approach to patients with amenorrhea enrico gil c. oblepias, md, fpogs associate professor...
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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 down
differentials to a more manageable and
economical number.
Dichotomously dividing these into primary
and 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 months
in a previously menstruating women of
reproductive 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 causes
B. Pituitary causes
C. Ovarian causes
D. 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 pain
possible difficulty with micturition
possible 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