Amenorrhea
UNC School of Medicine
Obstetrics and Gynecology Clerkship
Case Based Seminar Series
Objectives for Amenorrhea
 Define amenorrhea and oligomenorrhea
 Explain the pathophysiology and identify the etiologies of
amenorrhea and oligomenorrhea
 Describe the symptoms and physical examination findings
of amenorrhea and oligomenorrhea
 Discuss the steps in the evaluation and management of
amenorrhea and oligomenorrhea
 Describe the consequences of untreated amenorrhea and
oligomenorrhea
Definition
 Amenorrhea – absence of menses
 Primary amenorrhea – absence of menarche
 Absence of menarche by age 14 without secondary sexual characteristics
 Absence of menarche by age 16 with secondary sexual characteristics
 Secondary amenorrhea – absence of menses in a previously
menstruating woman
 Absence of menses for > 6 months or duration of 3 menstrual cycles
 Oligomenorrhea – reduction in frequency of menses
 Cycle lengths > 35 days, but < 6 months
Primary Amenorrhea: Etiology
 Pregnancy
 Thyroid disease
 Hyperprolactinemia
 Prolactinoma
 Hypergonadotropic hypogonadism
 Gonadal dysgenesis (i.e. Turner syndrome)
 Premature ovarian failure
 Hypogonadotropic hypogonadism
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Constitutional delay of puberty
Congenital GnRH deficiency (Kallman syndrome)
Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa)
CNS tumor (i.e. Craniopharyngioma)
 Normogonadotropic
 Congenital (i.e. Mullerian agenesis, Androgen Insensitivity syndrome)
 Outflow tract obstruction (i.e. Imperforate hymen, Transverse vaginal septum)
 Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease)
Primary Amenorrhea: Etiology
 Most common etiologies:
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
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Chromosomal abnormalities causing gonadal dysgenesis – 50%
Hypothalamic hypogonadism – 20%
Absence of the uterus, cervix, or vagina – 15%
Transverse vaginal septum or imperforate hymen – 5%
Pituitary disease – 5%
Primary Amenorrhea: History
Findings
Association
Completion of stages of puberty? Development of
axillary and pubic hair? Breast development?
Ovarian or pituitary failure
Chromosomal abnormality
Family history of delayed or absent puberty?
Familial disorder
Constitutional delay of puberty
Height relative to family members?
Turner’s syndrome
Symptoms of virilization?
PCOS
Ovarian or adrenal tumor
Presence of Y chromosome
Recent stress? Change in weight, diet, or exercise?
Functional hypothalamic amenorrhea
Medications (i.e. antidepressants, antipsychotics)?
Hyperprolactinemia
Galactorrhea?
Hyperprolactinemia
Headaches, visual field defects, fatigue, polyuria or
polydipsia?
Hypothalamic-pituitary disease
Primary Amenorrhea: Physical Exam
 Evaluation of pubertal development (height, weight) and growth chart
 Breast development (Tanner staging)
 Evaluation for features of Turner’s syndrome
 Webbed neck, low hair line, shield chest, widely spaced nipples
 Examine skin for hirsutism, acne, striae, increased pigmentation, and
vitiligo
 Pelvic exam



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Clitoral size
Intactness of hymen
Depth of vagina
Presence of vaginal septum
Presence of cervix, uterus, and ovaries
Tanner Stages
Stage 1: Prepubertal, no
palpable breast tissue or
pubic hair.
Stage 2: Development of
breast bud; sparse,
straight pubic hair.
Stage 3: Enlargement of
breast; pubic hair darker,
coarser, and curlier.
Stage 4: Areola and papilla
project above the breast;
pubic hair adult-like in
appearance.
Stage 5: Recession of
areola to match contour
of breast; pubic hair
extends to thigh.
Figure from: Roede, MJ, van Wieringen, JC. Growth diagrams 1980: Netherlands third nation-wide survey.
Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.
Primary Amenorrhea: Evaluation
Secondary sexual characteristics present?
No
Yes
Measure FSH
Perform ultrasound of uterus
Uterus absent
or abnormal
FSH < 5
FSH > 20
Hypogonadotropic
hypogonadism
Hypergonadotropic
hypogonadism
 Hypothalamic amenorrhea
 Constitutional delay
Karyotype
of puberty
 Kallman syndrome
 CNS tumor
46,XX
Premature
ovarian failure
Uterus present
or normal
Karyotype analysis
Outflow obstruction
analysis
46,XY
46,XX
No
Yes
Androgen
insensitivity
syndrome
Müllerian
agenesis
Evaluate for
2° amenorrhea
Imperforate hymen
Transverse vaginal
septum
45,XO
Turner’s
syndrome
 PCOS
 Cushing’s
Secondary Amenorrhea/Oligomenorrhea:
Etiology
 Pregnancy
 Thyroid disease
 Hyperprolactinemia
 Prolactinoma
 Breastfeeding, Breast stimulation
 Medication (i.e. Antipsychotics, Antidepressants)
 Hypergonadotropic hypogonadism
 Postmenopausal ovarian failure
 Premature ovarian failure
 Hypogonadotropic hypogonadism




Functional hypothalamic amenorrhea (i.e. Anorexia or Bulimia nervosa)
CNS tumor (i.e. Craniopharyngioma)
Sheehan’s syndrome
Chronic illness
 Normogonadotropic
 Outflow tract obstruction (i.e. Asherman’s syndrome, Cervical stenosis)
 Hyperandrogenic anovulation (i.e. PCOS, Cushing’s disease, CAH)
Secondary Amenorrhea/Oligomenorrhea:
Etiology
 Most common etiologies:





Ovarian disease – 40%
Hypothalamic dysfunction – 35%
Pituitary disease – 19%
Uterine disease – 5%
Other – 1%
Secondary Amenorrhea/Oligomenorrhea:
History
Findings
Association
Recent stress? Change in weight, diet, or exercise?
Functional hypothalamic amenorrhea
Development of acne, hirsutism, striae, central obesity, PCOS
increased skin pigmentation or deepening voice?
Cushing’s disease
Ovarian or adrenal tumor
Medications (i.e. antidepressants, antipsychotics)?
Hyperprolactinemia
Chronic illness?
Functional hypothalamic amenorrhea
Headaches, visual field defects, fatigue, polyuria or
polydipsia?
Hypothalamic-pituitary disease
Symptoms of estrogen deficiency (hot flashes, vaginal
dryness, decreased libido, or poor sleep)?
Premature ovarian failure
Postmenopausal ovarian failure
Galactorrhea?
Hyperprolactinemia
History of obstetrical catastrophe, severe bleeding,
D&C, endometritis, or other infection?
Sheehan’s syndrome
Asherman’s syndrome
Secondary Amenorrhea/Oligomenorrhea:
Physical Exam
 General
 Evaluation of height, weight, and BMI
 Examine skin for hirsutism, acne, striae, acanthosis nigricans, thickness or
thinness, and easy bruisability
 Thyroid exam
 Breast exam
 Express for galactorrhea
 Pelvic exam
 Atrophy
 Vaginal dryness
Secondary Amenorrhea/Oligomenorrhea:
Evaluation
Negative urine pregnancy test
Check TSH and prolactin
Normal prolactin,
Abnormal TSH
Both normal
Progestin challenge test
Thyroid disease
Withdrawal bleed
No withdrawal bleed
Normogonadotropic
hypogonadism
Estrogen/progestin
Challenge test
 Hyperandrogenic
anovulation
No withdrawal bleed
 PCOS
 Cushing’s
Outflow obstruction
 Asherman’s
 Cervical stenosis
Normal TSH,
Abnormal prolactin
Prolactin < 100 ng/mL
Prolactin > 100 ng/mL
• Medication
MRI to evaluate
for prolactinoma
Negative MRI
Consider other
causes
Withdrawal bleed
Check FSH
 Medication
FSH > 20 IU/L
Hypergonadotrpoic
hypogonadism
 Ovarian failure
FSH < 5IU/L
MRI to evaluate for
pituitary tumor
Normal MRI
 Hypothalamic
Hypogonadotropic amenorrhea
hypogonadism  Chronic illness
Secondary Amenorrhea/Oligomenorrhea:
Evaluation
 Progestin challenge test
 Medroxyprogesterone acetate 10 mg daily for 10 days
 IF withdrawal bleed occurs – Not outflow tract obstruction
 IF no withdrawal bleed occurs – Estrogen/Progestin challenge test
 Estrogen/Progestin challenge test
 Oral conjugated estrogen 0.625 – 2.5 mg daily for 35 days
 Medroxyprogesterone acetate 10 mg daily for 26-35 days
 IF no withdrawal bleed occurs – Endometrial scarring
 Hysterosalpingogram or Hysteroscopy to evaluate endometrial cavity
Secondary Amenorrhea/Oligomenorrhea:
Evaluation
 Evaluation of hyperandrogenism
 Symptoms: hirsutism, acne, alopecia, masculinization, and virilization
 Differential diagnosis:
 Adrenal disorders: Atypical congenital adrenal hyperplasia (CAH),
Cushing’s syndrome, Adrenal neoplasm
 Ovarian disorders: PCOS, Ovarian neoplasms
 Lab: Testosterone, DHEA-S, 17α-hydroxyprogesterone
Hormone
Level
Indication
Testosterone
< 200 ng/dL
PCOS
> 200 ng/dL
Evaluate for adrenal or ovarian tumor
< 700 ng/dL
PCOS
> 700 ng/dL
Evaluate for adrenal or ovarian tumor
DHEA-S
17α-hydroxyprogesterone > 4 ng/mL
Consider ACTH stimulation test to diagnose
CAH
Amenorrhea/Oligomenorrhea: Management
 Treatment should be directed at…
 Correcting the underlying pathology
 Helping woman to achieve fertility (IF desired)
 Preventing the complications of disease process
 Consequences of untreated amenorrhea/oligomenorrhea:
 Hypoestrogenism – Osteoporosis, Infertility
 Hyperestrogenism – Heart disease, Stroke, Diabetes Mellitus, Breast cancer
(controversial), Endometrial hyperplasia and Endometrial cancer
Amenorrhea/Oligomenorrhea: Management
Diagnosis
Management
Ovarian insufficiency
 Premature ovarian failure
 Postmenopausal ovarian failure
Hormone replacement therapy (HRT)
*Congenital anatomic lesions
Surgical correction
*Presence of Y chromosome (i.e. AIS)
Gonadectomy
*Gonadal dysgenesis (i.e. Turner syndrome)
Estrogen + progestin, growth hormone
IVF (IF pregnancy desired)
Hyperprolactinemia
Dopamine agonist (Bromocriptine, Cabergoline)
Functional hypothalamic amenorrhea
Increase caloric intake > energy expenditure
Hypothalamic or pituitary dysfunction
(non-reversible)
OCP’s, pulsatile GnRH or exogenous gonadotropins
CNS tumor
 Craniopharyngioma
 Prolactinoma
Surgical resection
Microadenoma (< 10mm) – Dopamine agonist
Macroadenoma (>10mm) – Trans-sphenoidal resection
PCOS
OCP’s, weight loss, and metformin
Asherman’s syndrome
Hysteroscopic lysis of adhesions
*Causes of primary amenorrhea only
Bottom Line Concepts
 A thorough history and physical examination as well as laboratory testing can
help narrow the diagnosis of amenorrhea.
 In patients with primary amenorrhea, the presence or absence of sexual
development should direct evaluation.
 Constitutional delay of puberty is a diagnosis of exclusion.
 The definitive method to identify hypothalamic-pituitary dysfunction is to
measure FSH and prolactin levels.
 If the patient has abnormal uterine development, a karyotype analysis should
be performed to diagnose müllerian agenesis versus chromosomal
abnormalities.
 In a patient with secondary amenorrhea, pregnancy should be ruled out prior
to further workup.
 Treatment goals of amennorrhea and oligomenorrhea include prevention of
complications such as osteoporosis, endometrial hyperplasia and heart
disease; preservation of fertility; and in primary amenorrhea, progression of
normal pubertal development.
References and Resources
 APGO Medical Student Educational Objectives, 9th edition, (2009), Educational
Topic 43 (p92-93).
 Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010), Charles RB
Beckmann, Frank W Ling, Barabara M Barzansky, William NP Herbert, Douglas
W Laube, Roger P Smith. Chapter 35 (p315-319).
 Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and Gynecology,
5th edition (2009), Neville F Hacker, Joseph C Gambone, Calvin J Hobel.
Chapter 32 (p355-363).
 Master-Hunter T, Helman DL. Amenorrhea: evaluation and treatment. Am Fam
Physician. 2006 Apr 15; 73(8): 1374-82.