8th Edition APGO Objectives for Medical Students

Amenorrhea

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RationaleThe absence of normal menstrual

bleeding may represent an anatomic or endocrine problem. A systematic approach to the evaluation of amenorrhea will aid in the diagnosis and treatment of its cause.

Objectives:The student will be able to list:

a) Definitions of primary amenorrhea, secondary amenorrhea and oligomenorrhea

b) Causes of amenorrhea

c) Evaluation methods

d) Treatment options

Definitions

Primary: No menses by age 14 yr. in the

absence of growth or development of secondary sexual characteristics

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

Secondary: In a woman who has been

menstruating, absence of menstruation for a length of time equivalent to a total of at least 3 of the previous cycle intervals, or 6 months of amenorrhea

Oligomenorrhea:

menses at intervals >35 days Normal menstrual cycle

Causes

Anything that interferes with normal sequence which culminates in menstruation, i.e. disorders of the CNS (hypothalamus), anterior pituitary, ovary, uterus or outflow tract

Causes - Pregnancy

most frequent cause of amenorrhea

Causes - Hypothalamic dysfunction

(hypogonadotropic hypogonadism) Suppression of GnRH pulsatile secretion -

second most frequent cause This causes low FSH and LH and, therefore,

also a low estrogen level and no withdrawal bleeding following progesterone challenge

Stress - corticotropin-releasing hormone (CRH) directly inhibits hypothalamic GnRH secretion (probably by augmenting endogenous opioid secretion)

Weight loss - especially anorexia Excess exercise related both to percent

body fat and energy expenditure Severe emotional stress Chronic disease

Kallmann’s syndrome Amenorrhea with anosmia Caused by mutation of short arm of X

chromosome that encodes a protein responsible for functions necessary for neuronal migration

Cells that produce GnRH originate in olfactory area and migrate during embryogenesis along cranial nerves that connect nose and forebrain

Effects 5 to 7 times more males than females

May be X-linked, autosomal dominant, or autosomal recessive

CNS tumor - hamartomas Other - sarcoidosis

Causes - Pituitary Dysfunction

hypogonadotropic, hypogonadism, i.e. low

FSH, LH and estrogen levels Pituitary adenomas (benign adenomas

of lactotrophs) Produce prolactin, elevated levels inhibit

pulsatile secretion of GnRH Common

Found in 1/3% of women with secondary amenorrhea

Only 1/3 of women with high prolactin levels have galactorrhea

Almost never malignant (only 40 cases of primary pituitary cancer in the world literature through 1989) If large (>1 cm, referred to as macroadenoma):

May compress optic chiasm causing bitemporal hemianopsia and/or headaches

Diagnosed via imaging studies (MRI or CT) in patients with elevated prolactin level

Treatment Surgical - rarely used as complete

cure rate is low and recurrence common

Medical - dopamine agonists (bromocriptine or cabergoline) - remember, inhibit pituitary prolactin secretion

Surveillance - many microadenomas (<10mm) regress spontaneously or remain small. Note: this does not treat patient ﾕ s hypoestrogenic status

Causes - Pituitary Dysfunction

Hyperthyroidsm Elevated thyrotropin-releasing hormone levels

stimulate pituitary cells that secrete prolactin. In addition, thought to be associated with

declining hypothalamic content of dopamine and, therefore, a removal of dopaminergic suppression of prolactin secretion.

Causes - Pituitary DysfunctionLesions compressing the pituitary stalk causing

interference with delivery of hypothalamic GnRH (all rare compared to pituitary adenomas) Other pituitary tumors - craniopharyngiomas,

meningiomas, gliomas, metastatic tumors, chordomas

• May also cause optic chiasm compression even when small Non-neoplastic intrasellar - gummas, tuberculomas,

fat deposits Lesions near the pituitary- internal carotid artery

aneurysms, obstruction of the aqueduct of Sylvius

Causes - Pituitary Dysfunction

Empty sella syndrome Congenital incompleteness of sellar diaphragm

that allows an extension of subarachnoid space into the pituitary fossa

Found in 5% of autopsies, 85% are women, incidence of 4-16% in patients who present with amenorrhea/ galactorrhea 2

Causes - Pituitary Dysfunction

Pituitary infarction - Sheehan’s syndrome Acute necrosis of pituitary gland due to

postpartum hemorrhage, with hypotension, decreased perfusion and shock

Symptoms of panhypopituitarism seen early in the postpartum period, especially failure of lactation and loss of pubic and axillary hair

Is life threatening Exceedingly rare in U.S.

Causes - Pituitary Dysfunction

Lactation (physiologic hyperprolactinemia)

Causes - Premature Ovarian FailurePremature ovarian failure

(hypergonadotropic hypogonadism) - elevated FSH and LH

Defined as ovarian failure at age <40 yr.

Due to early depletion of ovarian follicles

normal karyotype is also linked to neurosensory deafness (Perrault syndrome)

Etiologies Autoimmune - need to evaluate for other

autoimmune disorders, especially thyroid, adrenal

Infection - such as mumps oophoritis Irradiation or chemotherapy Castration Gonadal dysgenesis

• Most common cause of primary amenorrhea • Karyotype if age <30 yr. • May be abnormal karyotype (45, X; or

mosaics) or may be normal • If Y chromosome present, even in

mosaic, gonads need to be removed to prevent tumor formation or virilization

• Gonadal dysgenesis associated with

Causes - Chronic Anovulation

Chronic anovulation due to increased androgens

Cushing’s syndrome Congenital adrenal hyperplasia Polycystic ovarian syndrome

Causes - Disorders of UterusDisorders of the uterus or

outflow tract - normal FSH, LH and prolactin; no withdrawal with progesterone challenge

Müllerian anomalies Discontinuity by segmental

disruptions of the Müllerian tube, i.e. obliteration of vaginal orifice, complete transverse vaginal septa, absence of a cervix, imperforate hymen

Absence of uterus in normal (46, XX) female - Mayer- Rokinatsky-Kuster-Hauser syndrome

• 2nd most common cause of primary amenorrhea

• Müllerian development with congenital absence of uterus and/or vagina

• Müllerian anomalies frequently associated with urinary tract anomalies, including ectopic kidney, renal agenesis, horseshoe kidney, and abnormal collecting ducts (remember, genital and urinary systems develop in close proximity and timing during embryogenesis.) May also be associated with skeletal anomalies

Causes - Absence of Uterus

Absence of uterus in a phenotypic female but genotypic male (46, XY) - called testicular feminization - androgen insensitivity

Causes - Absence of Uterus Male pseudohermaphrodite 3rd most common cause of primary amenorrhea X-linked recessive disorder of the gene responsible for the androgen

intracellular receptor; therefore, despite normal male levels of testosterone, there is a lack of testosterone action

Patients appear normal female at birth except for possible presence of inguinal hernias. Growth and development are normal, except tend to be eunuchoid (long arms, big hands and feet) and tall. (May commonly become actresses!) Breasts are large with scant glandular tissue. Uteri absent, and vagina is blind canal and usually short. Testes abdominal or in an inguinal hernia

This is the one exception to removing X, Y gonads in a phenotypic female as soon as diagnosed. These patients should have gonads removed after puberty, as it allows for more normal development of puberty, and testicular tumors in these patients have not been encountered prior to puberty

Causes - Endometrial atrophy

Endometrial atrophy secondary to prolonged progesterone administration

Depo-Provera Oral contraceptives Norplant

Causes - Endometrial Damage Asherman’s syndrome -

endometrial scarring Generally result of

overzealous postpartum curettage, but may also be after other uterine surgery

Diagnosed with hysterosalpingogram, sonohysterogram or hysteroscopy

Generally will not have a withdrawal bleed from Provera

May also present with multiple miscarriages, dysmenorrhea, hypomenorrhea or infertility

Treated by hysteroscopic lysis of adhesions

Infection Tuberculosis - common

cause of amenorrhea in undeveloped countries

Schistosomiasis IUD related infection or

severe PID

Treatment

A. Treat the cause, i.e. hypothyroidism, pituitary adenoma, infection, stress, outflow tract scarring or obstruction, etc.

TreatmentB. If anovulatory, need to give periodic

progesterone to prevent endometrial hyperplasia Desires conception - ovulation induction

(progesterone in pregnancy will, in essence, prevent hyperplasia, as will the pregnancy itself)

Not desiring pregnancy at this time • Oral contraceptives • Cyclic progestins

Treatment

C. Hypoestrogenic anovulation - need to induce estrogen production or give estrogen to prevent bone loss. Then need to make sure patient also has progesterone so they don ﾕ t have “unopposed estrogen”causing endometrial hyperplasia or carcinoma: Gonadotropins - typically used only for fertility Pulsatile GnRH - typically used only for fertility Oral contraceptives ･ HRT

Frequent sources of confusion

Post-pill amenorrhea should be evaluated same as any other amenorrhea if has been 6 mo. since discontinuing OCPs or 12 mo. since last injection of Depo- Provera

Frequent sources of confusionIs it medically necessary for a woman to have a period

once a month? No, but estrogen is necessary to build and maintain bone mass, decrease risk of cardiovascular disease, etc. Estrogen alone (unopposed estrogen) significantly increases risk of endometrial hyperplasia and adenocarcinoma. Progesterone counteracts these risks. The combination of estrogen and cyclic progesterone will produce a bleeding cycle. The two hormones given together continuously (ex., taking oral contraceptives without taking the placebo week) creates amenorrhea without the adverse risks discussed above

Frequent sources of confusionIf a woman is not menstruating, where does all

that blood go? (A question often asked by patients, friends and family) - depends on the cause of amenorrhea. For example: if imperforate hymen is cause, a hematometrium may develop along with severe endometriosis. In the case of continuous use of OCPs or Depo-Provera, the endometrium is atrophic so cannot “build up”

Frequent sources of confusionIf a woman is amenorrheic and doesn’t

want to have periods, should she be evaluated? Be treated? Yes, to rule out disease processes and evaluate for bone loss depending on length of time she was amenorrheic. She may still be able to be amenorrheic - for instance, if treated with continuous OCPs.

Frequent sources of confusionCan a woman who is amenorrheic

become pregnant? Yes, depending on the cause of amenorrhea

References

Speroff L et al. Clinical Gynecologic Endocrinology and Infertility, 6th ed. Williams and Wilkens: Baltimore, MD, 2000.

Adapted from Association of Professors of Gynecology and Obstetrics Medical Student Educational Objectives, 7th edition, copyright 1997

Clinical Case

Amenorrhea

Patient Presentation

A 26-year-old G2P2 woman with LMP= 6 months ago presents with a concern regarding no periods. She delivered two full term healthy children vaginally and their ages are 5 and 3. She stopped breastfeeding 2 years ago. She has noted a persistent breast discharge, but no breast masses. She is not using any contraception, but parenting has taken a toll on the husband-wife relationship and they infrequently find the opportunity to have intercourse.

Patient PresentationOb-gyn history G2 P2. 2 full-term vaginal

deliveries of a 6-0 pound girl and a 7-8-pound boy. Pap smears are up-to-date and normal. No STDs.

Past medical history Postpartum depression,

which resolved after one year on an SSRI.

Past surgical history Cholecystectomy after

her first pregnancy

Social history Nonsmoker. Occasional

alcohol. No street drugs. Married. Works as a housewife.

Family history Noncontributory.

Patient Presentation

ROS Increased stress since the delivery of the

second child. Occasional hot flashes. Fatigue. Headaches. Difficulty losing the pregnancy weight gain.

Physical exam VS: BP= 120/80, P= 64, R= 18, Ht= 5’8”, Wt=

160 poundsGeneral: tired appearing Caucasian woman in no apparent distress

Patient PresentationHEENT: NC/AT Neck: No thyromegaly palpable Lungs: clear CV: Regular rate, no murmurs Breasts: bilateral milky white discharge with expression. No

masses, dimpling or retraction Abdomen: non-tender, no distension, no masses, no

hepatosplenomegaly Ext: Non-tender, no edema, DTRs 1+/= bilaterally Pelvic exam: Normal external genitalia, moist vagina with

decreased rugae, no discharge, Cervix is multipara, non-tender, and no lesions, uterus is non-tender, mobile and normal size, adnexae are non-tender and no palpable masses

Allergies: None Medications: Multi-vitamin

Patient Presentation

Laboratory/studies: HCG= negative FSH= 3.5 mIU/mL TSH= 2.5 uIU/mL Prolactin= 130 ng/mL; repeat on fasting, 100ng/mL Breast discharge smear reveals multiple fat droplets MRI of the head reveals a 0.8 cm mass in the anterior pituitary

Diagnoses Amenorrhea Galactorrhea Prolactinoma (Pituitary microadenoma)

Treatment

This patient was treated with Cabergoline (a dopamine agonist) on a weekly basis and the dose was increased until her prolactin level was in the normal range. She tolerated the medication well. She had return of menses within a few months time. Her galactorrhea slowly resolved. She is now being followed on an annual basis.

Teaching Points

1. There are multiple causes of amenorrhea and the student should become familiar with them. This patient with her symptomatology could have easily have been pregnant, had hypothyroid disease, premature ovarian failure or hypothalamic amenorrhea associated with stress. It is important to consider the entire differential diagnoses list prior to treatment.

Teaching Points

2. Prolactinomas are the most frequent pituitary tumor and these microadenomas tend to have an indolent course.

3. The elevated prolactin levels produce amenorrhea by inhibiting the pulsatile secretion of GnRH and result in low gonadotropins and estrogen levels.

Teaching Points

4. It is important to also evaluate both the TSH and prolactin levels in these patients. Hypothyroidism may be present with increased prolactin levels since TRH can stimulate both TSH and prolactin secretion.

5. Only 1/3 of women with high prolactin levels will have galactorrhea.

Questions

Amenorrhea