Dr. Afaf Ibrahim Dr. Afaf Ibrahim AlNouryAlNoury

Associate professor ofAssociate professor of OBS & GYNOBS & GYN

King Abdul Aziz UniversityKing Abdul Aziz University

AmenorrheaAmenorrhea

WelcomeWelcome.….…

AmenorrheaAmenorrhea

Few problem in gynecologic Few problem in gynecologic endocrinology are as challenging or endocrinology are as challenging or

taxing to the clinician as amenorrhea.taxing to the clinician as amenorrhea.

Definition of amenorrheaDefinition of amenorrhea Any patient fulfilling the following criteria should be Any patient fulfilling the following criteria should be

evaluated as having the clinical problem of amenorrhea:evaluated as having the clinical problem of amenorrhea:

1.1. No period by age 16 regardless of the presence of No period by age 16 regardless of the presence of normal growth and development with the appearance normal growth and development with the appearance secondary sexual characteristics.secondary sexual characteristics.

2.2. No period by age 14 in the absence of growth or No period by age 14 in the absence of growth or development of secondary sexual characteristics.development of secondary sexual characteristics.

3.3. In a woman who has been menstruating , the absence of In a woman who has been menstruating , the absence of periods for a length of time equivalent to a total of at periods for a length of time equivalent to a total of at least 3 of the previous cycle intervals or 6 months of least 3 of the previous cycle intervals or 6 months of amenorrhea.amenorrhea.

It is useful to employ a diagnostic evaluation that It is useful to employ a diagnostic evaluation that segregates causes of amenorrhea into the following segregates causes of amenorrhea into the following compartments:compartments:

Compartment I:Compartment I:

Disorders of the outflow or uterine target organ.Disorders of the outflow or uterine target organ. Compartment II:Compartment II:

Disorders of the ovary.Disorders of the ovary. Compartment III:Compartment III:

Disorders of the anterior pituitary.Disorders of the anterior pituitary. Compartment IV:Compartment IV:

Disorders of central nervous system (hypothalamic) Disorders of central nervous system (hypothalamic) factors.factors.

Central nervous system

Hypothalamus

AnteriorPituitary

Ovary

Uterus

environment

menses

Compartment IV

Compartment III

Compartment II

Compartment I progesteroneEstrogen

LHFSH

Gn RH

Evaluation of amenorrheaEvaluation of amenorrhea A careful history and physical examination should seek the A careful history and physical examination should seek the

following:following:

evidence for psychological dysfunction or emotional stress, evidence for psychological dysfunction or emotional stress, family history of apparent genetic anomalies , signs of a family history of apparent genetic anomalies , signs of a physical problem with a focus on nutritional status, abnormal physical problem with a focus on nutritional status, abnormal growth and development, the presence of a normal reproductive growth and development, the presence of a normal reproductive tract , and evidence for CNS disease. A patient with amenorrhea tract , and evidence for CNS disease. A patient with amenorrhea is then exposed to a combined therapeutic and laboratory is then exposed to a combined therapeutic and laboratory dissection according to the depicted flow diagrams.dissection according to the depicted flow diagrams.

The initial step in the workup of the amenorrheicThe initial step in the workup of the amenorrheic patient patient after excluding pregnancy begins with a measurement of after excluding pregnancy begins with a measurement of thyroid-stimulating hormone (TSH), aprolactin level , and thyroid-stimulating hormone (TSH), aprolactin level , and a pregestational challenge.a pregestational challenge.

Step 1Step 1

Amenorrhea TSH

Prolactin Presentational challenge

+withdrawal bleed

Normal prolactinNormal TSH

An ovulation

hypothyroidism

Elevated TSH

There are two rare situations associated with a negative withdrawal There are two rare situations associated with a negative withdrawal response , despite the presence of adequate levels of endogenous estrogen. response , despite the presence of adequate levels of endogenous estrogen. In both situations, the endometrium is decidualized and , therefore , it will In both situations, the endometrium is decidualized and , therefore , it will not be shed following the withdrawal of exogenous progestin. not be shed following the withdrawal of exogenous progestin.

Polycystic ovaries.Polycystic ovaries. Specific adrenal enzme deficiency.Specific adrenal enzme deficiency. All anovulatory patients require therapeutic management.All anovulatory patients require therapeutic management. Minimal therapy of anovulatory women requires the monthly Minimal therapy of anovulatory women requires the monthly

administration of a progestational agent.administration of a progestational agent. If , at any time , an anovulatory patient fails to have withdrawal bleeding If , at any time , an anovulatory patient fails to have withdrawal bleeding

on a monthly progestin program , this is a sign (providing the patient is on a monthly progestin program , this is a sign (providing the patient is not pregnant ) that she has moved to the negative withdrawal bleed not pregnant ) that she has moved to the negative withdrawal bleed category. category.

Step 2Step 2 Orally active estrogen is administered in quantity and Orally active estrogen is administered in quantity and

duration certain to stimulate endometrial proliferation duration certain to stimulate endometrial proliferation and withdrawal bleeding provided that a completely and withdrawal bleeding provided that a completely reactive uterus and patent outflow tract exist.reactive uterus and patent outflow tract exist.

If there is no withdrawal flow , the diagnosis of a If there is no withdrawal flow , the diagnosis of a defect in the compartment I systems (endometrium , defect in the compartment I systems (endometrium , outflow tract) can be made with confidence.outflow tract) can be made with confidence.

If withdrawal bleeding does occur , one can assume If withdrawal bleeding does occur , one can assume that compartment I system have normal functional that compartment I system have normal functional abilities if properly stimulated by estrogen.abilities if properly stimulated by estrogen.

Step 3Step 3

Clinical stateClinical state Serum FSHSerum FSHSerum LHSerum LHNormal adult femaleNormal adult female5-20 IU/L , with the ovulatory 5-20 IU/L , with the ovulatory

midcycle peak about 2 times midcycle peak about 2 times the base levelthe base level

5-20 IU/L , with the 5-20 IU/L , with the ovulatory midcycle peak ovulatory midcycle peak

about 2 times the base levelabout 2 times the base level

Hypogonadotropic state: Hypogonadotropic state: prepubertal, hypothalamic prepubertal, hypothalamic , or pituitary dysfunction , or pituitary dysfunction

Less than 5 IU/LLess than 5 IU/LLess than 5 IU/LLess than 5 IU/L

Hypogonadotropic state: Hypogonadotropic state: prepubertal, hypothalamic prepubertal, hypothalamic , or pituitary dysfunction , or pituitary dysfunction

Greater than 20 IU/LGreater than 20 IU/LLess than 40 IU/LLess than 40 IU/L

This step involves an assay of the level of This step involves an assay of the level of gonadotropins in the patient.gonadotropins in the patient.

Step 3 is designed to determine whether the lack of Step 3 is designed to determine whether the lack of estrogen is due to a fault in the follicle (compartment II) estrogen is due to a fault in the follicle (compartment II) or in the CNS-pituitary axis (compartments III and IV).or in the CNS-pituitary axis (compartments III and IV).

High GonadotropinsHigh Gonadotropins High gonadotropins accompanied by ovaries not contain High gonadotropins accompanied by ovaries not contain

follicles follicles ))overian failure)overian failure) There are rare situation in which high gonadotropins can be There are rare situation in which high gonadotropins can be

accompanied by ovaries that contain folliclesaccompanied by ovaries that contain follicles..1.1. On rare occasions , tumors can produce gonadotropins.On rare occasions , tumors can produce gonadotropins.2.2. A single gonadotropin deficiency.A single gonadotropin deficiency.3.3. Due to a gonadotropin-secreting pituitary adenoma.Due to a gonadotropin-secreting pituitary adenoma.4.4. Duing the perimenopausal periodDuing the perimenopausal period5.5. In the resistant or insensitive ovary syndromeIn the resistant or insensitive ovary syndrome6.6. Secondary amenorrhea caused by premature ovarian failure can be Secondary amenorrhea caused by premature ovarian failure can be

due to autoimmune disease.due to autoimmune disease.7.7. Calactosemia is a rare inherited autosomal recessive disorder of Calactosemia is a rare inherited autosomal recessive disorder of

galactose metabolism due to a deficiency of galactose-1-phosphate galactose metabolism due to a deficiency of galactose-1-phosphate uridyl transferase.uridyl transferase.

8.8. The final rare clinical situation is that associated with specific The final rare clinical situation is that associated with specific enzymatic deficiencies the 17-hydroxylase deficiency (P450c17) enzymatic deficiencies the 17-hydroxylase deficiency (P450c17) is present in both ovaries and the adrenal gland.is present in both ovaries and the adrenal gland.

The need for chromosome evaluationThe need for chromosome evaluation All patients under the age of 30 who have been assigned the All patients under the age of 30 who have been assigned the

diagnosis of ovarian failure on the basis of elevated gondotropins diagnosis of ovarian failure on the basis of elevated gondotropins must have a karyotype determination.must have a karyotype determination.

The presence of mosaicism with a Y chromosome requires excision The presence of mosaicism with a Y chromosome requires excision of the gonadal areas because the presence of any testicular of the gonadal areas because the presence of any testicular component within the gonad carries with it a significant chance of component within the gonad carries with it a significant chance of malignant tumor formation.malignant tumor formation.

Normal conadotropinsNormal conadotropins Why is it that hypoestrogenic (negative progestational withdrawal) Why is it that hypoestrogenic (negative progestational withdrawal)

patients will frequently have normal circulating levels of FSH and patients will frequently have normal circulating levels of FSH and LH as measured by immunoassay.LH as measured by immunoassay.

The molecules are qualitatively altered and biologically inactive.The molecules are qualitatively altered and biologically inactive. Another very rare possibility is an inherited disorder of Another very rare possibility is an inherited disorder of

gonadotropin synthesis leading to the production of gonadotropin synthesis leading to the production of immunologically active but biologically inactive hormones.immunologically active but biologically inactive hormones.

Low GonadotropinsLow Gonadotropins

If the gonadotrpin assay is abnormally low , or in If the gonadotrpin assay is abnormally low , or in the normal range , one final localization is the normal range , one final localization is required to distinguish between a pituitary required to distinguish between a pituitary (compartment III) or CNS-hypothalamic (compartment III) or CNS-hypothalamic (compartment IV) cause for the amenorrhea.(compartment IV) cause for the amenorrhea.

This is achieved by imaging evaluation of the This is achieved by imaging evaluation of the sella turcica for signs of abnormal.sella turcica for signs of abnormal.

Amenorrhea TSHProlactinProgestional challenge

Galactorrhea TSHProlactin coned-down

view of sella Turcica

-withdrawal +withdrawalElevated TSH

Normal prolactin normal TSH

Prolactin > 100 or abnormal coned-down view

Estrgen and progestin cycle

-Withdrawal bleed+Withdrawal bleed

FSH , LH assay

low High normal

Coned-down view of sella turcicaAbnormal coned - view

End organ problem

Hypothalamic amenorrhea

hypothyroidism

Anovulation

MRI

Ovarianfailure

Compartment I: Disorders of the Outflow Compartment I: Disorders of the Outflow Tract or UterusTract or Uterus

Imperforate hymen Imperforate hymen Obliteration of the vaginal orifice , and lapses in continuity of Obliteration of the vaginal orifice , and lapses in continuity of

the vaginal canal.the vaginal canal. The cervix or the entire uterus may be absent.The cervix or the entire uterus may be absent. The uterus be present , but the cavity absent.The uterus be present , but the cavity absent. The endometrium may be congenitally,lacking.The endometrium may be congenitally,lacking.

A Sherman's syndromeA Sherman's syndrome

Mullerian AnomaliesMullerian Anomalies

Lack of mullerian development (mayer-Rokitansky-Lack of mullerian development (mayer-Rokitansky-kuster syndrome) is the diagnosis for the individual with kuster syndrome) is the diagnosis for the individual with primay amenorrhea and no apparent vagina.primay amenorrhea and no apparent vagina.

Mullerian AgenesisMullerian Agenesis

Androgen insensitivity (feminization)Androgen insensitivity (feminization)

The male pseudohermaphrodite is a genetic and gonadal male with failure of The male pseudohermaphrodite is a genetic and gonadal male with failure of virilization.virilization.

Transmission of this disorder is by means of an x-linked recessive gene that is Transmission of this disorder is by means of an x-linked recessive gene that is responsible for the androgen intracellular receptor.responsible for the androgen intracellular receptor.

Differences between mullerian agenesis and Testicular feminizationDifferences between mullerian agenesis and Testicular feminization

Mullerian agenesisMullerian agenesisTesticular Feminization Testicular Feminization

Karyotype Karyotype 46,xx46,xx46,xy 46,xy

Heredity Heredity Not knownNot knownMaternal x-linked recessive; 25% Maternal x-linked recessive; 25% risk of affected child,25% risk of risk of affected child,25% risk of

carriercarrier

Sexual hair Sexual hair Normal femaleNormal femaleAbsent to sparse Absent to sparse

Testosterone leveTestosterone leveNormal femaleNormal femaleNormal to slightly elevated male levelNormal to slightly elevated male level

Other anomaliesOther anomaliesFrequentFrequent RareRare

Conadal neoplasisConadal neoplasisNormal incidenceNormal incidence 5%incidence of malignant tumors5%incidence of malignant tumors

Clinically , the diagnosis should be considered in:Clinically , the diagnosis should be considered in:1.1. AA female child with inguinal hernias because the testes are female child with inguinal hernias because the testes are

frequently partially descended.frequently partially descended.

2.2. A patient with primary amenorrhea and an absent uterus.A patient with primary amenorrhea and an absent uterus.

3.3. A patient with absent body hair.A patient with absent body hair.

This syndrome is marked by a unique combination:This syndrome is marked by a unique combination:1.1. Normal female phenotype.Normal female phenotype.

2.2. Normal make karyotype. 46 .XY.Normal make karyotype. 46 .XY.

3.3. Normal or slightly elevated mate blood testosterone levels and Normal or slightly elevated mate blood testosterone levels and a high LH.a high LH.

Compartment II: Disorders of the OvaryCompartment II: Disorders of the Ovary Problems in gonadal development can present with either primary or Problems in gonadal development can present with either primary or

secondary amenorrhea from 30 to 40% of primary amenorrhea cases secondary amenorrhea from 30 to 40% of primary amenorrhea cases have gonadal streaks due to abnormal development:gonadal have gonadal streaks due to abnormal development:gonadal dysgensis. These patients can be grouped according to the following dysgensis. These patients can be grouped according to the following karyotypes:karyotypes:

• 50%-45,x50%-45,x• 25%-Mosaics 25%-Mosaics • 20%-46,xx20%-46,xx

Turner syndromeTurner syndromeMosaicismMosaicism

XY conadal DysgenesisXY conadal Dysgenesis

Conadal agenesisConadal agenesis

The resistant Ovary syndromeThe resistant Ovary syndrome

Premature Ovarian FailurePremature Ovarian Failure

Compartment III : disorders of the Anterior PituitaryCompartment III : disorders of the Anterior Pituitary Hypogonadism and delayed puberty deserve brain evaluation by Hypogonadism and delayed puberty deserve brain evaluation by

MRI.MRI.Compartment IV:Central Nervous System DisordersCompartment IV:Central Nervous System DisordersHypothalamic AmenorrheaHypothalamic Amenorrhea Patients with hypothalamic amenorrhea (hypogonadotropic hypogonadism ) have Patients with hypothalamic amenorrhea (hypogonadotropic hypogonadism ) have

a deficiency in GnRH pulsatile secretion. a deficiency in GnRH pulsatile secretion. Hypothalamic problems are usually diagnosed by exclusion of pituitary lesions Hypothalamic problems are usually diagnosed by exclusion of pituitary lesions

and are the most common category of hypogonadotropic amenorrhea , a and are the most common category of hypogonadotropic amenorrhea , a functional suppression of reproduction ,often a psychobiologic response to life functional suppression of reproduction ,often a psychobiologic response to life events.events.

The degree of GnRH suppression determines how these patients present clinically.The degree of GnRH suppression determines how these patients present clinically. Mild duppression can be associated with a marginal effect on reproduction , Mild duppression can be associated with a marginal effect on reproduction ,

specifically an inadequate luteal phase.specifically an inadequate luteal phase. Moderate suppression of Gn RH secretion can yield anovulation with menstrual Moderate suppression of Gn RH secretion can yield anovulation with menstrual

irregularity , and profound suppression is manifested by hypothalamic irregularity , and profound suppression is manifested by hypothalamic amenorrhea.amenorrhea.

11. Onset between ages 10 and 30.. Onset between ages 10 and 30.22. Weight loss of 25% or weight below normal for age and height.. Weight loss of 25% or weight below normal for age and height.33. Special attitudes:. Special attitudes:• Denial.Denial.• Distorted body image.Distorted body image.• Unusual hoarding or handing of food.Unusual hoarding or handing of food.44. . At least one of the following:At least one of the following:• Lanugo.Lanugo.• Bradycardia,Bradycardia,• Overactivity,Overactivity,• Episodes of overeating (bulimia),Episodes of overeating (bulimia),• Vomiting , which may be self disorderVomiting , which may be self disorder5.5. Amenorrhea Amenorrhea 6.6. No known medical illness. No known medical illness.7.7. No other psychiatric disorder. No other psychiatric disorder.8.8. Other characteristics: Other characteristics: constipation.constipation. Low blood pressure .Low blood pressure . Hypercarotenemia.Hypercarotenemia. Diabetes insipidus.Diabetes insipidus.

Weight loss, anorexia , bulimiaWeight loss, anorexia , bulimia

Diagnosis of Anorexia NervosaDiagnosis of Anorexia Nervosa

Exercise and AmenorrheaExercise and Amenorrhea

↑CRH

Stress

↑Endorphins

↓T3

↓T4

↓TSH

↓TRH

↓GnRH

↑ACTH

↑Corticol

↑Somatostatin

-

Inherited Genetic DefectsInherited Genetic Defects

1- Amenorrhea and Anosmia , kallmann’s syndrome.1- Amenorrhea and Anosmia , kallmann’s syndrome.2- Molecular Explanations for Hypogonadotropic Amenorrhea. 2- Molecular Explanations for Hypogonadotropic Amenorrhea. 3-Adrenal Hypopasia.3-Adrenal Hypopasia.

Postpill AmenorrheaPostpill AmenorrheaHormone TherapyHormone Therapy::

The patient who is hypoestrogenic and who is not a candidate The patient who is hypoestrogenic and who is not a candidate for induction of ovulation deserves hormone therapy.for induction of ovulation deserves hormone therapy.

This includes patients appropriately and diagnosed as having This includes patients appropriately and diagnosed as having gonadal failure, patients with hypothalamic amenorrhea , and gonadal failure, patients with hypothalamic amenorrhea , and postgonadectomy patients.postgonadectomy patients.

* *periodic measurements of bone density are worthwhile to assess adequacy of periodic measurements of bone density are worthwhile to assess adequacy of hormonal treatment and to provide evidence of lifestyle and dieting changeshormonal treatment and to provide evidence of lifestyle and dieting changes..

It is not enough to provide hormone therapy when It is not enough to provide hormone therapy when disturbed mensrual function is secondary to disturbed mensrual function is secondary to psychobiologic stress responses. appropriate support and psychobiologic stress responses. appropriate support and counseling are necessary to help patients develop coping counseling are necessary to help patients develop coping mechanisms other than extreme dieting and exercise. mechanisms other than extreme dieting and exercise.

All available skills and resources should be utilized to All available skills and resources should be utilized to promote healthy attitudes and healthy behaviors. promote healthy attitudes and healthy behaviors.

The presence of amenorrhea in athletes and recreational The presence of amenorrhea in athletes and recreational exercisers should be regarded as a sign of negative exercisers should be regarded as a sign of negative balance, a condition requiring appropriate interventions.balance, a condition requiring appropriate interventions.

NoteNote::

Thank you and Thank you and best regardsbest regards