Chapter
2. The normal human ovary part II: how steroid hormones work
The “functional context” of steroid–target cell interactions
General principles of steroid hormone–cognate receptor–DNA transcription activation
The mechanisms of E2 and E receptor signaling (Fig. 2.1)
Nuclear genomic: ligand-dependent E2 action
The generation of functional diversity
Steroid receptor co-regulators
Co-activators and their mechanism of action (see Figs. 2.4–2.6), (Table 2.1, 2.2)
Co-repressors and their mechanism of action
The balance of co-activation/co-repression in health and disease
Nuclear receptor subtypes
Genomic receptor subtype distribution and function in the reproductive system
Genomic receptor subtype distribution and function in non-reproductive systems
Cell-surface, non-genomic steroid signaling (Table 2.4, Fig. 2.1c)
Rapid signaling by ERs at the plasma membrane (Table 2.4, Fig. 2.1c)
Ligand-independent activation of ER: interaction with peptide growth factors (Fig. 2.7)
DNA-independent genomic actions of ER
SERMs as “proof of principle” (Figs. 2.3, 2.8, Table 2.5)
Functional diversity of E action in health and disease
The role of E in skeletal maturation and homeostasis
The role of E in regulation of fuel homeostasis and metabolism (Fig. 2.9)
Mechanisms of ER action in regulation of fuel homeostasis
The role of E in metabolism (Fig. 2.9)
E and E receptor subtype and brain function (Table 2.6)
Brain aromatase and local E neuro-protection
Breast tissue responses to E, ERs, SERMS, and subtype-selective ER agonists (Fig. 2.8)
The role of E in breast development and function
The role of ERα and ERβ in breast cancer (Figs. 2.10, 2.11)
The next frontiers of estrogen function
Molecular endocrine targeted therapy using ERβ subtype agonists (Table 2.5)
27-Hydroxycholesterol: an endogenous SERM as a contributor to the morbidity and mortality of the metabolic syndrome in aging women (Fig. 2.11)
27-Hydroxycholesterol and coronary artery endothelium
27-Hydroxycholesterol and breast cancer
27-Hydroxycholesterol and skeletal homeostasis
Progesterone: functions and mechanism of actions
The progesterone receptor (Fig. 2.13)
Progesterone action is mediated by two PR isoforms [68,74,75]
Relative expression of the PR isoforms contributes to selectivity of PR action
PR expression in target tissues in the human
The role of PR co-regulators in P action in human tissue
The next frontier in progesterone function
“Progesterone resistance”
The paradoxical effects of progesterone/progestin on breast cancer and osteoporosis (Fig. 2.14)
How ovarian steroid hormones work: overall conclusion
3. Gonadal dysgenesis: ovarian function and reproductive health in Turner syndrome
Indications for karyotype
Medical care for adults with TS
Medical follow-up and estrogen replacement therapy
Risk factors for coronary artery disease
Thyroid and celiac disease
Ovarian hormone replacement
Ovarian function and reproductive health in Turner syndrome patients
4. Pathology of benign and malignant ovarian epithelial tumors
Pathology of ovarian benign epithelial tumors
Pathology of ovarian malignant epithelial neoplasms
High-grade serous carcinoma (HGOC)
5. Ovarian tumors of borderline malignancy
Mucinous borderline tumors
Pseudomyxoma peritonei and pseudomyxoma ovarii
Mucinous tumors involving the ovaries with borderline-like appearance
Endometrioid borderline tumors
Ovarian borderline tumors, other types
Ovarian borderline tumors and their relation to invasive carcinoma
6. Precursors of ovarian epithelial tumors
Ovarian low-grade (type I) cancer precursors
Ovarian type II or high-grade ovarian serous carcinoma precursors
Ovarian dysplasia: ovarian intra-epithelial neoplasia (OIN)
Laparoscopic confocal optic biopsy
7. Peritoneal and tubal serous carcinoma
The fallopian tube from women at risk (BRCA+)
The precursor spectrum in the fallopian tube
Latent precursors in the fallopian tube: secretory cell outgrowths (SCOUTs)
Secretory cell outgrowths with increased p53 immuno-staining (p53 signatures)
Secretory cell outgrowths with preserved p53 function and loss of PAX2 expression
Tubal intra-epithelial neoplasia
The link between low- and high-grade serous cancer and peritoneal disease
Level 1: pelvic serous carcinoma with normal fallopian tubes
Level 2: pelvic serous carcinoma with involvement of the endosalpinx
Level 3: disseminated pelvic serous carcinoma associated with serous tubal intra-epithelial carcinoma
Level 4: irrefutable primary tubal carcinoma
Level 5: serous borderline tumors (SBT) and the fallopian tube
Do peritoneal carcinomas come from tubal intra-epithelial neoplasms?
8. Pathology of ovarian germ cell tumors
Yolk sac tumor (endodermal sinus tumor)
Ovarian mixed GCT and sex-cord tumors
9. Metastatic ovarian tumors
Gastric cancer: metastatic tumors with signet-ring cells
Gastric cancer: metastatic intestinal-type adenocarcinoma of the stomach
Female genital tract tumors
Other uterine, vulvar, and vaginal tumors
Miscellaneous other ovarian metastases
10. Genetic etiology of sporadic ovarian cancer
Evidence for low-penetrance loci
Telomase reverse transcriptase: TERT
Spectrin repeat-containing, nuclear envelope 1: SYNE1
Progesterone receptor: PGR
Genome-wide association studies
Characterization of confirmed loci
Fine mapping using additional SNPs or targeted re-sequencing
Identification of variable regulatory elements
Epigenetics and tissue-specific expression and regulation of the gene of interest
Investigation of allele-specific function using expression quantitative trait loci (eQTLs)
Cell line, murine, and other animal models
Methods for identification of novel loci
Gene–gene and gene–environment interactions
Genomic copy number association
Analysis of rare and uncommon variants
Integrative genomic methods
11. Chronic anovulation and the polycystic ovary syndrome
The ovulatory menstrual cycle as a vital sign of health status
Causes of ovulatory failure (anovulation)
Etiology of chronic anovulation: a spectrum of vulnerabilities
“Central defects”: CNS – anterior pituitary dysfunction/disease (Fig. 11.4)
Supra-sellar dysfunction, disease (Fig 11.4)
Anterior pituitary tumors (Fig. 11.4)
Prolactinoma and hyperprolactinemia
Gonadal factors (Fig. 11.5)
Effects of gonadal infection or disease
Adverse androgen/estrogen ratios
Pathophysiologic system biology dysregulation (non-anatomic)
The polycystic ovary syndrome
What is meant by “system biology dysregulation” in PCOS?
The polycystic ovarian syndrome
Challenges and opportunities of PCOS
Pathogenesis and pathophysiology of PCOS
Defining alterations of androgen synthesis in PCOS
Adrenal androgen production
Steroidogenesis and hyperandrogenism in PCOS [25]
Are there congenital androgen biosynthetic enzyme gene defects in PCOS?
The key enzyme for androgen biosynthesis in both ovary and adrenal cortex: P450c17 (Fig. 11.10) [25]
Origins of hyperandrogenemia in PCOS
Metabolic aspects of PCOS
Obesity and adipose tissue dysfunction in PCOS
Insulin secretion and action in PCOS: insulin resistance
How insulin resistance affects PCOS pathophysiology
What causes insulin resistance in PCOS?
Hyperandrogenism as the catalyst in PCOS
Polycystic ovary morphology
Gross morphology and histology (Fig. 11.11)
Ultrasound appearance (Fig. 11.14)
Hyperplasia of thecal stromal cells/stromal hyperthecosis [110]
Intra-ovarian regulation of ovarian morphology
Influence of gonadotropins on PCOM
The search for the “culpable gene” [126]
Maternal PCOS: pregnancy complications and the transgenerational transfer of the PCOS phenotype to female progeny
PCOS and pregnancy complications
Pre-pregnancy cardio/endocrine/metabolic status of the PCOS woman and the genesis of intra-pregnancy complications
Physiology of normal pregnancy
PCOS maternal “constraints”
Fetal epigenetic “best match” intra-uterine strategies
Reaction to in utero under-nutrition
Reaction to maternal over-nutrition [131]
The evidence for the adverse effects of maternal hyperlipidemia during pregnancy
Maternal–fetal lipid dynamics and metabolism in pregnancy [150]
The life-cycle trajectory of long-term morbidity in PCOS
Diabetes mellitus (Fig. 11.20)
Management of PCOS (Fig. 11.22)
General approach to management
Management of androgenization
Anovulation, dysfunctional uterine bleeding, and infertility control of endometrial dysfunction and disease
The endometrium in chronic anovulation/amenorrhea
Goals and management strategy
Control of metabolic dysfunction
Control of metabolic dysfunction
Oral contraceptive, metformin, and anti-androgen combinations
12. Endometriosis of the ovary
Results of surgical treatment
Hormonal medical treatment
Assisted reproduction and endometriosis
Fertility preservation in patients with severe endometriosis
13. New advances and new horizons in assisted reproduction
Induction: an ovulation overview
Human menopausal gonadotropins
Gonadotropin-releasing hormone agonist
Gonadotropin-releasing hormone antagonists
Additional medications used for ovulation induction: GH and more
14. Endometriosis and ovarian cancer
Theories regarding pathogenesis of endometriosis
Evidence for an endometrial factor in the predisposition to disease
Evidence for a peritoneal factor in the predisposition to disease
Evidence for an immune factor in the predisposition to disease
The relationship of endometriosis and ovarian malignancy
Genomic instability and mutations
Diagnosis of endometriosis
Treatment of endometriosis
Causal relationship and clinical patterns
15. Laparoscopic surgery of the benign ovary and new laparoscopic developments
To puncture or not to puncture is the question
Organization of the surgical procedure
Installation of the patient and of the laparoscopic trocars and instruments
Cystectomy after puncture (Fig. 15.5)
Cystectomy without puncture
Ovarian cysts (Fig. 15.6)
Para-tubal cyst (Fig. 15.7)
Extraction of the cyst or mass (Fig. 15.9)
Intra-operative indications (Table 15.2)
16. Ultrasound, MRI, CT, and PET imaging of ovarian cancer
Positron emission tomography imaging
Patient preparation for imaging and FDG PET/CT protocols
Adnexal mass characterization; benign versus malignant lesions
Staging of ovarian cancer
Restaging and response to therapy
Surveillance of ovarian cancer
Imaging of recurrent ovarian cancer
17. Ovarian cysts and tumors of the fetus, child, adolescent, and young adult
Fetal and neonatal ovarian cysts
Ovarian cysts of children and adolescents
Polycystic ovary syndrome in adolescents
Ovarian torsion in the young patient
Diagnosis of ovarian torsion
18. Should the ovaries be removed during a hysterectomy?
Physiologic versus premature ovarian aging
Accurate and timely diagnosis of ovarian aging
Age-specific OR assessments
What are the best tools to assess OR?
What controls ovarian aging genetically?
The importance of androgens
Can we treat “old” ovaries?
Potential conflicts of interest statement
The dimensions of the challenge: an aging population
Ovarian follicle endowment, attrition, and exhaustion
The “timing” of menopause: factors controlling follicle reserve and attrition
Definitions: peri-menopause, menopause, and the menopausal transition
Endocrinology of peri-menopause
Clinical characteristics of peri-menopause
Vasomotor symptoms in the peri-menopause
Menstrual flow and cycle-related symptoms
Bone loss begins in peri-menopause [1,29,30]
Therapeutic considerations for peri-menopause
Dysfunctional uterine bleeding
Endocrinology of menopause
Clinical manifestations of menopause
Problems of estrogen excess
Management and therapeutic considerations of estrogen excess
Estrogen deficiency: hormone therapy in early post-menopause
Early post-menopause: symptoms, signs, and system changes
Psychophysiologic effects
The magnitude of the problem
Sites and frequency of fracture in women
Measuring bone density status and assessing the rate of bone loss
Biochemical markers of bone turnover
Prevention and treatment of osteopenia and osteoporosis
Other treatment modalities
A complicating factor: serotonin
Specific symptoms, signs, and system changes in late post-menopause
Muscle mass and strength [70,71]
Cognition, dementia, and Alzheimer’s disease
The mid-life transition: women 35–65 years of age
Weight gain and re-distribution
Visceral adiposity and the emergence of the MetS
The MetS appears and worsens as age and weight increases
MetS in normal weight “metabolically obese” women [88]
Waist circumference: a sentinel sign of “silent” emerging MetS
Risks of cardiovascular and endocrine/metabolic disease associated with the menopausal transition
The cardiovascular lifetime risk pooling project [91] (Fig. 20.9)
The effect of menopause on cardiovascular function and disease [92,93]
Decades of “silent” progression
Estrogen and cardiovascular disease: evidence from basic science
A favorable effect of estrogen on the vascular system
The consequences of hypoestrogenism independent of age
Age, the MetS, and cancer
Endogenous estrogen and breast cancer incidence
The effect of weight, BMI, and diet on post-menopausal breast cancer
Post-menopausal breast cancer and the MetS
Insulin and insulin-like growth factors (IGF-1, IGF-2)
Hypercholesterolemia and breast cancer
27-Hydroxycholesterol is an endogenous agonist at the breast [123]
Progesterone as an exogenous mammary gland agonist [124]
The effects of hormone therapy in the menopause
Hormone therapy and cardiovascular disease: evidence from observational studies [1,3,4]
Cardiovascular disease: evidence from randomized, prospective clinical trials
The Women’s Health Initiative
The Estrogen plus progestin arm
The timing hypothesis [3,6]
Cancer and hormone therapy
Breast cancer and menopausal hormone therapy
A clinical approach to post-menopausal hormone therapy
Management decisions: hormone replenishment in the post-menopause
21. Clues to ovarian tumors: new concepts of symptoms, signs, syndromes, and paraneoplastic syndromes
Symptoms: new advancements and discoveries
Increased abdominal size/bloating
Difficulty eating/feeling full
Residual ovarian syndrome
Polycystic ovary syndrome
Metabolic and endocrine syndromes
Palpable post-menopausal ovary
Ovarian non-Hodgkin lymphoma and HIV
Autoimmune hemolytic anemia syndrome
Humoral hypercalcemia of malignancy
Parathyroid hormone receptor
Zollinger–Ellison syndrome
Multiple endocrine neoplasia type 1
Ovarian tumors with functioning stroma
Chorionic gonadotropin secretion
Inappropriate antidiuresis syndrome
Chromosomal abnormalities
Androgen-insensitivity syndrome (testicular feminization)
Tumors associated with abnormal sexual development
22. When is ovarian carcinoma discovered in stage I?
Histopathology and classification
Why are the non-serous ovarian carcinomas diagnosed at an earlier stage than the serous carcinomas?
Is early diagnosis of ovarian cancer possible?
23. Early detection of ovarian cancer
Incidence, prevalence, mortality rates, and natural history
Classification and staging of ovarian carcinoma
Presentation of ovarian cancer: history, signs, and symptoms
Comparing symptoms in cases and controls
Comparing symptoms in early and late stage ovarian cancer
Comparing symptoms in type I versus type II ovarian cancer
Impediments to symptoms being adequate for diagnosis or screening
Screening/risk assessment
Genetic testing/counseling
Syndromes associated with ovarian cancer
Li Fraumeni syndrome (LFS), p53 signature, and ovarian cancer
How to achieve the detection of early stage ovarian cancer
Ultrasound contrast imaging
Pulse inversion harmonic imaging
Tools and techniques to develop ovarian cancer-specific biomarkers
Novel ovarian cancer biomarkers
Serologic factors and acute-phase proteins
Macrophage colony-stimulating factor
Cytokines and other inflammatory mediators
Epidermal growth factor receptor
Vascular endothelial growth factor
Implementation of biomarker-based screening
Evaluating screening on mortality
Metastasis-related gene synuclein gamma
Satellite 2 and satellite alpha
24. Laparoscopic evaluation and management of adnexal masses and ovarian cancer
Borderline ovarian tumors
Early stage invasive ovarian cancer
Advanced-stage invasive ovarian cancer
Assessment of the feasibility of laparoscopic optimal cytoreductive surgery in ovarian cancer
Feasability of neoadjuvant chemotherapy
Second-look laparoscopy and insertion of intra-peritoneal catheters
Cytoreductive surgery for primary advanced or recurrent ovarian cancer
Hand-assisted laparoscopy in ovarian cancer
Robotics and ovarian cancer
Concerns about laparoscopy and ovarian cancer
Inadequate resection and staging
Tumor cell peritoneal dissemination with carbon-dioxide (CO2) pneumoperitoneum
Surgical training and patient referral
Pathophysiology and future direction of ovarian cancers
25. Ovarian cancer: the initial laparotomy
Ovarian tumors of borderline or low malignant potential
Role of the gynecologic oncologist
Prophylactic oophorectomy
26. Chemotherapy of ovarian cancer
Epithelial ovarian cancer
Early stage high-risk epithelial ovarian cancer
Advanced stage epithelial ovarian cancer
Neoadjuvant chemotherapy in epithelial ovarian cancer
Anti-angiogenic and targeted therapy in ovarian cancer
Borderline ovarian tumors
27. Intra-peritoneal chemotherapy
Rationale for intra-peritoneal chemotherapy and early phase clinical trials
Phase 2 trial of platinum-based intra-peritoneal chemotherapy in ovarian cancer
Phase 3 randomized trials of primary cisplatin-based intra-peritoneal chemotherapy of advanced ovarian cancer
Concerns with the results of these evidence-based trials and the toxicity of intra-peritoneal chemotherapy in the management of ovarian cancer
Intra-peritoneal chemotherapy is too toxic
The favorable survival outcome was the direct result of a greater concentration of cisplatin reaching the systemic circulation with the higher dose of intra-peritoneal cisplatin (100 mg/m2) compared with intravenous cisplatin (75 mg/m2) used in the control arms of the two most recent studies
The “control arm” of the last intra-peritoneal trial should have been carboplatin plus paclitaxel rather than cisplatin plus paclitaxel to truly evaluate the relative efficacy versus toxicity
Suggested strategies to decrease the toxicity of intra-peritoneal therapy and make the approach more acceptable in routine clinical practice
Future research directions
28. Malignant germ cell tumors and sex cord-stromal tumors in adults and children
Malignant germ cell tumors
Epidemiology and risk factors
Classification and pathology
Management of recurrent disease
Special management issues
Epidemiology and risk factors
Classification and pathology
Adjuvant or nonsurgical therapy
Treatment of recurrent disease
29. Palliative care of ovarian cancer
Principles of pain management
Other pain dimensions/adjuvant therapy
End-of-life/terminal phase
Altchek's Diagnosis and Management of Ovarian Disorders
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