A. Normal Menstrual Cycle

1. Normal Zones of the Uterus
   1. Endometrium divided into basalis and functionalis
   2. Myometrium
   3. Outer Stroma
2. For the first 2 weeks of the cycle, uterus is Proliferative and dependent on Estrogen
   1. Estrogen from granulosa cells following FSH stimulation
   2. Functionalis layer exhibits tubular to coiled glands
   3. Glands secrete alkaline watery solution which promotes sperm motility
   4. Spiral Arteries are narrow and inconspicuous
   5. Many mitoses seen in the glandular tissue
3. Ovulation occurs ~14 days due to FSH and LH surge (GnRH controlled)
   1. Progesterone, made by granulosa cells, begins to accumulate
   2. Second estrogen peak also occurs
   3. Endometrial glands become enlarged and more coiled due to progesterone
   4. Gland cells store glycogen in vacuoles (days 17-19)
4. Gland cells in Secretory Phase
   1. Copious secretions to bathe implanted zygote
   2. Glands become enlarged and much more coiled (saw-tooth)
   3. Stromal cells develop vacuolar and eosinophilic changes = predecidualization
5. By day 27 the entire stroma has become predecidualized
6. The uterus is supported by progesterone (progestational hormone)
   1. Progesterone synthesis by granulosa lutein cells stimulated by FSH & LH
   2. Towards end of menstrual cycle, LH levels decrease
   3. Note that in pregnancy, trophoblasts make hCG, which serves LH function
7. In the absence of pregnancy (HCG), newly formed corpus luteum degenerates
   1. Progesterone levels fall
   2. Endometrium undergoes collapse and breakdown
   3. Menses commences on day 28 for 3-7 days

B. Pregnancy and Labor [1,7]

1. Maximum fecundity (probability of conception during one menstrual cycle) ~30%
2. 50-60% of all conceptions progress beyond 20 weeks of pregnancy
3. Corpus luteum production of progesterone leads to endometrial stromal changes
4. Maintenance of corpus luteum and progesterone depends on trophoblast HCG
5. Gestational endometrium has widely dilated glands
6. Cells have abundant glycogen
7. Labor is synchronized contraction of the uterus to expel the fetus
8. Parturition is the action of giving birth to the young
9. Placenta produces corticotropin releasing hormone (CRH), which increases in an exponential fashion during pregnancy, reaches a critical level, and stimulates labor
10. Towards the end of pregnancy, fetal growth in uterus outstrips uterine growth, increasing pressure on uterine wall; this stimulates uterine contractions (labor)

C. Evaluation of the Uterus

1. Endovaginal Ultraound
   1. To assess for thickened endometrium
   2. In 92% of abnormal endometrial biopsies, ultrasound showed >5mm endometrium
   3. In 96% of endometrial cancer by biopsy result, ultrasound showed >5mm endometrium
   4. Therefore, ultrasound measured endometrium <5mm is likely benign uterine condition
   5. Thickened endometrium may represent polyps, hyperplasia, or cancer
2. Hysteroscopy [3]
   1. Direct endoscopic visualization of endometrial cavity
   2. Evaluation of polyps, endometrial cavity, suspicious areas (hyperplasia, neoplasia)
   3. High diagnostic accuracy for endometrial cancer
   4. Moderate diagnostic accuracy for hyperplasia (biopsy therefore required)
3. Endometrial biopsy is often required for definitive diagnosis
4. Prolapse of uterus (also cervical or vaginal prolapse)

D. Uterine (Pelvic Organ) Prolapse [2,5]

1. Also called cervical or vaginal prolapse, more recently "Pevlic Organ Prolapse" or POP
   1. "Tissue coming out of vagina"
   2. Protrusion of pelvic organs into or out of vaginal canal
   3. Tissue protruding may be uterus, small bowel, colon, or bladder
2. POP due to loss of support of anterior or posterior vaginal wall or vaginal apex
   1. Present in ~14% of women
   2. Usually correlated with vaginal delivery
   3. 11X increase in risk with >3 vaginal deliveries
   4. Of women with POP, ~38% have Stage I, 35% Stage II, 2% Stage III
3. Symptoms (Table 1, Ref [5])
   1. Tissue protruding from vagina
   2. Urinary hesitancy and/or incomplete voiding
   3. Urinary frequency, urgency or frank dysuria
   4. Urinary incontinence
   5. Defacatory dysfunction, fecal incontinence
   6. Sexual dysfunction - dyspareunia, reduced sensation, libido dysfunction
4. Staging
   1. Stage 0: perfect support
   2. Stage 1: no point lower than 1cm above hymenal ring
   3. Stage 2: lowest point within 1cm of hymenal ring
   4. Stage 3: lowest point >1cm below hymenal ring but not completely prolapsed
   5. Stage 4: complete prolapse
5. Treatment
   1. Observation with pelvic floor strengthening exercises ("Kegel exercises")
   2. Pessaries: supportive or insertive device
   3. Ring pessary with or without floor is a common supportive pessary
   4. Gelhorn and cube pessaries are common space-occupying devices
   5. Surgical repair - require repeat procedure in <30% of cases
   6. Procedure is usually sacrocolpopexy; stress urinary incontinence symptoms in 44% [6]
   7. Burch culposuspension added to sacrocolpopexy reduces stress urinary incontinence symptoms to ~24% [6]
   8. Hysterectomy is generally recommended with surgery for prolapse
6. Prevention
   1. Unclear efficacy
   2. Weight loss
   3. Reduction of heavy lifting
   4. Treatment of constipation
   5. Moedication or reduction of obstetric risk factors
   6. Pelvic-floor physical therapy

1. Defined as presence of endometrial glands and stroma within myometrium >3mm.
2. About 15% of surgically removed uteri show adenomyosis
3. Presentation includes dysfunctional uterine bleeding and dysmenorrhea
4. Disease is often asymptomatic
5. Pathology
   1. Myometrium contains small, soft red areas, possible cysts
   2. Glands lined by mildly proliferative or inactive endometrium
   3. Surrounded by endometrial stroma, within the myometrium

B. Endometriosis

1. Presence of benign endometrial glands and stroma outside of uterus
2. Prevalence in 3% of women of reproductive age
3. Regresses at natural or artificial menopause
4. Sites involved:
   1. Ovary (80% of pelvic endometriosis)
   2. Fallopian tube
   3. Serosa of uterus
   4. Other pelvic regions - sacrospinous ligaments
   5. Gastrointestinal Tract
   6. Rarely lungs, pleura, extremities
5. Pathogenesis
   1. Unclear etiology
   2. Foci of menstrual endometrium may be regurgitated through fallopian tubes and implant on pelvic organs: ovaries, uterosacral ligaments, colon and rectum
   3. Possible that hematogenous or lymphatic spread occurs to distant sites
6. Pathology
   1. Diagnosis by laparoscopy: early lesions red or bluish ("mulberry") nodules
   2. Foci may become cystic, lumina fill with clotted blood = "chocolate cyst"
   3. Fibrosis is the end result, causing contraction, tubule immobility and pain
   4. In addition, foci of healed endometriosis has hemosiderosis = "powder burns"
7. Signs and Symptoms
   1. Depend primarily on location and dissemination of endometriosis
   2. Dysmenorrhea is most common complaint
   3. Dyspareunia
   4. Infertility
8. Treatment discussed in specific outline

C. Dysfunctional Uterine Bleeding

1. Defined as abnormal bleeding with no organic (functional) cause
2. One of most common gynecologic disorders or reproductive age
3. Most cases appear to be related to endocrine disorders involving pituitary axis
4. Most common disorder is anovulatory bleeding

D. Anovulatory Bleeding

1. Most common cause of dysfunctional uterine bleeding
2. Most often occurs at either end of reproductive life (menarche and menopause)
3. Failed ovulation leads to excessive and prolonged estrogen stimulation
   1. Failed inhibin production leads to failed repression of FSH
   2. Failed progesterone production leads to failed negative feedback
   3. No progesterone to stabilize endometrium
4. Estrogen withdrawal bleeding ("breakthrough") can occur if estrogen level falls
   1. Endometrium will continue to proliferate (never enter secretory phase)
   2. Fall in estrogen leads to stromal fluid loss and loss of vascular support causing
   3. Compression of blood vessels.
   4. Result is stasis, thrombosis, infarction, hemorrhage
   5. Dysfunctional uterus due to failed progesterone (no corpus luteum)
5. Histology
   1. Glands frequently disordered
   2. Glands appear crowded due to stromal necrosis and collapse of endometrium

1. Glandular Tumors ±> Polyps ±> Adenocarcinoma
2. Stromal Tumors ±> Stromal Nodule ±> Stromal Sarcoma
3. Mesodermal Tumor ±> Adenofibroma ±> Mixed Mesodermal Tumor
4. Smooth Muscle ±> Leiomyoma (fibroid) ±> Leiomyosarcoma

B. Polyps

1. Localized overgrowth that project from endometrial surface to cavity (exophytic)
2. Most common in perimenopausal period, due to estrogenic stimulation (growth)
3. Symptoms include intermenstrual bleeding
   1. May be due to surface ulceration or hemorrhagic infarction
   2. Note that uterine cancers may present with bleeding, so must evaluate
4. Diagnosis by endovaginal ultrasound, confirmation with endometrial biopsy
5. Polyps not thought to be neoplastic, but ~1% contain adenocarcinoma

C. Endometrial Hyperplasia

1. Proliferative disease spectrum including adenocarcinoma
2. Proliferation results from unopposed estrogenic stimulation
   1. Exogenous agents
   2. Also occurs in granulosa cell tumors of ovary
   3. Polycystic Ovary Syndrome (PCO)
   4. Obesity often associated with disease: adipose converts androgens ±> estrogens
3. Exogenous Agents Causing Endometrial Hyperplasia
   1. Exogenous estrogens without progesterones
   2. Tamoxifen (Nolvadex®), a selective estrogen receptor modifier, causing hyperplasia
   3. Raloxifene (Evista®), another SERM, does not cause endometrial hyperplasia
4. Classification of Endometrial Hyperplasia
   1. Based on cytologic atypia and abnormal glands
   2. Simple hyperplasia (cystic, mild): minimal glandular crowding, no atypia
   3. Complex (moderate): glandular complexity, crowding, no cytologic atypia
   4. Note: ~3% of such lesions progress to adenocarcinoma
   5. Atypical (severe)
   6. Cytologic atypia with marked glandular crowding
      1. Epithelia are enlarged and hyperchromatic, with prominant nucleoli
      2. About 25% progression to adenocarcinoma
5. Diagnosis
   1. Most commonly associated with vaginal bleeding
   2. Hysteroscopy less sensitive than ultrasound
   3. Endovaginal ultrasound showing thickened endometrium
   4. Endometrial biopsy is required for definitive diagnosis
   5. Endometrial curettage with pathological evaluation
6. Treatment
   1. Depends on severity of hyperplasia, patient's age, fertility desires, risk factors
   2. Progestin therapy to down regulate estrogen receptors, decrease responses
   3. Hysterectomy is therapy of choice in woman who has completed child bearing
   4. Subtotal hysterectomy may be preferred over total [4]

References

1. Norwitz ER, Schust DJ, Fisher SJ. 2001. NEJM. 345(19):1400
2. Jelovsek JE, Maher C, Barber MD. 2007. Lancet. 369(9566):1027
3. Clark TJ, Voit D, Gupta JK, et al. 2002. JAMA. 288(13):1611
4. Thakar R, Ayers S, Clarkson P, et al. 2002. NEJM. 347(17):1318
5. Cundiff GW. 2005. JAMA. 293(16):2018
6. Brubaker L, Cundiff GW, Fine P, et al. 2006. NEJM. 354(15):1557
7. Smith R. 2007. NEJM. 356(3):271