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					 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
      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:
     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         Ovarian or pituitary failure
axillary and pubic hair? Breast development?            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   Hypothalamic-pituitary disease
polydipsia?
        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
                                    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


      FSH < 5                FSH > 20                        Uterus absent                       Uterus present
                                                              or abnormal                          or normal
Hypogonadotropic        Hypergonadotropic
 hypogonadism             hypogonadism
                                                           Karyotype analysis                    Outflow obstruction
 Hypothalamic amenorrhea
 Constitutional delay
  of puberty             Karyotype analysis
 Kallman syndrome                                       46,XY          46,XX              No                 Yes
 CNS tumor
                    46,XX                45,XO
                                                       Androgen       Müllerian     Evaluate for Imperforate hymen
                                                      insensitivity   agenesis     2° amenorrhea Transverse vaginal
                  Premature              Turner’s      syndrome                     PCOS                    septum
                ovarian failure         syndrome                                    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   Hypothalamic-pituitary disease
polydipsia?
Symptoms of estrogen deficiency (hot flashes, vaginal   Premature ovarian failure
dryness, decreased libido, or poor sleep)?              Postmenopausal ovarian failure
Galactorrhea?                                           Hyperprolactinemia
History of obstetrical catastrophe, severe bleeding,    Sheehan’s syndrome
D&C, endometritis, or other infection?                  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,                               Normal TSH,
              Both normal
                                                            Abnormal TSH                                Abnormal prolactin


          Progestin challenge test                                                   Prolactin < 100 ng/mL                 Prolactin > 100 ng/mL
                                                              Thyroid disease

Withdrawal bleed               No withdrawal bleed                                                                            MRI to evaluate
                                                                                         • Medication
                                                                                                                             for prolactinoma

Normogonadotropic              Estrogen/progestin
  hypogonadism                   Challenge test                                                                                Negative MRI
 Hyperandrogenic                                                                                                             Consider other
  anovulation
                                                                                                                                  causes
 PCOS           No withdrawal bleed       Withdrawal bleed                                                                      Medication
 Cushing’s
                   Outflow obstruction        Check FSH
                    Asherman’s                               FSH > 20 IU/L       Hypergonadotrpoic
                    Cervical stenosis                                              hypogonadism
                                                                                   Ovarian failure

                                                                                                               Normal MRI     Hypothalamic
                                                              FSH < 5IU/L       MRI to evaluate for
                                                                                                             Hypogonadotropic amenorrhea
                                                                                 pituitary tumor
                                                                                                              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
 DHEA-S                  < 700 ng/dL   PCOS
                         > 700 ng/dL   Evaluate for adrenal or ovarian tumor
 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                        Hormone replacement therapy (HRT)
       Premature ovarian failure
       Postmenopausal ovarian failure
*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        OCP’s, pulsatile GnRH or exogenous gonadotropins
(non-reversible)
CNS tumor                                    Surgical resection
       Craniopharyngioma                    Microadenoma (< 10mm) – Dopamine agonist
       Prolactinoma                         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.

				
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