently increased by stress or eating.
 women should be screened for thyroid disease because hypothyroidism can cause hyperprolactinemia 3- High serum FSH concentration
A high serum FSH concentration indicates primary ovarian insufficiency (premature ovarian failure) 4- Normal or low serum FSH conc.:
A serum FSH concentration that is low or "normal" is inappropriately low in the presence of a low serum estradiol concentration and indicates secondary (hypogonadotropic) hypogonadism. 5- Normal labs and hx of uterine inst.:
Evaluation for Asherman's syndrome (intrauterine adhesions) should be performed. 6- High serum androgen concentrations :
Depending upon the clinical picture, a high serum androgen value may be consistent with the diagnosis of PCOS or may raise the question of an androgen-secreting tumor of the ovary or adrenal gland. Case study 1 A 24-year-old G2 P2 woman delivered vaginally 8 months previously. Her delivery was complicated by postpartum hemorrhage requiring curettage of the uterus and a blood transfusion of two units of erythrocytes. She complains of amenorrhea since her delivery. She denies taking medications or having headaches or visual abnormalities. Her pregnancy test is negative. She was not able to breast-feed her baby.
What is the most likely diagnosis?
What are other complications that are likely with this condition? Case study 2 A 33-year-old woman complains of 7 months of amenorrhea following a spontaneous abortion. She had a dilation and curettage (D and C) at that time. Her past medical and surgical histories are unremarkable. She experienced menarche at age 11 years and notes that her menses have been every 28 to 31 days until recently. Her general physical examination is unremarkable. The thyroid is normal to palpation, and breasts are without discharge. The abdomen is nontender. The pelvic examination shows a normal uterus, closed and normal-appearing cervix, and no adnexal masses. A pregnancy test is negative.
What is the most likely diagnosis?
What is the next test to confirm the diagnosis? Treatment Hypothalamic amenorrhea:
Lifestyle changes: For many athletic women, simply explaining the need for adequate caloric intake to match energy loss results in increased caloric intake or reduced exercise, followed by resumption of menses
Cognitive behavioral therapy: may be effective for restoring ovulatory cycles in some women
Leptin administration: women with hypothalamic amenorrhea (HA) have relative leptin deficiency.
Hyperprolactinemia :
The management of women with amenorrhea due to hyperprolactinemia depends upon the cause of the hyperprolactinemia and the patient’s goals (eg, pursuing fertility or not). Treat the cause Primary ovarian insufficiency (premature ovarian failure):
Women with primary ovarian insufficiency should receive estrogen therapy for prevention of bone loss. This can be either an oral contraceptive,  or replacement doses of estrogen and progestin
Polycystic ovary syndrome:
Treatment of hyperandrogenism is directed toward achieving the woman's goal (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS.
Intrauterine adhesions: 
Therapy of Asherman’s syndrome consists of hysteroscopic lysis of adhesions followed by long-term estrogen administration to stimulate regrowth of endometrial tissue. Thank you Normal Menstrual Cycle The menstrual cycle starts at age of puberty (avg=12) and stops at age of menopause (45-55).
At the beginning, longer cycles are common, but it tends to shorten and become more regular with age.
A cycle is counted from the first day of 1 period to the first day of the next period.
The average menstrual cycle is 28 days long.
It can range anywhere from 21 to 35 days.
Menstrual period varies in flow (light, moderate or heavy) and in length (3-5 days) Hypergonadotropic Hypogonadism (48.5%) abnormal sex chromosomes (ie, Turner syndrome)

normal sex chromosomes (46,XX or 46,XY) Hypogonadotropic Hypogonadism (27.8%) - Congenital abnormalities
Isolate GnRH deficiency
Forms of hypopituitarism
Congenital CNS defects
Constitutional delay

- Endocrine disorders
Congenital adrenal hyperplasia
Cushing syndrome
Hyperprolactinemia - Tumor
Pituitary adenoma
Unclassified malignant tumor

- Systemic illness

- Eating disorder Eugonadism - anatomic abnormalities
congenital absence of the uterus and vagina (CAUV)
cervical atresia
- intersex disorders
androgen insensitivity
17-ketoreductase deficiency
inappropriate feedback
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