chapter 27. amenorrhea berek & novak’s gynecology 14 th edition (p 1035~1068) r3 jung mi byun

Chapter 27. Amenorrhea

Berek & Novak’s Gynecology

14th edition (p 1035~1068)

R3 Jung Mi Byun

Overview

Primary amenorrhea

: absence of menses

– at age 13years when there is no visible secondary sexual characteristic development

– at age 15years in the presence of normal secondary sexual characteristics

Secondary amenorrhea– A woman who has previously menstruated– absence of menstruation for three normal menstrual cycles

or 6 months

Overview

Premature gonadal failure occurs in conjunction with primary amenorrhea – associated with genetic abnormalities (30%)

Diagnosis – History – Physical examination

• 2nd sexual characteristics • anatomic abnormalities (relatively few)

– Lab • hCG• FSH (differentiate between hypergonadotropic and hypogonatropic forms of hypogonadism)

Overview

Treatment

<Goal >– correcting the primary cause of amenorrhea– to initiate and maintain secondary sexual characteristics– maintenance of bone mass– Ovulation induction for patients desiring pregnancy

Mehthod– medical or surgical therapy– hormone replacement

Overview

Normal menstrual cycle

Posterior arcuate nucleusAnterior suprachiasmatic nucleus

Overview

Amenorrhea Mechanism– any of the components : nonfunctional

→ bleeding cannot occur. (Amenorrhea)

Amenorrhea : 3~4% of reproductive age women, not pregnant.

hypothalamus, pituitary, ovary, outflow tract, feedback mechanism

Decision tree for evaluation of amenorrhea.

Physical exam

) No Yes

High Normal

Karyotype Karllman’s syndromePhysiology delayDisorders of low

estrogen status

before puberty

XXY lineTurner’s (XO)

Secondary sexual

characteristics

Absent Present

Normal

FSH level

Absent uterus

•5α-reductase deficiency•17-20 desmolase deficiency•17α-hydroxylasedeficiency (all with XY karyotype)

HCG +

PregnancyPrimary

HCG -

Primary

No Yes

Secondary if risk of

endometial scarring

advise HSG &

culrutres to exclude

Asherman’s, cervical

stenosis and infection

Physical exam

Normal Abnormal

TSH, PRL, FSH,

Clinical evaluation of estrogen status

Mullerian anomalyAndrogen insensitivityTrue hermaphroite

Normal TSH Abnormal TSH

High PRL HyperthyroidismHypothyroidism

Normal PRL Hyperprolactinemia

Normal PRL

Normal FSH High FSH

Normal estrogen Low estrogen Ovarian failure-

chromosomal

radiaton

chemotherapy

infection

autoimmuneGalactosemiaSavage syndromeIdiopathic

Chronic anovulatory

Polycystic ovarian

syndrome

Idiopathic

Ovarian neoplasm

Grandulosa cell

androgen-

secreting

Feedback disorders Obesity Cushing’ syndrome Androgen-secreting

adrenal tumors Congenital adrenal

hyperplasia

Neurological exam

CT/MRI, EEG

Normal Abnormal

Chronic disease

pulmonary

renal

liver

diabetesAddison’s disease

Hypothalamic

dysfunction AnorexiaExercise-inducedStressPseudocyesisMalnutrition

Pituitary-hypothalamic

lesions

tumors

infection

infarction

pituitary failure

Sheehan’sDiabetic vasculitisToxic-lead

Amenorrhea

without Secondary Sexual Characteristics

Amenorrhea

with Secondary Sexual Characteristics

and Anatomic Abnormalities

Amenorrhea without Secondary Sexual

Characteristics

Absence of secondary sexual characteristics

(breast development : 1st sign of estrogen exposure in puberty)

→ woman has never been exposed to estrogen stimulation

Absence of a uterus suggests certain enzyme deficiencies and indicate the presence of antimullerian hormone (AMH) in an XY individual .

Cause of Primary Amenorrhea

Hypergonadotropic Hypogonadism– Genetic Disorders– Enzyme Deficiencies– Gonadotropin Receptor Mutation

Other causes of Primary Ovarian Failure

Hypogonadotropic Hypogonadism

Genetic Disorders

Other Hypothalamic / Pituitary Dysfunctions

Table 27.1 Amenorrhea Associated with a Lack of Secondary Sexual Charateristics

Abnormal physical examination

5α-reductase deficiency in XY individual

17, 20-desmolase deficiency in XY individual

17α-hydroxylase deficiency in XY individual

Hypergonadotropic hypogonadism

Gonadal dysgenesis

Pure gonadal dysgenesis

Partial deletion of X chromosome

Sex chromosome mosaicism

Environmental and therapeutic ovarian toxins

17α-hydroxylase deficiency in XX individual

Galactosemia

Other

Hypogonadotropic hypogonadism

Physiologic delay

Kallmann’s syndrome

Central nervous system tumors

Hypothalamic/pituitary dysfunction


Hypergonadotropic Hypogonadism LH, FSH ↑ : d/t decreased negative estrogen feedback.

Associated with genetic abnormalities

(Approximately 30% of patients with primary amenorrhea)

Syndrome of gonadal dysgenesis or Turner syndrome

Other disorder : – structurally abnormal X chromosomes,– mosaicism, – pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks),– enzyme deficiencies that prevent normal estrogen production,– Gonadotropin-receptor inactivating mutations


Hypergonadotropic Hypogonadism Genetic Disorder

Gonadal Dysgenesis Turner syndrome(45,X)

:m/c chromosomal abnormality causing gonadal failure and primary amenorrhea

P.Ex– short stature, webbed neck– shield chest,– cubitus valgus – short metacarpals, – low hair line,– high arched palate, – multiple pigmented nevi, – short fourth metacarpals

Study– cardiac (30%: coarctaion of the aorta)– renal (horseshoe kidney),– autoimmune(thyroiditis)



Abnormal X Chromosome– 46, XX individuals with partial deletions of the X chromosome

: variable phenotypes depending on the amount and location of

the missing genetic material

– Deletion of the long arm of the X chromosome(Xq-) Xq13~Xq26

- sexual infantilism

- normal stature

- no somatic abnormalities, no streak gonads

- eunuchoid in appearance, delayed epiphyseal closure (some)

– Deletion of the short arm of the X chromosome (Xp)

: phenotypically similar to individual with Turner syndrome



Mosaicism

– 45,X/46XX (m/c)– Clinical finding :taller and fewer abnormalities than pure 45,X– 20% : spontaneous menstruation (+)



Pure Gonadal Dysgenesis– Phenotypically female with sexual infantilism, – primary amenorrhea, – normal stature, – no chromosomal abnormalities (46, XX or 46, XY)– Gonads

: usually streaks, some development of 2nd sexual characteristics

< Swyer syndrome >– mutations in the SRY (sex-determining region gene on the Y

chromosome) located at Yp11 result in XY females with

gonadal dysgenesis– 15~20% of women (46,XY)



Mixed gonadal dysgenesis– XY

– Ambiguous genitalia with a streak gonad on one side and a malformed testis on the opposite

– SRY gene mutation (small proportion )


Hypergonadotropic Hypogonadism Enzyme deficiencies

Congenital Lipoid Adrenal Hyperplasia

– Autosomal recessive disorder

– Cholesterol → Pregnenolone

– Not defect of the P450scc gene

– 15 different mutations in the steroidogenic acute regulatory protein(StAR) : facilitates the transport of cholesterol from the outer to the inner mitochondrial membrane.

– hypoNa, HyperK, acidosis in infancy

– XX, XY(m/c) – no uterus

– phenotype : female

– Genetic cluster : Japanes/Korean and Palestinian Arab population

– Tx :mineralocorticoid and glucocorticoid replacement



17α-Hydroxylase & 17, 20-Desmolase Deficiency

– mutation in the CYP 17 gene

→ abnormalities in both the 17 α-hydroxylase and 17, 20-desmolase functions of the protein

– Karyotype : 46, XX 46,XY

(no uterus)

– primary amenorrhea, no 2nd sexual characteristic, female phenotype, HTN, hypoK,

– ACTH ↑

– Meneralocorticoid production ↑

→ Na retension, K loss, HTN

– Primordial follicle

– Gonadotropin ↑



Aromatase Deficiency

– Autosomal recessive abnormality

– Androgen estrogen

– Most mother of affected children

: become virilized during pregnancy. → suspected before birth.

– At birth

: female child-clitoromegaly and posterior labioscrotal fusion

– At puberty

: no breast development,

primary amenorrhea,

worsening virilization .

absent growth spurt,

delayed bone age,

multicystic ovaries Tx : estrogen supply


Aromatizing

Hypergonadotropic Hypogonadism Gonadotropin receptor Mutations

Luteinizing Hormone Receptor Mutation – Inactivation of LH receptors has been identified in XY pseud

ohermaphrodites with primary amenorrhea in the absence of secondary sexual characteristics

– caused by homozygous premature stop codon, deletions, and missense mutations in the LHR gene located on chromosome 2.

Follicle-stimulating Hormone receptor Mutation – Autosomal recessive – single amino acid substitution in the extracellular domain of

the FSH receptor– Primary or early secondary amenorrhea, – variable development of secondary sexual characteristics– high levels of FSH and LH


Other Causes of Primary Ovarian Failure

Irradiation

Chemotherapy

with alkylating agents (e.g. cyclophosphamide)

Combination of radiation and other chemothrapeutic agents

Galactosemia



Hypothlamus fails to secrete adequate amounts of GnRH

Pituitary disorder associated with inadequate production or release of pituitary gonadotropins is present.



Physical Delay

Kallmann Syndrome

Central Nervous System Tumors


Hypogonadotropic HypogonadismPhysiologic Delay

most common manifestation of hypogonadotropic hypogonadism

Amenorrhea

: result from the lack of physical development caused by delayed

reactivation of the GnRH pulse generator

physiologic delay of puberty are usually short for their chronologic age

normal for their bone age


Hypogonadotropic HypogonadismKallmann Syndrome

2nd most common hypogonadotropic hypogonadism

insufficient pulsatile secretion of GnRH (Kallmann syndrome), which has varied modes of genetic transmission

→ leads to deficiencies in FSH and LH

caused by developmental or genetic defects, inflammatory processes, tumors, vascular lesions, or trauma

normal height for their age,


Genetic Disorders

5α-Reductase Deficiency

Gnoadotropin-releasing Hormone Receptor Mutations

Follicle-stimulating Hormone Deficiency


Genetic Disorders 5α-Reductase Deficiency

XY , virilization at puberty,

Testes(+) : functioning Y chromosomes

No mullerian structure, d/t functioning AMH

Low gnoadotropin level

D/Dx> androgen insensitivity : not develop breasts at puberty

gonadotropin level: low

male differentiation of the urogenital sinus and external genitalia : not

Normal internal male genitalia (derived from the wolffian ducts using testosterone)

Male pattern hair growth, muscle mass, voice deepening


5 α-Reductase Deficiency

Genetic Disorders Gonadotropin-releasing Hormone Receptor Mutations

GnRH receptor : G-protein-coupled receptor

Abnormal GnRH function

17% of sporadic cases of idiopathic hypogonadotropic

hypogonadism with normal olfaction


Genetic Disorders Follicle-stimulating Hormone Deficiency

FSH deficiency

: treatment for delayed puberty and primary amenorrhea caused

hypoestrogenism.

FSH↓ LH ↑ : distinguished from other hypoestrogenism

Low serum androgen levels

: FSH-stimulated follicular development is prerequisite for thecal cell androgen production


Other Hypothalamic / Pituitary Dysfunctions

Malnutrition

Malabsorption

Weight loss

Anorexia nervosa

Excess ecercise

Chronic disease

Neoplasia

Marijana

Hypothyroidism

Polycystic ovarian syndrome (PCOS)

Cushing syndrome

Hyperprolactinemia

infiltrative disorders of the central nervous system


Diagnosis

Treatment

Amenorrhea without Secondary Sexual

Characteristics

Diagnosis

History– short stature but consistent growth rate, – a family history of delayed puberty, – normal physical findings

(including assessment of smell, optic disks, and visual fields)

– Headache, – visual disturbance, – short stature, symptoms of diabetes insipidus, – weakness of limbs – Galactorrhea

Physical Examination

Physical delay

CNS lesion

Amenorrhea without Secondary Sexual Characteristics

Diagnostic workup

History& P.Ex (-)

FSH

↑

(Hypergonadotropic hyporogonadism)

↓

(hypogonadotropic hypogonadism)

Karyotype

Abnormal Turner syndrome Partial deletion of the X

chromosome, mosaicision, Pure gonadal dysgenesis, Mixed gonadal dysgenesis

Normal

17-α hydroxylase deficiency

•Serum Progesterone↑(>3.0)

•17α-hydroxyprogesterone↓ (0.2ng/mL)

•Deoxycorticosterone (DOS)↑

→ ACTH stimulation test

: ACTH bolus administration

→S-progesterone↑

→17α-hydroxyprogesterone ( - )

Coarctation of the aorta (30%)Thyroid dysfunction → Echocardiography : every 3~5yrs→ TFT : yearlyEvaluation for hearing loss and hypertension


Diagnostic workup

if galactorrhea, headaches, visual field defect (+)

→ CT, MRI

Physiologic delay – distinguish from insufficient GnRH secretion – history– absence of a CNS lesion on CT or MRI– X-ray : delayed bone age

Gonadotropin-deficiency– distinguished from physiologic delay

: response to GnRH stimulation

Physiologic delay Gonadotropin-deficiency

LH : normal LH and FSH ↓


Treatment of Amenorrhea

All forms of gonadal failure

Hypergonadotropic hypogonadism

→ cyclic estrogen and progestin therapy

: to initiate, mature, and maintain 2nd sexual characteristics

prevention of osteoporosis (additional benefit of estrogen)



Initiation conjugated estrogen 0.625mg/day

(Premarin ) or estradiol 1mg/day (Progynova )

short stature : higher estrogen doses (x) normal stature : higher estrogen,

after then reduced to the

maintenance doses after

several months

estrogen +progestin (medroxyprogesterone acetate) (Provera ) daily or

progesterone

to prevent unopposed estrogen stimulation

of the endometrium in patients with uterus

Medrosyprogesterone acetate 2.5mg daily or 5~10mg for 12~14days every

1~2months

Oral micronized progesterone

(utrogestan ) 100mg daily or 200mg for 12~14days every

1~2months

Progesterone suppositories

(progest ) 50mg daily or 100mg 12~14days every

1~2 months

R

R

R

R

R



Mosaicism and gonadal streak

: ovulation (+), able to conceive either spontaneously or after

the institution of estrogen replacement therapy

17α –hydroxylase deficiency– corticosteroid and estrogen replacement– If uterus(+) : progestin supply


Treatment of Amenorrhea Aim of therapeutic measures

: correcting the primary cause of amenorrhea

– Craniopharyngiomas

: resected with a transphenoidal approach or during craniotomy depending on the size of the tumor

– Germinomas

: radiosensitive ( surgery : rare indication )

– Prolactinomas and hyperprolactinemia

: dopamine agonists (bromocriptine or cabergoline)

– malnutrition, malabsorption, weight loss, anorexia nervosa,

exercise amenorrhea, neoplasia, and chronic disease

: specific therapies


Treatment of Amenorrhea Aim of therapeutic measures

: correcting the primary cause of amenorrhea

– Hypogonadotropic hypogonadism of hypothalamic origin - treated with long-term administration of pulsaile GnRH indwelling catheter

and a portable pump

- cyclic estrogen and progestin therapy at least until sexual maturity is

achieved

- hormone replacement to treat hypoestrogenic symptom

- nonestrogenic regimens

eg. Bisphosphomates

(for maintenance of bone mass and prevention of osteoporosis)

– Kallmann syndrome : hormone replacement

– Physiologic delay

: reassurance that the anticipated development will occur eventually



Karyotypes contain a Y cell line

(45,X/46, XY mosaicism, or pure gonadal dysgenesis 46, XY)

– Predisposed to gonadal ridge tumor,

such as gonadoblastomas, dysgerminomas, yolk sac tumors

→ remove gonads to prevent malignant transformation


Causes

– Anatomic Abnormalities

– Androgen insensitivity

– True Hermaphroditismm

Amenorrhea with Secondary Sexual

Characteristics and Anatomic Abnormalities

Anatomic AbnormalitiesCause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities

Secondary sexual characteristics present

Mullerian anomalies

Imperforate hymen

Transverse vaginal septum

Mayer-Rokitansky-Kuster-Hauser syndrome (MRK syndrome)

Androgen insensitivity

True hermaphrodites

Absent endometrium

Asherman’s syndrome

Secondary to prior uterine or cervical surgery

Curettage, especially postpartum

Cone biopsy

Loop electroexcision procedure

Secondary to infections

Pelvic inflammatory disease

IUD-related

Tuberculosis

Schistosomiasis

Anatomic causes of Amenorrhea

Anatomic Abnormalities

Mayer-Rokistanky-Kuster-Hauser(M.R.K.H.) syndrome XX, female result of the mullerian ducts failing to form properly early in embryonic de

velopment, its underlying cause is unknown. associated with galactose metabolism characterized by congenital absence of the uterus and vagina associated with

– anomalies of the kidneys ranging from ectopic to congenital absence,

– skeletal abnormalities

Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities

Androgen Insensitivity

Gynotype : XY

Phenotype : female

Male pseudohermaphrodites

(Previously called testicular feminization )

Defects in the androgen receptor

: gene located on the X chromosome

- absence of the gene that encodes for the androgen receptor

- abnormalities in the binding domains of the receptor



Develop secondary sexual characteristics but not menses

Testosterone : range of normal males

☜ antimullerian hormone: present and function (+)

Internal female (mullerian) structure

(uterus, vagina, fallopian tube) : (-)

Testes (+) in the abdomen or in inguinal hernias

: normally functioning genes on the Y chromosome



Blind vaginal pouch and scant or absent axillary and pubic hair

Abundant breast development at puberty

nipples : immature areolae : pale

Eunuchoidal tendency

(long arms with big hands and feet)


Figure 27. 2

A : A well-developed patient with complete androgen insensitivity

Note the characteristic paucity of pubic hair and well-developed breast

B : Another patient with andtrogen insensitivity syndrome with a contrasting thin

body hiatus. This is a 17-uear-old twin 46,XY.

True Hermaphroditism

XX, XY and mosaic genotypes

Both male and female gonadal tissue ( +)

External genitalia : ambiguous

Breast development (+)

15% of XX true hermaphrodites : have SRY translocation

10% of XX true hermaphrodites : have Y chromosomal

mosaicisism within the gonad


Diagnosis

Treatment

Amenorrhea with Secondary Sexual

Characteristics and Anatomic Abnormalities

DiagnosisPhysical Examination Others

Imperforate hymen presence of a bulging membrane that distend during Valsalva maneuver

USG or MRI : useful

skeletal malformation exam

IVP for renal abnormalities

Transverse septum or

complete absence of the cervix and uterus in a female

blind vaginal pouch in a male pseudohermaphrodite : difficult to differentiate

karyotype determination

(Y chromosome)

Absent endometrium not diagnosed by P.Ex Evaluation of endocrine abnormalities

(estrogen & progesterone

challenge test)

Asherman syndrome not diagnosed by P.Ex HSG,

saline infusion

USG

Hysteroscopy

Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities

Treatment Imperforate hymen

: making a cruciate incision to open the vaginal orifice

Transverse septum : surgical remove

Hypoplasia or absence of the cervix in the presence of a functioning uterus

: surgery to repair the cervix : not successful

→ hysterctomy is required

Vagina : absent or short

: progressive dilation is usually successful in making it

functional


Treatment

Complete androgen insensitivity

: testes removed after pubertal development is complete to prevent

malignant degeneration

Asherman syndrome– removed using hysteroscopic resection with scissors or electro

cautery – pediatric foley catheter : placed in the uterine cavity for 7~10da

ys postop – a 2-month course of high –dose estrogen therapy with monthly

progesterone withdrawal is used to prevent reformation of adhesions


Cause

Ovarian failure

Pituitary / Hypothalamic Lesions

Altered Hypothalamic Gonadotropin –releasing Hormone secretion

Weight Loss and Dieting

Cause

Anorexia Nervosa

Exercise

Stress-induced Disorder

Obesity

Other Hormonal Factors

Amenorrhea with Secondary Sexual Characteristics an

d Nonanatomic Causes

Ovarian Failure

Amenorrhea with 2nd sexual characteristics and Nonanatomic causess

Chromosomal etiology

Iatrogenic Causes

Radiation

Chemotherapy

Surgical alteration of on blood supply

Infections

Autoimmune disorders

Galactosemia (mild form or heterozygote)

Savage syndrome

Cigarette smoking

Idiopathic

Causes of Ovarian failure after Development of Secondary Sexual Chracteristics

Normal : menopause– Age of menopause : determined by genetic inheritance

Premature ovarian failure – ovarian failure <40years (1~5% of women)– cause : decreased follicular endowment or accelerated

follicular atresia

Ovarian Failure


Ovarian FailureCause

Cigarette smoking– Alters both gametogenesis and hormonogensis – Inverse dose-response relationship with age of menopause

Sex chromosome disorders– Deletion of the X chromosome (Turner syndrome)

: associated with premature ovarian failure despite normal

development of the ovaries– d/t accelerated atresia of the follicles



Fragile X carriers– Cause of inherited (X-linked) mental retardation – 4-5% of premature ovarian failure– If premature ovarian failure is present in another family member, the chan

ce of finding a premutation increases to 15%

Iatrogenic causes– radiation,

sterility dose : 800cGy,

ovarian failure :150cGy in some pts. esp. >40yrs – chemotherapy (esp. alkylating agents : cyclophosphamide)– surgical interference with ovarian blood supply, – infection



Infections– Mumps– Tubo-ovarian abscess

: follicular destruction and premautre ovarian failure

Autoimmune Disorders– Part of a polyglandular autoimmune syndrome– Myasthenia gravis,– Idiopathic thrombocytopenia purpura (ITP)– Rheumatoid arthritis,– Vitiligo,– Autoimmune hemolytic anemia– Diabetes mellitus– Other autoimmune disorder



Lack of functional galactose-1-phosphate uridyl transferase (GALT) Galactose metabolites : toxic effects on ovarian follicles causing premature destruction associated cataracts, MR


Galactosemia


Savage syndrome– Gonadotropin resistance, – Likely d/t FSH receptor dysfunction– High level of FSH and LH levels– Biopsy : not advised

Autosomal gene mutations– Associated with hearing loss in Perrault syndrome




Pituitary and Hypothalamic Lesions

Pituitary and Hypothalamic

Craniopharyngioma

Germinoma

Tubercular granuloma

Sarcoid granuloma

Dermoid cyst

Pituitary

Nonfunctioning adenoma

Hormone-secreting adenomas

Prolactinoma

Cushing’s desease

Acromegaly

Primary hyperthyroidism

Infarction

Lymphocytic hypophysitis

Surgical or radiologic ablations

Sheehan’s syndrome

Diabetic vasculitis


Hypothalamic Tumors

Craniopharyngiomas (m/c), Germinomas, Tubercular or sarcoid granulomas, Dermoid cysts

→ prevent appropriate hormonal secretion



Pituitary Lesions

Hypopituitarism : rare

: d/t large portion of the gland must be destroyed before decreased

hormonal secretion affects the patient clinically

– Gland destroyed by tumors (nonfunctioning or hormone secreting)

– Infarction

– infiltrating lesions such a lymphocytic hypophysitis, granulomatous lesions, and surgical or radiologic ablations



Pituitary Lesions

Sheehan syndrome

– Associated with postpartum necrosis of the pituitary resulting from a hypotensive episode

– Pituitary apoplexy : severe form

– Severe : retro-orbital headache or abnormalities in visual fields and visual acuity

– Mild : not lactate, lose pubic and axillary hair, not menstruate after delivery



Pituitary Lesions

Diabetic vasculitis and sickle cell anemia

Prolactinomas


Altered Hypothalamic Gonadotropic-releasing Hormone Secretion


Abnormalities Affecting Release of Gonadotropin-Releasing Hormone

Variable estrogen status Euestrogenic states

Anorexia nervosa Obesity

Exercise-induced Hyperandrogenism

Stress-induced Polycystic ovary syndrome

Pseudocyesis Cushing’s syndrome

Malnutrition Congenital adrenal hyperplasia

Chronic diseases Androgen-secreting adrenal tumors

Diabetes mellitus Androgen-secreting ovarian tumors

Renal disorders Granulosa cell tumor

Pulmonary disorders Idiopathic

Liver disease

Chronic infections

Addison’s disease

Hyperprolactinemia

Thyroid dysfunction



GnRH : Gonadotropin releasing hormoneTRH :Thyrotropin releasing hormone CRH:corticotrophic releasing hormone,ACTH adrenocorticotrophic hormone, GHRH : Growth hormone releasing hormone


Pulsatile secretion of GnRH caries in both frequency and amplitude throughout the menstrual cycle and tightly regulated

Follicular phase

: frequency and amplitude of pulses↑

luteal phase

: frequency ↓ and amplitude↑↑↑

– pulse frequency ↓

: LH secretion ↓& FSH ↑

– Important aspect of enhancing FSH availability in late luteal phase

The pulsatile secretion of GnRH in the follicularand luteal phases of the cycle


Abnormal secretion of GnRH : 1/3 of patients with amenorrhea

Chronic disease, malnutrition, stress, psychiatric disorders, exercise

: inhibit GnRH pulses → altering the menstrual cycle.

Hyperprolactinemia, Cushing disease (excess ACTH), acromegaly (excess GH),

: secreted excess pituitary hormones → inhibit GnRH secretion

GnRH pulsatility ↓ : severe amenorrhea Less severe alterations in GnRH pulsatility : anovulation Slight defects in the pulsatility : luteal phase defect



Leptin

– hormone secreted by adipocytes that is involved in energy hemostasis

– Receptors : in the hypothalamus and bone

– correlate with nutritional changes and body mass index

– Leptin level ↓ : associated with hypothalamic amenorrhea


Weight Loss and Dieting


Loss of 10% body mass in 1year

: associated with amenorrhea

Anorexia Nervosa

Eating disorder : affects 5% ~ 10% of adolescent women in the US

Criteria for diagnosis

(Diagnostic and Statistical Manual of Mental Disorders -DSM-IV-)– Refusal to maintain body weight above 15% below normal – An intense fear of becoming fat– Altered perception of one’s body image

(ie. Patients see themselves as fat despite being underweight)– Amenorrhea


Anorexia Nervosa

Attempt to maintain their low body weight by food restriction, induced vomiting, laxative abuse, and intense exercise.

Mortality rate : 9%

Combinations of restrictive and binge eating

Binge eating : associated with bulimia consisting of vomiting, laxative abuse, and diuretics to control weight.

Signs of bulimia : tooth decay, parotid gland hypertorph (chipmunk jowls), hypokalemia, metabolic alkalosis


Exercise Decreased in the frequency of GnRH pulses

Assesed by measuring a decreased frequency of LH pulse

Hypoestrogenic state

Runners and ballet dancers > swimmer (high risk) (differences in body-fat content have been used to explain the different rates of

amenorrhea by sport)– minimum of 17% of body fat is required for the initiation of menses– 22% body fat for the maintenance of menses

Higher-intensity training, poor nutrition, stress of competition, and associated eating disorders increase an athlete’ risk for menstrual dysfunction

– Female athlete triad • amenorrhea, • osteoporosis, • eating disorder


Stress-induced Disorders

Caused by abnormalities in neuromodulation in hypothalamic

GnRH secretion(similar to those that occur with exercise and anorexia nervosa )


Obesity

>8.4% in women above 75% ideal body weight : menstrual disorder

Obese women

– Excess number of fat cells in which extraglandular aromatization of androgen to estrogen occurs

– Lower circulating levels of sex hormone-binding globulin

: allows a larger proportion of free androgens to be converted to estrone

– Excess estrogen : risk for endometrial cancer for these women.


Other Hormonal Factors

PCOS – irregular bleeding rather than amenorrhea– one of the most common causes of amenorrhea– result of peripheral alteration in IGF-1, androgen, estrogen level

s, which leads to hypothalamic dysfunction

Elevations in androgens (eg. Sertoli-Leydig, hilus and lipoid cell tumors) and estrogens (e.g. granulosa cell tumors) by ovarian tumors

: lead to abnormal menstrual patterns, including amenorrhea

Excess secretion of GH, TSH, ACTH and prolactin from pituitary gland

: cause abnormal feedback inhibition of GnRH secretion leading to amenorrhea


Diagnosis

Treatment

Amenorrhea with Secondary Sexual Characteristics an

d Nonanatomic Causes

Diagnosis

Pregnancy test (urine or S-hCG)

Pregnancy (-)

– Serum TSH

– Serum prolactin

– FSH levels

– Estrogen status

– Imaging of the pituitary and hypothalamic assessment as necessary


Diagnostic work-upPregnancy test (-)

Check TSH & prolactin level

Both normalNormal PRL

abnormal TSH

Normal TSH

Abnormal PRL

Progesterone challenge test

Thyroid disease

PRL < 100pg/mL PRL >100pg/mL

Withdrawal bleeding (+) Withdrawal bleeding(-)

Normogonadotropic hypogonadism

Estrogen /Progesteron challenge test

Consider othersPerform MRI to evaluate f

or prolactinoma

Withdrawal bleeding (+)

Withdrawal bleeding(-)

MRI (-)

Consider others

Check FSH & LH level

Outflow obstruction

FSH>20IU/L

LH > 40IU/LFSH&LH<5 IU/L

Hypergonadotropic hypergonadism

MRI to evaluate for pituitary tumor

Normal MRI

Hypogonadotropic hypogonadism


•2.5mg conjugated estrogen or 2mg micronized estradiol, for 25days with 5~10mg of MPA for the last 10days

Asherman syndrome confirmed by showing filling defects on HSG or by visualizing adhesion

s with hysteroscopy

Progesterone challenge test • medroxyprogesterone acetate, (MPA) 5mg or 10mg for 10dsys po 100~200 mg progesterone in oil IM→ withdrawal bleeding within 2~10days after the last dose• Serum estradiol > 40pg/mL

Diagnosis

Follicle-stimulating Hormone Levels

S-FSH > 25~40mIU/mL (on at least two blood samples)

: hypergonadotropic amenorrhea

Dx for cause of ovarian failure– History : chemotherapy, radiation therapy– Galactose 1 phosphate uridyl transferase (GALT) level– Fragile X carrier status– Karyotype (<30years of ages) : presence of a Y cell line– autoimmune disorder– Ovarian biopsy : not advised


DiagnosisFollicle-stimulating Hormone Levels

Extent of an autoimmune workup required for a patient with ovarian failure

– Screening with nonspecific test (ANA, RA, ESR)

– Normal PTT : exclude lupus anticoagulant

– Serum electrolytes, calcium, phosphorus concentrations : evaluate possibility that parathyroid autoantibodies are active

– TSH, antithyroglobulin antibodies, antimicrosomal antibodies

– 24hr urinary free cortisol : detect the presence of antiadrenal antibodies

– Parietal cell antibodies, islets of Langerhans antibodies and antiadrenal antibodies : unclear

→ repeated yearly d/t transient nature of autoimmune disorders


Diagnosis

Assessment of the Pituitary and Hypothalamus

Hypoestrogenic & FSH level : not high

→ pituitary and hypothalamic lesions should be excluded

– A complete neurologic examination

– CT or MRI

– After anatomic lesions have been excluded, the patient’s history of weight changes, exercise, eating habits, body image, and career or school achievements are important factors in differentiating anorexia nervosa, malnutirition, obesity or exercise-induced or stress-induced menstrual disorders.


Diagnosis

Hypothalamic dysfunction caused by chronic disease, anorexia nervosa, stress, and malnutrition – may be more severe or– may exist for a more prolonged time in hypoestrogenic

patients than in euestrogenic patients.

Appropriate clinical findings– Androgen levels (hirsutism…)– IGF-1 levels : Acromegaly – 24hr urinary cortisol

: Cushing syndrome ( truncal obesity, hypertension, erythmatous striae)


Treatment Thyroid abnormalities

: thyroid hormone, radioactive iodine, antithyroid drugs

Hyperprolactinemia

: dopamine agonists (bromocriptine or cabergoline)

Surgery for particularly large pituitary tumors

Ovarian failure : hormone replacement

Y cell line(+) : Gonadectomy

Surgical removal, radiation therapy, or a combination of both is generally advocated for treatment of central nervous tumors other than prolactinoma


Treatment

Treatment of amenorrhea associated with hypothalamic dysfunction

Hormonally active ovarian tumors : surgical removed

Obesity, malnutrition or chronic disease, Cushing syndrome and acromegaly : specially treat

Pseudocyesis and stress-induced amenorrhea : respond to psychotherapy

Exercise–induced amenorrhea : improve with moderation of activity and weight gain, when appro

priate

Anorexia nervosa : demands a multidisciplinary approach


TreatmentTreatment of amenorrhea associated with hypothalamic dysfunction

Chronic anovulation or PCOS : treated after identifying the desires of the patient (menstruation, hirsutism or infertility)

– endometrium should be protected from the environment of unopposed estrogen

– oral contraceptives or progestin

– Estrogen +progestin replacement for successful menstrual regulation and prevention of osteoporosis

Medroxyprogessterone acetate (10mg for 10days/month)

Congenital adrenal hyperplasia

: glucocorticoid administration (ie. Dexamethasone 0.5mg at bedtime)


TreatmentHirsutism

R/O androgen-secreting tumors, congenital adrenal hyperplasia

Aim of treatment : decreasing coarse hair growth

– Oral contraceptives

– Antiandrognes • Spironolactone Flutamide• Cyproterone acetate (strong progestin)

– GnRH Agonist• Add-back therapy

– 5α- reductase inhibitors

– Eflornithine hydrochloride (topical cream)


TreatmentOvulation Induction

Clomiphene citrate : 1st choice for ovulation induction

Relative safety, efficacy, route of administration (oral), relatively low cost

Indication – adequate levels of estrogen and normal FSH and prolactin, – inappropriate gonadotropin release

(an increased LH-to-FSH ratio ie. PCOS)

Pregnancy rate : 40%

Rate of expected ovulation : 80%



Clomiphene citrate : 1st choice for ovulation induction

Contraindication

: pregnancy, liver disease, pre-existing ovarian cysts

Side effects

: hot flashes(>11% of pts), poorly understood visual symptoms

Incidence of multiple gestation : 6.25~12.3%

Regimen – 50mg daily for 5days– beginning on the 3rd~5th day of menstrual or withdrawal blee

ding



Longer courses of clomiphene citrate : adjunctive therapy with glucocorticoids and hCG

PCOS : insulin resistance – insulin sensitizing agents (biguanide metformin and thiazolidinediones)

Injectable gonadotropins– FSH– Complication : multiple pregnancy (10~30%)

GnRH : chronic anovulation associated with low levels of estrogen and gonadotropins

Ovarian failure and desire pregnancy ; oocyte donation


Continual pulsatile secretion of GnRH is necessary d/t extremely short half life (only 2~4 minutes) – rapid proteolyti

c cleavage Continual infusion : gonadotropin secretion (-) downregulation - the number of gonadotroph cell surface GnRH receptor ↓ Palsatile pattern : led to physiologic secretion patterns and folli

cular growth, upregulate or autoprime - The gonadotroph to increase its number of GnRH receptors Pulsatile secretion of GnRH caries in both frequency and amplit

ued throughout the menstrual cycle and tightly regulated Follicular phase : increase in both frequency and amplitude of

pulses During luteal phase : progressive lengthening of the interval be

tween pulses and amplitude higher

chapter 27. amenorrhea berek & novak’s gynecology 14 th edition (p 1035~1068) r3 jung mi byun

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