1. Obstetrics and Gynecology Clerkship Case Based Seminar Series
Amenorrhea
UNC School of Medicine
Obstetrics and Gynecology Clerkship
Case Based Seminar Series

2. 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

3. 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

4. Primary Amenorrhea: Etiology
Pregnancy
Thyroid disease
Hyperprolactinemia
Prolactinoma
Hypergonadotropic hypogonadism
Gonadal dysgenesis (i.e. Turner syndrome)
Premature ovarian failure
Hypogonadotropic hypogonadism
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)

5. Primary Amenorrhea: Etiology
Most common etiologies:
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%

6. 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?
Headaches, visual field defects, fatigue, polyuria or polydipsia?
Hypothalamic-pituitary disease

7. 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
Clitoral size
Intactness of hymen
Depth of vagina
Presence of vaginal septum
Presence of cervix, uterus, and ovaries

8. 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.

9. Primary Amenorrhea: Evaluation
Secondary sexual characteristics present? No
Yes
Measure FSH
Perform ultrasound of uterus
FSH < 5
FSH > 20
Uterus absent or abnormal
Uterus present or normal
Hypogonadotropic
hypogonadism
Hypergonadotropic
hypogonadism
Karyotype analysis
Outflow obstruction
Hypothalamic amenorrhea
Constitutional delay of puberty
Kallman syndrome
CNS tumor
Karyotype analysis
46,XY
46,XX No
Yes
46,XX
45,XO
Müllerian agenesis
Evaluate for
2° amenorrhea
Androgen insensitivity syndrome
Imperforate hymen
Transverse vaginal septum
Premature
ovarian failure
Turner’s
syndrome
PCOS
Cushing’s

10. 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)

11. Secondary Amenorrhea/Oligomenorrhea: Etiology
Most common etiologies:
Ovarian disease – 40%
Hypothalamic dysfunction – 35%
Pituitary disease – 19%
Uterine disease – 5%
Other – 1%

12. Secondary Amenorrhea/Oligomenorrhea: History
Findings
Association
Recent stress? Change in weight, diet, or exercise?
Functional hypothalamic amenorrhea
Development of acne, hirsutism, striae, central obesity, increased skin pigmentation or deepening voice?
PCOS
Cushing’s disease
Ovarian or adrenal tumor
Medications (i.e. antidepressants, antipsychotics)?
Hyperprolactinemia
Chronic illness?
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?
History of obstetrical catastrophe, severe bleeding, D&C, endometritis, or other infection?
Sheehan’s syndrome
Asherman’s syndrome

13. 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

14. Secondary Amenorrhea/Oligomenorrhea: Evaluation
Negative urine pregnancy test
Progestin challenge test
Negative MRI
Consider other causes
No withdrawal bleed
Prolactin < 100 ng/mL
Prolactin > 100 ng/mL
Check FSH
Estrogen/progestin
Challenge test
Normogonadotropic
hypogonadism
Hypergonadotrpoic hypogonadism
Withdrawal bleed
FSH > 20 IU/L
Outflow obstruction
Medication
MRI to evaluate for pituitary tumor
Normal MRI
Hypogonadotropic hypogonadism
MRI to evaluate for prolactinoma
Both normal
Normal TSH, Abnormal prolactin
Hyperandrogenic anovulation
PCOS
Cushing’s
Check TSH and prolactin
Normal prolactin,
Abnormal TSH
Thyroid disease
FSH < 5IU/L
Asherman’s
Cervical stenosis
Ovarian failure
Hypothalamic amenorrhea
Chronic illness

15. 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 – 2.5 mg daily for 35 days
Medroxyprogesterone acetate 10 mg daily for days
IF no withdrawal bleed occurs – Endometrial scarring
Hysterosalpingogram or Hysteroscopy to evaluate endometrial cavity

16. 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
DHEA-S
< 700 ng/dL
> 700 ng/dL
17α-hydroxyprogesterone
> 4 ng/mL
Consider ACTH stimulation test to diagnose CAH

17. 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

18. 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

19. 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.

20. 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 (p ).
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 (p ).
Master-Hunter T, Helman DL. Amenorrhea: evaluation and treatment. Am Fam Physician Apr 15; 73(8):