A. Introduction

1. Primary Amenorrhea
   1. Lack of menarche within 2 yrs of full development of secondary (2°) sex characteristics
   2. Failure of menarche by 18 years of age
2. Secondary Amenorrhea
   1. Cessation of menstruation after its establishment
   2. Oligomenorrhea: intermittently missed periods
   3. Pregnancy should be ruled out before proceeding
3. Components Required Normal Menses
   1. I - Uterus (steroid responsive endometrium) and intact outflow tract
   2. II - Gonadotropin responsive ovaries
   3. III - Anterior pituitary intact
   4. IV - Normally functioning Hypothalamus and CNS

B. Criteria for Evaluation

1. Failure of secondary sex characteristics by age 14
2. Menses not by age 16 even with normal secondary characteristics
3. Secondary amenorrhea persists >6 months or irregular (>42d) cycle

C. Normal Female Hormone Fluctuations

1. Consider 30 day menstrual cycle
   1. Day 1 is beginning of cycle
   2. Day 30 is conclusion of menses
   3. Day 14-16 is ovulation
2. FSH starts at low levels and peaks around day 14
   1. FSH peaks along with LH surge, at ovulation
   2. FSH returns to low levels through day 28, when it returns to moderate levels
3. LH starts at low levels, peaks on day 14-15 with ovulation, returns to low levels
4. Estradiol levels peak day 11-12, may drop, and peak again day 25 (menustruation)
5. Progesterone levels are low and peak on day 24-25 with second estrogen peak
6. Normal menstruation is inhibited under "stressful" conditions
   1. The mediators of the "stress" response include:
   2. The hypothalamic-pituitary-adrenal (HPA) system
   3. The Locus Ceruleus-Norepinephrine (LC/NE) system
7. The stress systems affect the following female hormones [6]:
   1. CRH, ß-endorphin and cortisol each inhibits GnRH secretion
   2. Cortisol also inhibits LH secretion
   3. Cortisol inhibits synthesis of estrogen and progesterone
   4. Cortisol inhibits estradiol actions
   5. Norepinephrine (NE) stimulates GnRH secretion
   6. Estradiol stimulates CRH synthesis and potentiates norepinephrine actions

[Figure] "Hormonal Changes During Menses"

D. Examination

1. Standard Assessment
   1. History and General Physical - exercise and diet, family menstrual history
   2. Digital and Speculum Exam
   3. Endogenous estrogen assessed with progesterone challenge or by estradiol levels
2. Standard Hormone Profiles
   1. Estradiol levels may be obtained, and are easier than progesterone challenge
   2. Serum Testosterone
   3. Serum Follicle Stimulating Hormone (FSH) ± Leuteinizing Hormone (LH)
   4. Serum Thyroid Stimulating Hormone (TSH)
   5. Serum Prolactin Level (>20µg/L should prompt investigation)
3. Ambiguous genitalia
   1. Excessive androgens in utero
   2. Hyperandrogenism (eg. Congenital Adrenal Hyperplasia)
4. Lack of Secondary Sex Characteristics (no prior exposure to estrogens)
   1. Ovarian Failure
   2. Hypothalamic / Pituitary Dysfunction
5. Normal Secondary Sex Characteristics
   1. Endocrine Causes
   2. Metabolic Causes
   3. Physical Lesions (Congenital versus Acquired)
6. Estrogen Assessment
   1. Assess function of endogenous estrogens (also get serum estrogen level)
   2. Give progesterone challenge and observe for uterine shedding
   3. Medroxyprogesterone acetate 10mg po x 5days
   4. Positive response means abnormal progesterone
   5. Negative response means abnormal estrogen

E. Differential Diagnosis

1. Primary Amenorrhea
   1. Pituitary Microadenoma (usually prolactinoma)
   2. Idiopathic
   3. Chromosomal
   4. Physiologic: Pregnancy, constitutional delay of puberty
2. Ambiguous Genitalia
   1. Congenital Adrenal Hyperplasia (CAH)
   2. True Hermaphroditism: 46XX with both testicular and ovarian tissue
   3. Turners' Syndrome [2]
   4. 46, XO, webbed neck
      1. Increased arm carrying angle
      2. Broad chest with widely spaced nipples
      3. Blunted secondary sex characteristics
3. No Secondary Sex Characteristics: Central Failure (decreased FSH + LH)
   1. Pituitary Disease
   2. Kallman's Syndrome
   3. CNS Masses
4. No Secondary Sex Characteristics: End Organ Failure (increased FSH + LH)
   1. Gonadal dysgenesis (eg. 45, X)
   2. Turners' Syndrome (46, XO)
5. Normal Secondary Sex Characteristics
   1. Identify congenital genitourinary abnormality of uterus, cervix, vagina
   2. Exclude abnormal endometrium (eg. Asherman's Syndrome)
   3. Pituitary Failure (uncommon)
   4. Chronic Anovulatory Syndrome [3]
   5. Radiotherapy and/or Chemotherapy
   6. Hepatic Cirrhosis
6. Endocrine Causes
   1. Pregnancy - most common cause; must rule out in all cases
   2. Exercise / Weight Loss (Anorexia / Bulimia)
   3. Hypothyroidism
   4. Hyperprolactinemia
   5. Pharmacologic Agents (Anti-Dopamine, Contraceptive Pills)
   6. Hypothalamic hypogonadism

F. Evaluation of Secondary Amenorrhea

1. Physical Causes
   1. Physical Examination often unrevealing
   2. Marked Weight Loss
   3. Frequent Strenuous Exercise - likely most common
   4. Obtain Pelvic or Transvaginal Ultrasound
2. Congenital Anomalies
   1. May require ultrasound for detection
   2. Vaginal Septum leads to Outflow Obstruction (usually have cyclical pain)
   3. Cervical or Uterine Obstruction (eg. Uterine Septum)
   4. Imperforate Hymen
3. Laboratory Evaluation [1]
   1. Initially, FSH, LH, prolactin and estradiol should be obtained
   2. Measure TSH only in women with symptoms of thyroid disease or obesity
   3. Serum testosterone should be measured in women with hirsutism or obesity
   4. Most common cause of secondary amenorrhea is pregnancy, and this must be ruled out
4. Based on initial laboratory evaluation, classify secondary amenorrhea:
   1. Hypergonadotropic hypogonadism: increased FSH, low estrogen (similar to menopause)
   2. Hyperprolactinemia (50% with galactorrhea): MRI scan for tumor, measure prolacin
   3. Phenothiazines: anti-dopaminergic agents lead to elevated prolactin
   4. Hypothyroidism can also lead to hyperprolactinemia
   5. Hypogonadotropic Hypogonadism - low FSH, LH and estradiol (pituitary or hypothalamic failure)
   6. Polycystic Ovarian Syndrome - FSH and estradiol usually normal; LH, androgens up
5. Pituitary Failure
   1. Pituiary disease is an uncommon cause of amenorrhea
   2. The presentation is that of hypogonadotropic hypogonadism
   3. Most common pituitary cause is Pituitary Tumor
   4. Pituitary Necrosis (Sheehan's Syndrome) may occur, particularly peripartum
6. Asherman's Syndrome
   1. Intrauterine Adhesions
   2. Usually after Dilatation and Curretage (D and C), especially post infection
7. Hypothalamic Hypogonadism (Amenorrhea) [6,7]
   1. Amenorrhea occurs in low energy states in absence of organic disease
   2. Exercise, anorexia and starvation all associated with this syndrome
   3. Arises with impaired secretion of gonadotropin-releasing hormone (GnRH)
   4. Leads to low or normal gonadotropin (FSH, LH), low estrogen, absent menstrual cycles
   5. Essentially a regression to prepubertal or peripubertal pattern of gonadotropin secretion
   6. Relative energy deficit plays major role in abnormal GnRH secretion
   7. Reduced leptin concentrations appear to be central in this syndrome
   8. Pharmacologic replacement of leptin may lead to normalization of endocrine axes, menses
   9. Recombinant human leptin improves markers of ovarian follicular maturation hormones [6]

G. Management

1. Based on underlying dysfunction
2. Most cases of amenorrhea not due to menopause can be treated
   1. Oral contraceptive pills are often effective in these patients
   2. However, Polycystic ovarian syndrome is difficult to treat
   3. Radiation or chemotherapy induced ovarian failure generally does not reverse
   4. In these cases, pretreatment egg harvesting and cryopreservation is preferred
3. Stress Induced Amenorrhea can usually be reversed by treating underlying condition(s)
4. Recombinant human leptin improved function in hypothalamic amenorrhea [6]

---

References

1. Baird DT. 1997. Lancet. 350:275
2. Saenger P. 1996. NEJM. 335:1749
3. Franks S. 1995. NEJM. 333:853
4. McIver B, Romanski SA, Nippoldt TB. 1997. Mayo Clin Proc. 72(12):1161
5. Chrousos GP, Torpy DJ, Gold PW. 1998. Ann Intern Med. 129(3):229
6. Welt CK, Chan JL, Bullen J, et al. 2004. NEJM. 351(10):987
7. Chan JL and Mantzoros CS. 2005. Lancet. 366(9474):74