# Lecture 5: Female Reproductive Disorders ## Unit 2.4: Reproductive System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the evaluation and causes of amenorrhea 2. Explain polycystic ovary syndrome pathophysiology and management 3. Describe endometriosis and adenomyosis 4. Explain uterine fibroids and their clinical impact 5. Describe pelvic inflammatory disease 6. Explain common benign and malignant gynecologic conditions --- ## Section 1: Amenorrhea - Definitions and Evaluation Framework Amenorrhea, the absence of menstruation, represents one of the most common reasons for gynecologic consultation and requires a systematic approach to diagnosis. Primary amenorrhea is defined as the absence of menarche by age 15 in the presence of normal secondary sexual characteristics, or by age 13 in their absence. Secondary amenorrhea refers to the cessation of menses for three or more months in a woman who previously had regular cycles, or for six or more months in a woman with previously irregular cycles. The compartment model provides a logical framework for evaluating amenorrhea by systematically examining each level of the hypothalamic-pituitary-ovarian-outflow tract axis. Compartment IV encompasses the hypothalamus, which generates the pulsatile GnRH signal. Compartment III represents the pituitary gland, responsible for FSH and LH secretion. Compartment II includes the ovaries, the source of estrogen and progesterone production. Compartment I comprises the outflow tract—the uterus and vagina—which must be anatomically intact and responsive to hormonal stimulation to produce menstrual bleeding. The initial workup follows a standardized approach. A pregnancy test must always be performed first, as pregnancy remains the most common cause of secondary amenorrhea. TSH evaluates for thyroid dysfunction, which can disrupt menstrual regularity through effects on the hypothalamic-pituitary axis. Prolactin levels screen for hyperprolactinemia, which inhibits GnRH pulsatility. FSH helps distinguish ovarian from central causes, while estradiol assessment indicates the overall estrogenic status. Interpretation of these initial laboratories guides further evaluation. Elevated FSH with low estradiol indicates ovarian failure, classified as hypergonadotropic hypogonadism. Low or normal FSH with low estradiol suggests a central cause at the hypothalamic or pituitary level, termed hypogonadotropic hypogonadism. Normal FSH and estradiol levels in the setting of amenorrhea point toward outflow tract obstruction or polycystic ovary syndrome. Panel A: Amenorrhea evaluation beginning with pregnancy test, then TSH and prolactin testing to rule out thyroid dysfunction and hyperprolactinemia. Panel B: FSH and estradiol decision points with elevated FSH/low E2 indicating Compartment II ovarian failure (POI, Turner syndrome). Panel C: Low-normal FSH/low E2 pathway leading to Compartments III-IV central causes (hypothalamic amenorrhea, pituitary disorders) with MRI evaluation. Panel D: Normal FSH/normal E2 pathway leading to Compartment I outflow tract abnormalities or PCOS, with pelvic ultrasound and progesterone challenge test for further evaluation. --- ## Section 2: Causes of Amenorrhea by Compartment Hypothalamic causes of amenorrhea (Compartment IV) are among the most common in reproductive-age women. Functional hypothalamic amenorrhea results from suppression of GnRH pulsatility due to inadequate energy availability. Common triggers include excessive exercise, significant weight loss, eating disorders, and chronic psychological stress. The hypothalamus interprets these conditions as unfavorable for reproduction and downregulates the reproductive axis. Kallmann syndrome represents a congenital cause characterized by the failure of GnRH neurons to migrate properly during embryonic development, resulting in hypogonadotropic hypogonadism combined with anosmia due to hypoplasia of the olfactory bulbs. Hypothalamic tumors such as craniopharyngioma can also disrupt GnRH secretion. Pituitary causes (Compartment III) frequently involve hyperprolactinemia, most commonly from a prolactinoma but also caused by medications including antipsychotics, metoclopramide, and others that block dopamine. Elevated prolactin directly inhibits GnRH secretion. Sheehan syndrome results from pituitary infarction following severe postpartum hemorrhage, leading to panhypopituitarism including gonadotropin deficiency. Empty sella syndrome, where the pituitary gland appears flattened within an enlarged sella turcica, can also cause amenorrhea. Ovarian causes (Compartment II) include primary ovarian insufficiency, defined as ovarian failure occurring before age 40 and characterized by elevated FSH levels greater than 25-40 mIU/mL on two occasions at least four weeks apart. Turner syndrome, with its 45,X karyotype, presents with primary amenorrhea, short stature, webbed neck, and streak gonads. Polycystic ovary syndrome, while classified under ovarian causes, involves the entire hypothalamic-pituitary-ovarian axis. Outflow tract abnormalities (Compartment I) cause primary amenorrhea despite normal hormonal function. Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) involves congenital absence of the uterus and upper vagina with normal ovarian function and female secondary sexual characteristics. Asherman syndrome develops from intrauterine adhesions following curettage, typically after complicated pregnancy, causing secondary amenorrhea. Imperforate hymen and transverse vaginal septum both cause primary amenorrhea with cyclic pelvic pain from trapped menstrual blood (hematocolpos), creating the characteristic bluish bulge at the introitus. Panel A: Compartment IV (Hypothalamus) causes showing functional hypothalamic amenorrhea in stressed athlete, and Kallmann syndrome with absent olfactory bulbs causing anosmia. Panel B: Compartment III (Pituitary) causes illustrating prolactinoma on MRI and Sheehan syndrome with necrotic pituitary following postpartum hemorrhage. Panel C: Compartment II (Ovaries) causes with POI showing small ovaries with few follicles, and Turner syndrome with 45,X karyotype. Panel D: Compartment I (Outflow) causes depicting Mullerian agenesis with absent uterus, Asherman syndrome with intrauterine adhesions on hysteroscopy, and imperforate hymen with hematocolpos. --- ## Section 3: Polycystic Ovary Syndrome - Pathophysiology Polycystic ovary syndrome affects approximately 6-10% of reproductive-age women, making it the most common endocrine disorder in this population and the leading cause of anovulatory infertility. PCOS demonstrates familial clustering, suggesting complex genetic inheritance, though specific causative genes remain incompletely characterized. The Rotterdam criteria establish the diagnosis when two of three features are present: oligo-ovulation or anovulation manifesting as irregular or absent menstrual cycles, hyperandrogenism either clinical (hirsutism, acne, androgenic alopecia) or biochemical (elevated total or free testosterone), and polycystic ovarian morphology on ultrasound showing twelve or more follicles measuring 2-9 mm per ovary or ovarian volume exceeding 10 mL. Critically, other causes of hyperandrogenism and anovulation must be excluded, including thyroid dysfunction, hyperprolactinemia, non-classical congenital adrenal hyperplasia, and androgen-secreting tumors. The pathophysiology involves interconnected hormonal and metabolic abnormalities. An elevated LH to FSH ratio, typically greater than 2:1, drives theca cell hyperfunction and excessive androgen production. Insulin resistance, present in 50-80% of women with PCOS regardless of body weight, exacerbates hyperandrogenism through multiple mechanisms. Elevated insulin stimulates ovarian androgen production directly and suppresses hepatic sex hormone-binding globulin synthesis, thereby increasing free androgen levels. The excess androgens undergo peripheral conversion to estrone in adipose tissue, creating chronic anovulation without the progesterone withdrawal necessary for normal menstruation. Follicular development arrests at the small antral stage, creating the characteristic "string of pearls" appearance on ultrasound. The metabolic syndrome components frequently accompany PCOS. Approximately 50% of affected women are obese, and metabolic syndrome prevalence reaches 33-47% even among lean women with PCOS. Impaired glucose tolerance occurs in 30-40% and frank type 2 diabetes in 7.5-10%, rates 5-10 times higher than age-matched controls. Panel A: Central ovary with multiple small peripheral follicles showing "string of pearls" appearance characteristic of PCOS on ultrasound. Panel B: Hormonal pathways showing increased GnRH pulsatility, elevated LH/FSH ratio at pituitary, theca cell androgen overproduction, and impaired granulosa cell aromatization. Panel C: Insulin resistance pathway with hyperinsulinemia leading to increased ovarian androgens and decreased hepatic SHBG synthesis, plus adipose tissue peripheral estrone conversion. Panel D: Clinical manifestations including hirsutism with excess facial hair, acne, androgenic alopecia, irregular cycles, and metabolic syndrome components (obesity, dyslipidemia, glucose intolerance). --- ## Section 4: Polycystic Ovary Syndrome - Clinical Features and Management The clinical manifestations of PCOS reflect the underlying hyperandrogenism and metabolic dysfunction. Menstrual irregularity typically presents as oligomenorrhea (cycles greater than 35 days) or amenorrhea, though some women experience dysfunctional uterine bleeding. Hirsutism, defined as excess terminal hair in a male-pattern distribution, affects 70-80% of women with PCOS and is assessed using the modified Ferriman-Gallwey score. Acne vulgaris and androgenic alopecia (thinning at the crown with preservation of the frontal hairline) represent additional androgenic manifestations. The reproductive consequences extend beyond irregular cycles. PCOS is the leading cause of anovulatory infertility, and affected women who do conceive face increased rates of miscarriage, gestational diabetes, preeclampsia, and preterm delivery. Long-term risks include endometrial hyperplasia and carcinoma from chronic unopposed estrogen, type 2 diabetes, and cardiovascular disease. Management strategies are tailored to the patient's primary concerns. For menstrual regulation and endometrial protection, combined oral contraceptives provide estrogen-progestin therapy that suppresses ovarian androgen production and ensures regular withdrawal bleeding. For women not desiring contraception, cyclic progestin therapy (10-14 days monthly) protects the endometrium. Hirsutism management combines hormonal suppression with mechanical hair removal. Combined oral contraceptives reduce ovarian androgen production, while spironolactone (50-200 mg daily) provides anti-androgen effects by blocking the androgen receptor. Improvement requires six months or longer, and laser hair removal or electrolysis address existing terminal hairs. For women desiring fertility, weight loss of 5-10% can restore ovulation in overweight patients. Letrozole, an aromatase inhibitor, has emerged as first-line ovulation induction, demonstrating higher live birth rates than clomiphene citrate in randomized trials. Clomiphene remains an alternative, and gonadotropin injections or in vitro fertilization are reserved for resistant cases. Metabolic management emphasizes lifestyle modification. Metformin may improve metabolic parameters and aid ovulation induction, though its role as primary treatment has diminished with evidence favoring lifestyle intervention and letrozole. Panel A: Rotterdam diagnostic criteria with checkboxes for oligo-ovulation, hyperandrogenism, and polycystic ovarian morphology, requiring two of three for diagnosis. Panel B: Menstrual regulation and endometrial protection pathway showing combined OCP for cycle control, plus hirsutism/acne treatment with COCs and spironolactone. Panel C: Fertility pathway showing stepped approach from lifestyle modification to letrozole (first-line) to clomiphene to gonadotropins to IVF. Panel D: Metabolic health management with weight loss goals, glucose monitoring, metformin as adjunctive therapy, and lifestyle modification emphasis. --- ## Section 5: Endometriosis - Pathogenesis and Clinical Features Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. This estrogen-dependent condition affects approximately 10% of reproductive-age women, with prevalence reaching 25-50% among women with infertility and up to 70-90% among women with chronic pelvic pain. Several theories attempt to explain the pathogenesis of endometriosis. Sampson's theory of retrograde menstruation, the most widely accepted hypothesis, proposes that menstrual endometrium refluxes through the fallopian tubes and implants on pelvic structures. While retrograde menstruation occurs in most women, only some develop endometriosis, suggesting that immune dysfunction allowing implant survival plays a critical role. The coelomic metaplasia theory suggests that peritoneal mesothelium can transform into endometrial tissue under hormonal or inflammatory stimulation. Lymphatic and vascular dissemination explains rare distant sites such as the lungs, pleura, and brain. More recent stem cell theories propose that endometrial stem cells may aberrantly implant and proliferate. The ovaries represent the most common site of involvement, where endometriomas (chocolate cysts) form from cyclic hemorrhage within implants. Other frequent locations include the uterosacral ligaments, posterior cul-de-sac (pouch of Douglas), broad ligaments, and peritoneal surfaces. Deep infiltrating endometriosis involves the bladder, bowel, and rectovaginal septum. The cardinal symptoms reflect the cyclic hormonal responsiveness of ectopic tissue. Dysmenorrhea, typically progressive and severe, often begins years after menarche. Deep dyspareunia particularly affects women with posterior cul-de-sac involvement. Chronic pelvic pain may become continuous rather than purely cyclic as inflammation and adhesions develop. Dyschezia (painful bowel movements), especially perimenstrual, suggests bowel involvement. Infertility results from distorted pelvic anatomy, inflammation impairing gamete function, and endometrial receptivity defects. Rarely, cyclic symptoms at distant sites create dramatic presentations such as catamenial pneumothorax or hemoptysis. Panel A: Sampson's theory showing uterus with retrograde menstruation through fallopian tubes and endometrial fragments implanting on pelvic surfaces. Panel B: Anterior pelvic view with endometriotic implants at common locations: ovaries with chocolate cyst inset, uterosacral ligaments, posterior cul-de-sac, bladder surface, and bowel serosa with involvement percentages. Panel C: Symptom correlation showing ovarian lesion linked to pelvic pain, cul-de-sac nodule linked to deep dyspareunia, and bowel implant linked to dyschezia. Panel D: Histology showing endometrial glands and stroma surrounded by hemosiderin-laden macrophages confirming ectopic endometrial tissue. --- ## Section 6: Endometriosis - Diagnosis and Treatment; Adenomyosis Diagnosis of endometriosis begins with clinical suspicion based on characteristic symptoms and physical examination findings. Pelvic examination may reveal uterosacral nodularity, a fixed retroverted uterus from adhesions, or adnexal masses consistent with endometriomas. Transvaginal ultrasound reliably identifies ovarian endometriomas, which appear as cysts with homogeneous low-level internal echoes ("ground glass" appearance). MRI provides superior visualization of deep infiltrating endometriosis. However, laparoscopy remains the gold standard for definitive diagnosis, allowing direct visualization and histologic confirmation. The revised American Society for Reproductive Medicine staging system (stages I-IV) classifies disease extent, though staging correlates poorly with symptom severity or fertility outcomes. Treatment goals include pain relief, fertility enhancement when desired, and prevention of disease progression. Medical therapy is effective for pain but does not improve fertility. NSAIDs address dysmenorrhea. Hormonal suppression reduces estrogen stimulation: combined oral contraceptives (continuous preferred), progestins (oral, injectable, or levonorgestrel IUD), and GnRH agonists or antagonists all demonstrate efficacy. Add-back therapy with low-dose estrogen-progestin prevents bone loss during prolonged GnRH agonist use. Surgical treatment involves laparoscopic excision or ablation of visible lesions and lysis of adhesions. Conservative surgery preserves reproductive potential and provides significant pain relief in most patients, though recurrence rates reach 40-50% at five years. For women with completed childbearing and refractory symptoms, definitive surgery with hysterectomy and bilateral salpingo-oophorectomy provides the highest likelihood of cure. Adenomyosis, a related condition, involves the invasion of endometrial glands into the myometrium. It typically affects multiparous women in their 40s and may coexist with endometriosis. The classic presentation includes progressive dysmenorrhea and menorrhagia with a diffusely enlarged, globular, boggy uterus that is tender during menstruation. Ultrasound shows a heterogeneous myometrium with characteristic myometrial cysts, while MRI reveals a thickened junctional zone exceeding 12 mm. Medical management parallels endometriosis, with the levonorgestrel IUD demonstrating particular efficacy. Definitive diagnosis and treatment is achieved with hysterectomy. Panel A: Endometriosis diagnosis showing laparoscopic view of powder-burn lesions and red implants on peritoneum, endometrioma on ultrasound with ground glass echoes, and deep infiltrating nodule on MRI. Panel B: Endometriosis treatment ladder from NSAIDs through COCs, progestins, GnRH agonists, to laparoscopic excision, to hysterectomy/BSO. Panel C: Adenomyosis diagnosis showing globular enlarged uterus, transvaginal ultrasound with heterogeneous myometrium and myometrial cysts, and MRI with thickened junctional zone >12mm. Panel D: Adenomyosis treatment options including LNG-IUD, GnRH agonists, and hysterectomy, with cut specimen showing trabeculated myometrium with hemorrhagic foci. --- ## Section 7: Uterine Fibroids (Leiomyomas) Uterine leiomyomas are benign smooth muscle tumors that represent the most common pelvic neoplasm in women, with cumulative incidence reaching 70-80% by age 50. Black women face higher prevalence, earlier onset, larger tumors, and more severe symptoms than white women. Additional risk factors include nulliparity, obesity, early menarche, and family history. As estrogen-dependent tumors, fibroids characteristically grow during the reproductive years and regress after menopause. Fibroid classification by location determines symptomatology. Intramural fibroids, located within the myometrial wall, cause bulk symptoms and bleeding when large. Submucosal fibroids protrude into the endometrial cavity and disproportionately cause heavy menstrual bleeding and infertility relative to their size. The FIGO classification system further subdivides submucosal fibroids by the percentage extending into the cavity. Subserosal fibroids project from the outer uterine surface and primarily cause bulk symptoms. Pedunculated fibroids, attached by a stalk, may undergo torsion causing acute pain, and pedunculated submucosal fibroids may prolapse through the cervix. Clinical manifestations correlate with fibroid location and size. Heavy menstrual bleeding, the most common symptom, results primarily from submucosal fibroids distorting the endometrial cavity and increasing surface area. Bulk symptoms from large fibroids include pelvic pressure, urinary frequency from bladder compression, constipation from rectal compression, and increased abdominal girth. Pain occurs primarily with fibroid degeneration, often during pregnancy when rapid growth outstrips blood supply. Fibroids, particularly submucosal types, contribute to infertility and are associated with pregnancy complications including miscarriage, preterm birth, placental abruption, and malpresentation. Diagnosis begins with pelvic examination revealing an enlarged, irregular uterus. Transvaginal ultrasound serves as first-line imaging, visualizing fibroid number, size, and location. Saline infusion sonohysterography and hysteroscopy evaluate the uterine cavity when submucosal involvement is suspected. MRI provides detailed mapping essential for surgical planning, particularly for uterine-sparing procedures. Panel A: Uterus showing fibroid types: intramural (within wall), submucosal (protruding into cavity with FIGO type 0,1,2 classification), subserosal (bulging outward), and pedunculated (attached by stalk). Panel B: Symptom profiles with submucosal linked to heavy bleeding and infertility, intramural linked to bulk symptoms and bleeding, subserosal linked to bladder and bowel pressure symptoms, and pedunculated linked to torsion risk. Panel C: Imaging with transvaginal ultrasound showing hypoechoic mass with edge shadowing, and saline sonohysterogram demonstrating intracavitary component. Panel D: MRI T2-weighted image with fibroid mapping for surgical planning and FIGO classification system. --- ## Section 8: Uterine Fibroids - Management; Pelvic Inflammatory Disease Fibroid management is individualized based on symptoms, fibroid characteristics, patient age, and reproductive goals. Expectant management is appropriate for asymptomatic fibroids detected incidentally or in women approaching menopause, when natural regression can be anticipated. Medical therapies address symptoms without eliminating fibroids. Tranexamic acid reduces bleeding by preventing fibrinolysis. The levonorgestrel intrauterine device decreases menstrual blood loss, though may be expelled if significant cavity distortion exists. GnRH agonists induce a hypoestrogenic state causing fibroid shrinkage of 35-65% over three to six months, but side effects (hot flashes, bone loss) and rapid regrowth upon discontinuation limit long-term use; they are primarily employed preoperatively to reduce fibroid size and correct anemia. Newer GnRH antagonist combinations with add-back therapy (elagolix, relugolix) enable longer-term use with fewer hypoestrogenic effects. Procedural and surgical options provide more durable results. Uterine artery embolization, performed by interventional radiology, injects particles to occlude fibroid blood supply, achieving symptom improvement in 85-90% of patients. Myomectomy surgically removes fibroids while preserving the uterus for women desiring future pregnancy; approaches include hysteroscopic (submucosal), laparoscopic, or open depending on fibroid location and size. MRI-guided focused ultrasound offers a noninvasive option using thermal ablation. Hysterectomy provides definitive treatment and remains the only option guaranteeing no recurrence. Pelvic inflammatory disease encompasses infection of the upper genital tract including endometritis, salpingitis, and tubo-ovarian abscess. The pathogens are typically sexually transmitted, with Chlamydia trachomatis and Neisseria gonorrhoeae as primary organisms, often followed by polymicrobial infection. Risk factors include young age, multiple sexual partners, and prior PID. The diagnosis is clinical, requiring a low threshold given the consequences of untreated disease. Minimum criteria include cervical motion tenderness, uterine tenderness, or adnexal tenderness in a sexually active woman at risk. Additional supportive criteria include fever, abnormal cervical discharge, elevated inflammatory markers, and positive testing for gonorrhea or chlamydia. Empiric treatment is initiated when minimum criteria are met without alternative diagnosis. Outpatient treatment consists of ceftriaxone 500 mg intramuscularly plus doxycycline 100 mg twice daily for 14 days, with or without metronidazole for anaerobic coverage. Hospitalization for intravenous antibiotics is indicated for tubo-ovarian abscess, pregnancy, severe illness, inability to tolerate oral therapy, or surgical emergency. Sequelae of PID include tubal infertility (occurring in 15-20% after one episode), ectopic pregnancy from tubal damage, and chronic pelvic pain from adhesions. Fitz-Hugh-Curtis syndrome refers to perihepatitis with characteristic "violin string" adhesions between the liver capsule and anterior abdominal wall. Panel A: Fibroid management algorithm showing asymptomatic observation, medical options (tranexamic acid, LNG-IUD, GnRH agonist), and procedural options (UAE with catheter and embolization particles, MRI-guided focused ultrasound). Panel B: Surgical fibroid options including hysteroscopic myomectomy of submucosal fibroid, laparoscopic myomectomy, and hysterectomy for definitive treatment. Panel C: PID pathophysiology showing ascending infection from cervicitis to endometritis, salpingitis, and tubo-ovarian abscess, with clinical examination demonstrating cervical motion tenderness. Panel D: PID imaging and treatment showing laparoscopic view of inflamed tubes with purulent exudate, Fitz-Hugh-Curtis adhesions on liver, and treatment regimen with ceftriaxone plus doxycycline. --- ## Section 9: Ovarian Masses - Evaluation and Management Ovarian masses represent a common clinical challenge, requiring differentiation between functional cysts, benign neoplasms, and malignancies. The approach varies significantly by patient age, with malignancy risk substantially higher in postmenopausal women. Functional cysts arise from normal follicular physiology. Follicular cysts develop when a dominant follicle fails to rupture and continues to enlarge, typically resolving spontaneously within one to two menstrual cycles. Corpus luteum cysts result from hemorrhage into the corpus luteum; though usually asymptomatic, they may cause pain if rupture or torsion occurs. Theca lutein cysts are bilateral, multicystic ovarian enlargement occurring with markedly elevated hCG levels, characteristically seen with molar pregnancy or multiple gestation. Benign ovarian neoplasms include several histologic types. Mature cystic teratomas (dermoid cysts) are the most common ovarian neoplasm in young women, arising from germ cells and containing differentiated tissue including hair, sebum, teeth, and cartilage; the pathognomonic ultrasound finding is a hyperechoic Rokitansky nodule with posterior shadowing. Serous cystadenomas are thin-walled cysts filled with clear fluid. Mucinous cystadenomas tend to be larger and multiloculated with thick mucinous contents. Ovarian fibromas, solid benign tumors, may cause Meigs syndrome with ascites and right-sided hydrothorax that resolve with tumor removal. Malignant ovarian tumors are classified by cell of origin. Epithelial tumors account for 90% of ovarian cancers, with high-grade serous carcinoma representing the most common and lethal subtype. These tumors often arise from the fallopian tube fimbriae and carry BRCA1/2 mutations in 15-20% of cases. Germ cell tumors include dysgerminoma (the female equivalent of seminoma), immature teratoma, and yolk sac tumor; these occur predominantly in young women and are often curable with surgery and chemotherapy. Sex cord-stromal tumors such as granulosa cell tumors may be hormonally active, producing estrogen and causing precocious puberty or postmenopausal bleeding. Evaluation of an ovarian mass incorporates imaging characteristics and tumor markers. Features favoring malignancy include large size (greater than 10 cm), solid components, thick septations, nodularity, ascites, and bilaterality. CA-125 is elevated in approximately 80% of epithelial ovarian cancers but lacks specificity, particularly in premenopausal women where endometriosis, fibroids, and pregnancy may cause elevation. In premenopausal women with simple cysts under 5-7 cm, observation with repeat imaging in 6-8 weeks is appropriate. Postmenopausal women and those with concerning features require surgical evaluation. Panel A: Functional cyst ultrasound images showing simple anechoic follicular cyst, corpus luteum with "ring of fire" Doppler flow, and bilateral theca lutein cysts with multiple septations. Panel B: Benign neoplasm appearances including dermoid cyst with Rokitansky nodule and acoustic shadowing, thin-walled serous cystadenoma, and large multiloculated mucinous cystadenoma. Panel C: Malignant features showing complex mass with solid components, papillary projections, thick septations, and ascites, with benign versus malignant ultrasound characteristic comparison. Panel D: CA-125 test tube with interpretation guidelines differentiating premenopausal from postmenopausal patients and limitations in specificity. --- ## Section 10: Cervical and Uterine Malignancies Cervical cancer develops through a well-characterized progression from human papillomavirus infection to precancerous dysplasia to invasive carcinoma. High-risk HPV types 16 and 18 are responsible for approximately 70% of cervical cancers. The viral oncoproteins E6 and E7 inactivate the tumor suppressors p53 and Rb, respectively, driving malignant transformation. The cervical transformation zone, where columnar epithelium undergoes squamous metaplasia, is most vulnerable to HPV-induced dysplasia. Low-grade squamous intraepithelial lesions (LSIL/CIN1) frequently regress spontaneously, particularly in young women, while high-grade lesions (HSIL/CIN2-3) represent true precancers requiring treatment. Invasive cervical cancer is predominantly squamous cell carcinoma (70%), with adenocarcinoma comprising most remaining cases. Cervical cancer screening guidelines recommend initiating Pap smears at age 21 regardless of sexual activity onset. From ages 21-29, cytology alone is performed every three years. From ages 30-65, preferred screening is Pap plus HPV co-testing every five years or Pap alone every three years. Screening may cease after age 65 with adequate prior negative results. HPV vaccination provides primary prevention, with nonavalent vaccine covering types 16, 18, 31, 33, 45, 52, 58 (oncogenic) and 6, 11 (wart-causing). Management of abnormal cervical cytology follows standardized algorithms. Atypical squamous cells of undetermined significance (ASCUS) undergo reflex HPV testing; if positive, colposcopy is indicated. LSIL and HSIL require colposcopic examination with directed biopsies. Treatment of confirmed high-grade dysplasia typically involves excisional procedures (loop electrosurgical excision procedure, cold knife conization) or ablation. Endometrial carcinoma is the most common gynecologic malignancy in the United States. Type I endometrial cancers (80%) are endometrioid adenocarcinomas arising from endometrial hyperplasia in the setting of prolonged unopposed estrogen exposure. Risk factors include obesity, anovulation (PCOS), nulliparity, diabetes, and tamoxifen use. Type II cancers (serous, clear cell carcinomas) arise in atrophic endometrium of older women, are not estrogen-associated, and carry worse prognosis. The hallmark presentation is postmenopausal bleeding, which warrants endometrial sampling in all cases; approximately 10% of women with postmenopausal bleeding have endometrial cancer. Premenopausal women may present with abnormal uterine bleeding. Transvaginal ultrasound measuring endometrial thickness under 4 mm in postmenopausal women carries very low cancer risk. Endometrial biopsy provides tissue diagnosis, with hysteroscopy and dilation and curettage reserved when office biopsy is inadequate or nondiagnostic. Treatment is primarily surgical with hysterectomy, bilateral salpingo-oophorectomy, and staging lymphadenectomy, followed by adjuvant radiation or chemotherapy based on stage and risk factors. Panel A: Cervical cancer progression showing transformation zone cross-section, HPV infection of basal cells, and progression through CIN1/2/3 to invasive carcinoma. Panel B: Cervical evaluation with colposcopy images showing acetowhite changes, punctation, and mosaic patterns, plus LEEP procedure with wire loop and specimen. Panel C: Endometrial cancer types comparing Type I (low-grade endometrioid in obese patient with estrogen exposure) versus Type II (high-grade serous in thin elderly patient with atrophic endometrium). Panel D: Endometrial cancer workup showing transvaginal ultrasound with endometrial stripe measurement, Pipelle biopsy technique, and surgical staging with hysterectomy and lymph node dissection. --- ## Summary Amenorrhea evaluation follows the compartment approach: always rule out pregnancy first, then use FSH levels to distinguish ovarian failure (elevated FSH) from central causes (low/normal FSH), with normal hormone levels suggesting outflow tract abnormalities or PCOS. PCOS represents the most common cause of anovulatory infertility, diagnosed by Rotterdam criteria (two of three: oligo-ovulation, hyperandrogenism, polycystic ovaries after excluding other causes). Management targets the patient's primary concern: combined oral contraceptives for cycle regulation, anti-androgens for hirsutism, letrozole for ovulation induction. Endometriosis involves ectopic endometrial tissue causing dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Laparoscopy remains the gold standard for diagnosis. Treatment includes hormonal suppression for symptoms and surgical excision for pain relief and fertility enhancement. Uterine fibroids are classified by location (submucosal, intramural, subserosal) which determines symptom profile. Submucosal fibroids disproportionately cause heavy bleeding and infertility. Management ranges from observation to medical therapy to uterine artery embolization to myomectomy to hysterectomy. Pelvic inflammatory disease is diagnosed clinically with a low threshold to prevent tubal damage. Treatment is empiric with ceftriaxone plus doxycycline. Ovarian masses require differentiation of functional cysts (observation) from benign neoplasms from malignancy. Postmenopausal women with complex masses and elevated CA-125 require surgical evaluation. Cervical cancer is preventable through HPV vaccination and screening. Endometrial cancer presents with postmenopausal bleeding requiring prompt endometrial sampling. --- ## Key Terms | Term | Definition | |------|------------| | Amenorrhea | Absence of menstruation; primary if no menarche by age 15, secondary if cessation for 3+ months | | PCOS | Polycystic ovary syndrome; hyperandrogenism with anovulation | | Endometriosis | Endometrial glands and stroma located outside the uterine cavity | | Adenomyosis | Invasion of endometrial tissue into the myometrium | | Leiomyoma | Benign uterine smooth muscle tumor (fibroid) | | PID | Pelvic inflammatory disease; ascending infection of the upper genital tract | | Endometrioma | Ovarian cyst containing endometrial tissue with old blood (chocolate cyst) | | CIN | Cervical intraepithelial neoplasia; precancerous dysplasia graded 1-3 | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*