APPROACH TO PATIENTS WITH AMENORRHEA

Enrico Gil C. Oblepias, MD, FPOGSAssociate Professor University of the Philippines Philippine General Hospital

INTRODUCTION

Menstruation is the: • physical herald to physiologic capacity for

conceiving • monthly prepares the uterus for implantation• shedding of the uterine lining at the end of

the reproductive cycle

Amenorrhea is the: • absence of menstruation• is met with some extent with anxiety.

INTRODUCTION

FIRST STEP

Ask when the last menses were.

This will systematically cut downdifferentials to a more manageable andeconomical number.

Dichotomously dividing these into primaryand secondary cases of amenorrhea.

AMENORRHEA

Never had menses?

Primary amenorrhea: Failure of menarche to occur when expected

in relation to the onset of pubertal development.

No menarche by age 16 years with signs of pubertal development.

No onset of pubertal development by age 14 years.

Secondary amenorrhea:Absence of menstruation for 3 or more monthsin a previously menstruating women ofreproductive age.

Used to have menses?

AMENORRHEA

HPO AXIS

The menstrual cycle is actually 3 different inter-related cycles synchronously taking place at the same time.

These are:

(1) the ovarian cycle

(2) the hormonal cycle

(3) the endometrial cycle.

Amenorrhea is only a manifestation of the problem.

HPO AXIS

Problem may be endocrinologic or embryologic:

+/- secondary sexual characteristics

+/- female internal genitalia

PRIMARY AMENORRHEA

Quick Rules to Remember

No breast – no or low estrogen< FSH, LH – hypothalamic or pituitarian> FSH, LH – ovarian

No uterus 46XX –Mullerian agenesis 46XY – Pseudohermaphroditism

PHYSICAL EXAM

Primary Amenorrhea Without breast With breast

Without uterus Category 3 Category2

With uterus Category 1 Category 4

PHYSICAL EXAM

Category 1: Breasts Absent and Uterus Present

– Think low estrogen, check FSH

A. Gonadal failure: High FSH (hypergonadotropic)

1. 45X (Turner’s Syndrome)2. 46X; abnormal X (Deletion Disorders)3. Mosaicism (X/XX, X/XX/XXX)4. Pure XX (PGD, 46XX or Perrault syndrome ) 5. 17 alpha-hydroxylase deficiency (46XX)

PRIMARY AMENORRHEA

Category 1: Breasts Absent and Uterus Present

– Think low estrogen, check FSH

B. CNS-hypothalamic pituitary disorders: Low FSH (hypogonadotropic)

1. CNS lesions2. Inadequate GnRH – Kallmann’s3. Isolated gonadotrophin insufficiency

PRIMARY AMENORRHEA

High

Blood Pressure

Normal High

45 X46 X, abn X

MosaicPure gondal Dysgenesis

w/ 26 XX or 46 XY

17 alphaHydroxylaseDeficiency (Congenital

Adrenal Hyperplasia)

Karyotype

Serum FSH

HypergonadotropicHypogonadism

CT scan, Prolactin

HypogonadotropicHypogonadism

Normal High

Non-prolactinSecreting tumor

of the CNSInadequate

GnRH

PituitaryAdenoma

Low or Normal

Category 1: Breasts Absent and Uterus Present

Category 2: Breasts Present and Uterus Absent

– Think (+) estrogen, (?) MIF: check karyotype

A. Mayer Rokitansky Kuster Hauser Syndrome (46XX) vaginal agenesis and no uterus caused by random birth defect

B. Androgen Insensitivity Syndrome (46 XY)

cells are not receptive to testosterone thus patient has intra-abdominal testes and no uterus or vagina

PRIMARY AMENORRHEA

Karyotyping Testosterone

46XX Normal

46XY High

Congenital Absence of theUterus

Androgen Insensitivity(Testicular Feminization)

Category 2: Breasts Present and Uterus Absent

Category 3: Breasts Absent and Uterus Absent

– This is rare.– Think low estrogen and (+) MIF: check a karyotype

A. 17, 20-Desmolase deficiency (46 XY) B. 17 alpha hydroxylase deficiency (46 XY) C. Pure XY (PGD, 46XY or Swyer’s Syndrome)D. Agonadism

PRIMARY AMENORRHEA

Karyotype (XY)Laparoscopy

testes present

testes absent

Enzyme Deficiency:17, 20 desmolase17 - Hydroxylase

(with XY karyotype)

Agonadism

Category 3: Breasts Absent and Uterus Absent

Category 4: Breasts Present and Uterus Present

–Think (+) estrogen, (-) MIF– Evaluate like secondary amenorrhea

A. Hypothalamic causesB. Pituitary causesC. Ovarian causesD. Uterine causes and outflow tract causes (?)

PRIMARY AMENORRHEA

Prolactin

Normal High

Hypothalamic causes Pituitary causes Ovarian causes Uterine causes Outflow tract disorders

Pituitary Lesion(Prolactinoma)

Category 4: Breasts Present and Uterus Present

Cryptomenorrhea

Despite the absence of menstrual flow, withdrawal bleeding does take place – albeit concealed.

intermittent abdominal painpossible difficulty with micturitionpossible lower abdominal swelling

- imperforate hymen- transverse vaginal septum with functioning uterus- isolated vaginal agenesis with functioning uterus - isolated cervical agenesis with functioning uterus

Cryptomenorrhea

CNS; HP Disorder

Gonadal Failure

History and physical examination completed for a patient with primary amenorrhea

Secondary sexual characteristics present

No Yes

Measure FSH and LH levels

Uterus absent or abnormal

Uterus present or normal

Karyotype analysis Outflow obstruction

FSH and LH < 5 IU/ L

Hypogonadotropic hypogonadism

Hypergonadotropichypogonadism

Karyotype analysis 46, XY 46, XX

Mullerian Agenesis

Androgen Sensitivity Syndrome

NoYes

Evaluate for secondary amenorrhea

Imperforate hymen or transverse vaginal septum

Perform ultrasonography of uterus

Evaluation of Primary Amenorrhea

FSH > 20 IU/ L and LH > 40 IU/ L

Hypothalamus :25-35%

PCOS: 20-25%

Ovarian : 12%

Hyperprolactinemia : 13%

Pituitary : 7-16%

Uterine : 7%

other

SECONDARY AMENORRHEA

In women of reproductive age, pregnancy is the most common cause of secondary amenorrhea.

Pregnancy

The reality of this must be ascertained before any intervention is instituted for non-obstetric amenorrhea.

Give them a progestin challenge to induce menstruation.

Dichotomously dividing secondary cases of amenorrhea to those with and without estrogen priming of the endometrium

SECONDARY AMENORRHEA

10mg of progesterone orally for 5- 10 days

A withdrawal bleed occurring within ten days of a progesterone challenge is a positive result and a diagnosis of anovulation may be established.

PROGESTERONE CHALLENGE TEST (PCT)

POSITIVE • HP Dysfunction• Hyperthyroidism • PCOS

PROGESTERONE CHALLENGE TEST (PCT)

NEGATIVE • Hyperprolactenemia• Hypothyroidism• Hypopituitarism • POF• Asherman’s

Hypothalamic-Pituitary Dysfunction• can result from any condition that disturbs the

HPO axis• the immediate cause is a decrease or lack of

GnRH pulses• this may be idiopathic, or may be the result of

stress or weight loss • anorexia (most common cause of secondary

amenorrhea in teenagers)

POSITIVE PCT

Hyperthyroidism• although the sex binding globulin is increased,

testosterones and estrogen are also increased • relatively, compared to normal, there is more

circulating free estrogen and free testosterone with testosterone being converted further peripherally to estrogen

• the elevated estrogen concentration then leads to state similar to anovulation

POSITIVE PCT

Polycystic Ovaries Syndrome• a persistent anovulatory state • result in a steady supply of estrogen and the lack

of progesterone’s anti-estrogen effect • brings about continuous stimulation of the receptive

endometrium • the most common endocrinopathy in reproductive-

age women and amenorrhea or oligomenorrhea is quite frequent

POSITIVE PCT

Hyperprolactenemia• elevated levels of prolactin inhibits GnRH by

increasing the release of dopamine from the arcuate nucleus of the hypothalamus

• inhibiting gonadal steroidogenesis, which is the hypoestrogenism

• may be caused by either compression of the pituitary or excess production from a pituitary gland adenoma

NEGATIVE PCT

Hypothyroidism• alpha subunits of LH, FSH, and TSH are identical

and only vary in their beta subunits • a cross-reaction between the TSH, FSH, LH leads

to a negative feedback suppressing the release of FSH and LH affecting follicular maturation and ovulation

• the endometrium fails to go through the proliferation and secretory phases resulting in the absence of menstruation.

• stimulation of the anterior pituitary leading to an increased release of prolactin has also been considered

NEGATIVE PCT

Hypopituitarism• caused by necrosis of the anterior pituitary due to

blood loss and hypovolemic shock• Sheehan’s syndrome if obstetric in origin• Simmond’s syndrome if non-obstetric• FSH and LH become deficient and lead to the lack

of menstruation

NEGATIVE PCT

Premature Ovarian Failure• is an end organ phenomenon • occurring before the age of 40• characterized by (1) lack of ovarian response to

tropic stimulation; (2) lack of gonadal negative feed-back; (3) elevated circulating levels of FSH and LH

• pathogenesis of this disorder has not been determined

• it is possible that there is an autoimmune basis for this

NEGATIVE PCT

Asherman’s Syndrome• is characterized by the formation of scar tissues

obliterating the endometrial cavity that prevents the occurrence of normal menstrual periods

• occurs most frequently after a vigorous scraping during completion curettage

• can also result from other pelvic surgeries like cesarean sections, myomectomies, pelvic irradiation, schistosomiasis and genital tuberculosis

• cervical stenosis after a cone biopsy or LEEP

NEGATIVE PCT

Medroxyprogesterone acetate(5-10 mg BID for 5 days)

Uterine Bleeding No Uterine Bleeding

Step 2 Step 3

STEP 1: Evaluation of Secondary Amenorrhea

Uterine bleeding: positive responseLH

High(>25mIU/ml)

Normal or Low

Testosterone (Ovarian)DHEAS (Adrenal)

Ultrasound

HypothalamicDysfunction

(drug, stress or exercise, weight

loss)

Polycystic OvarianSyndrome

Prolactin

Normal HighInduce bleeding monthly with progestins,

oral contraceptives; Dexamethasone Spironolactone Induce uterine bleeding

monthly with DMPA 10 mg/day for 12 days

Work-up for hyperprolactinemia

Hyperthyroidism

TSH

STEP 2: Evaluation of Secondary Amenorrhea

No uterine bleeding: negative response

FSH

PrematureOvarian Failure

HypothalamicPituitaryDisorder

High (>30 mIU/ml)Normal or Low

TSH (hypothyroidism)Prolactin

(hyperprolactinemia)CT scan of CNS

If < 25 years old; karyotypeIf < 35 years old; antinuclear

antibodies, 24 hr urine cortisol test

NegativeEstrogen

Progesterone test

Asherman’sSyndrome

HSGHysteroscopy

STEP 3: Evaluation of Primary Amenorrhea

GENERAL PRINCIPLES OF MANAGEMENT OF AMENORRHEA

1. attempts to restore ovulatory function by treating underlying cause

2. if not possible, HRT (estrogen and progesterone) is given to hypo-estrogenic amenorrheic women

3. periodic progestogen may be given instead for anovulatory women

4. if Y chromosome is present gonadectomy is indicated

5. create outflow tract or at least a sexually functional vagina

6. many cases require frequent re-evaluation

Amenorrhea may be caused by any of the many differentials discussed herein. The appropriate management of this will depend on the accurate diagnosis of the etiology. A logical approach makes it possible to do it systematically and in a shorter period of time.

Some conditions may be correctable while others are not. Objectives of treatment may vary, but the underlying cause in each must be addressed at the very least every time.

CONCLUSION