Lecture 2 - Repro Endo Disease PDF

Reproductive and Endocrine Disease Shuo Xiao, PhD Office: EOHSI, 406 Tel: 848-445-3729 Email: [email protected] The whole picture of the Reproductive and Endocrine System Uterus (embryo/fetus development) https://anatomy-medicine.com/endocrine-system/ The whole picture of the Reproductive and...

Reproductive and Endocrine Disease Shuo Xiao, PhD Office: EOHSI, 406 Tel: 848-445-3729 Email: [email protected] The whole picture of the Reproductive and Endocrine System Uterus (embryo/fetus development) https://anatomy-medicine.com/endocrine-system/ The whole picture of the Reproductive and Endocrine System • • • • • • TRH: Thyrotropin-releasing hormone PIF: Prolactin inhibiting factor CRH: Corticotropin-releasing hormone GHRH: Growth hormone-releasing hormone GHIH: Growth hormone-inhibiting hormone GnRH: Gonadotropin-releasing hormone • • • • • • TSH: Thyroid stimulating hormone PRL: Prolactin ACTH: Adrenocorticotropic hormone GH: Growth hormone FSH: Follicle-stimulating hormone LH: luteinizing hormone Key concepts in the Reproductive and Endocrine System • The endocrine system (including reproductive system) consists of all glands and hormones produced from these glands. It regulates the body’s metabolic homeostasis and other crucial functions: cellular metabolism, sexual development, reproduction, sugar and mineral homeostasis, heart rate, bone health, and digestion, etc. • Major endocrine organs: hypothalamus, pituitary, thyroid, parathyroid gland, adrenal gland, gonad (ovary and testis), and other other hormone producing organs (heart, kidney, fat, placenta …). • The nervous system turns on a specific endocrine gland in a very fast way; but the endocrine system functions in a much slower acting pace via hormones and the binding of hormones with their specific receptors. There are negative and positive feedbacks in the endocrine system. • Hormones are distributed through the body via the blood circulation. They function through ubiquitously expressed receptors and cell-specific hormone receptors. • Hormones can be water- or lipid-soluble. Water-soluble hormones cannot pass through the plasma membrane and need to bind to the membrane receptors to exhibit hormonal functions. Lipid hormones can pass through the cell membrane and bind to intracellular receptors. Key concepts in the Reproductive and Endocrine System Water-soluble hormone Lipid-soluble hormone Williams Textbook of Endocrinology, 2020 Key concepts in the Reproductive and Endocrine System Cell signaling pathways • • Feedback between endocrine organs There are no good or bad hormones. A balance of hormones is essential to ensure a healthy life. Endocrine diseases can be caused by: (1) under or over hormone production; (2) resistance to the effects of a hormone (receptor or downstream signaling); and (3) neoplasms with under or over hormone production. The whole picture of the Reproductive and Endocrine System • Lecture 1: Male and female reproductive diseases • Lecture 2: Diseases in pituitary, thyroid, and parathyroid • Lecture 3: Diseases in adrenal gland, pancreas, and others https://anatomy-medicine.com/endocrine-system/ Q1: Two major functions? Epididymis Q1: Reproductive diseases you know https://www.niehs.nih.gov/health/topics/conditions/repro-health Learning Objectives/Outline of Reproductive diseases • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian cancer o Endometriosis o Endometrial hyperplasia and neoplasia Male Reproductive System Ureter Vas deferens Bladder Seminal vesicle Bladder Ureter Rectum Seminal vesicle Vas deferens Prostate Bulbourethral gland Corpus spongiosum Urethra Corpus cavernosum Prostate Bulbourethral gland Epididymis Penis Epididymis Glans Testis Scrotum Penis Testis Scrotum Urethra Q: whey testes are located outside the main body? Male Reproductive System Head Basal lamina Epididymis Leydig cells Seminiferous tubules Mid piece Nucleus Capillary Lumen Vas deferens Spermatozoa Testis • • • 250-300 seminiferous tubules 0.3 -1 m long for each 2.5 football field long for all Acrosome Tail Spermatid Secondary spermatocyte Primary spermatocyte Spermatogonium Basal lamina Leydig cells Mitochondria Sertoli cell Hormonal Control of Male Reproduction • The hypothalamus-pituitary-gonad (HPG) axis is essential for both male and female reproduction • Hypothalamus releases pulsatile gonadotropin-releasing hormone (GnRH) which transports to the anterior pituitary to stimulate the secretion of FSH and LH • FSH binds to surface FSH receptors in Sertoli cells and stimulate the production of anti-mullerian hormone (AMH during fetal life stage), inhibin, activin, estradiol • LH binds to surface LH receptors in Leydig cells and stimulate the production of androgen (testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA)) Q1: Are FSH and LH lipid or water soluble? Q2: Are FSHR and LHR membrane or nuclear receptors? • • • GnRH: gonadotropin releasing hormone LH: luteinizing hormone FSH: follicle-stimulating hormone Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian tumor o Endometriosis o Endometrial neoplasia Male Reproductive Disease – Cryptorchidism Two phases of testicular descent: • Phase I: the testis descends into the lower abdomen (AMH dependent, uncommon 5-10%) • Phase II: the testis descends into the scrotum via the inguinal canal (androgen-dependent, common, 90%) • A complete or partial failure of the intra-abdominal testes to descend into the scrotum • 1-3% in 1 year old boys (spontaneous descent occurs within a year), bilateral in 25% and unilateral in 75% of all patients • Clinical consequences: testicular dysfunction, infertility, and an increased risk of testicular cancer https://www.nejm.org/doi/pdf/10.1056/NEJMra1514010 Male Reproductive Disease – Cryptorchidism Normal testis Failed decent testis • Pathological changes occur as early as 2 years of age • Thick basement membrane (basal lamina), loss of spermatogonia with Sertoli cells only, similar pathological changes may also be seen in the contralateral testis (descended testis), indicating that cryptorchidism is a marker of defective gonad development. Male Reproductive Disease – Testicular Tumor Classification • Germ cell tumor (GCT, common 95%) • Sex-cord-stromal tumor (somatic cell origin) • Rare worldwide (1.5/100,000), highest in Caucasian males (7.2-8.7) and lowest in Africa (0.3-0.6) / Asia (0.4-1.7) Male Reproductive Disease – Testicular Tumor Embryonic stem cell Primordial germ cell • Associated with both environmental and genetic factors (Finnish immigrants to Sweden have increased GTCs) • Stay dormant and is activated upon puberty when hormone may stimulate germ cell growth • Environmental factors: gestational exposure to pesticides and non-steroid estrogens (endocrine Male Reproductive Disease – Testicular Tumor Seminomatous GCT (seminoma) Non-seminomatous GCT (nonseminoma) Homogeneous, gray-white, lobulated cut surface, non-hemorrhagic Distinct cell borders, pale nuclei, and abundant cytoplasm Aggressive, Hemorrhagic mass Non-distinct cell borders, cells with large, hyperchromatic (darker) nuclei arranged in sheets and poorly formed glands. • GCTs can be further classified into seminomatous (primordial germ cell-like cells) and nonseminomatous tumor (embryonic stem cell-like cells) Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian cancer o Endometriosis o Endometrial neoplasia Female Reproductive System Ovary Fallopian tube A Ovary B Fimbriae C Uterus F Cervix Vagina E D Female Reproduction – Ovary Early tertiary/antral follicle Dominant or Secondary preovulatory follicle follicle Primordial follicle Primary follicle Oocyte Granulosa cells Theca cells Ovulation Corpus luteum Female Reproduction – Ovary Antral follicle Corpus luteum Antral follicle embryology.med.unsw.edu.au webpath.med.utah.edu/ Female Reproduction – Uterus Outer connective tissues Endometrium Myometrium Uterine cavity Uterine artery • • Where an embryo implants and develops Three layers with histological and structural changes during menstrual cycle in response to ovarian hormones Female Reproduction – HPG hormonal regulation and Uterus Follicular phase Ovulation Luteal phase Proliferative phase LH Secretory phase Gonadotrophin levels FSH Ovarian cycle Tertiary follicle Antrum Dominant follicle Ovulation Corpus luteum Secretory vacuoles corpus luteum Progesterone Ovarian hormone levels Estrogen Late secretory phase Inhibin Uterine cycle Proliferative Phase Menses Day 28/0 7 Secretory phase 14 21 28/0 Menses Female Reproduction – Pregnancy Days 2–4: Cell division takes place Day 1: Fertilization Day 4-5: Blastocyst reaches uterus. Inner cellcell mass Inner mass Trophoblast Zygote Blastocyst Egg Ovulation Blastocyst Ovary Days 5–9: Implantation Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian tumor o Endometriosis o Endometrial neoplasia Female – Premature Ovarian Insufficiency/Failure (POI/POF) Normal POI • Amenorrhea or menopause before 40 years of age, with <1000 primordial follicles • Associated post-menopausal syndrome, endocrine disorders, and infertility, and systemic defects (e.g., bone loss) • Lab results: low estrogen, low AMH, high FSH, and absence of LH surge https://pubmed.ncbi.nlm.nih.gov/24512962/ Female – Premature Ovarian Insufficiency/Failure (POI/POF) • Fragile X Syndrome (FXR): mutation of FMR1 genes (X chromosome) causes abnormal brain development, intellectual disabilities, and POI and associated reproductive dysfunctions. https://www.nature.com/articles/ejhg200861 Female – Premature Ovarian Insufficiency/Failure (POI/POF) Doxorubicin 10 mg/kg BW via i.p. injection day 1 5-day-old CD-1 female mice Control Doxorubicin 3 day 1 Number of follicles/ ovary Number of various stages of follicles Total follicles 2500 Primordial 2000 Primary Secondary 1500 day 3 1000 ** * 500 0 ** * Series1 Day r nt Co 1 ol X DO 50 µm 3 n Co l tro X DO *p<0.05, **p<0.01. Wang et al, TAAP, 2020 Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian tumor o Endometriosis o Endometrial neoplasia Female – Ovarian Tumor/Cancer Ovarian tumor/cancer classification Based on malignance • Benign ovarian tumor (80%, 20 - 45 years of age) • Borderline ovarian tumor (slightly older age) • Malignant ovarian tumor or cancer (post-menopausal age) Based on origin • Ovarian surface/fallopian tube epithelium or endometriosis (most common) • Germ cell ovarian tumor, which migrate to the ovary from the yolk sac and are pluripotent (abnormal PGC) • Stromal/sex cord cell ovarian tumors (GC ovarian tumor) • Ovarian tumor – 80% are benign and 20% are cancerous; benign ovarian tumor can be asymptomatic • Ovarian cancer accounts for 3% of all cancers in women but is the 5th most common cause of death https://www.nejm.org/doi/pdf/10.1056/NEJMra1514010 Female – Ovarian Tumor/Cancer Ovarian tumor can also be broadly grouped into type I and type II • Type I: benign to borderline ovarian tumor • Type II: high-grade serous ovarian cancer (HGSC) • Pathogenesis of high-grade serous ovarian cancer  Ovulation-induced inflammation (protective effects birth control pills)  Germline mutation of BRCA1, BRCA2, or TP53 tumor suppressor genes • Low-grade serous ovarian cancer has KRAS and BRAF mutation Angelina Jolie Credit MacGregor/Reut Mutation in BRCA1 gene and performed salpingo-oophorectomy STIC: serous tubal intraepithelial carcinoma Female – Ovarian Tumor/Cancer Low-grade serous High-grade serous Stroma invasion Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian cancer o Endometriosis o Endometrial neoplasia Female Reproductive Disease – Endometriosis • The presence of endometrial tissues (glands + stroma) outside the uterus (ovaries, fallopian tube, or intestines …) • 10% in reproductive aged women (most common in 30s– 40s) • https://www.nejm.org/doi/full/10.1056/nejmcp1000274 https://www.nejm.org/doi/full/10.1056/nejm199306173282407 Female Reproductive Disease – Endometriosis • Three pathogenesis theories: (1) from uterine endometrium – retrograde menstruation or via blood vessels; (2) transformation of peritoneal cells; (3) from stem or progenitor cells • • Release of proinflammatory and angiogenic factors Treatments: hormones (aromatase inhibitor), surgery, pain killer https://www.nejm.org/doi/full/10.1056/nejmcp1000274 https://www.nejm.org/doi/full/10.1056/nejm199306173282407 Learning Objectives/Outline • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian tumor o Endometriosis o Endometrial hyperplasia and neoplasia Female – Endometrial hyperplasia Typical Atypical • • • • • Definition: abnormal proliferation of the endometrial glands relative to stroma; two types: typical and atypical Prevalence: 150/100,000 women with endometrial hyperplasia; Pathogenesis: prolonged and unopposed estrogen stimulation: obesity (why?), PCOS, anovulation, granulosa cell tumor, estrogenic substance exposure, mutation of tumor suppressor gene PTEN (20%) Symptoms: Irregular period (short, long or absence), heavy bleeding, anemia Treatment: progesterone therapy, hysterectomy Female – Endometrial neoplasia (most common) • • • • • (most common) Prevalence: 30/100,000 with endometrial cancer, rare < 40, peak in 55-65 years; Two types of endometrial neoplasia: endometrioid (adenocarcinoma, 80%) and serous endometrial carcinoma (more aggressive); Pathogenesis: type 1 is from endometrial hyperplasia in peri-menopausal women and type 2 is from endometrial atrophy in older post-menopausal women; Symptoms: irregular or post-menopausal bleeding, pelvic pain; Treatment: Chemo, radiation, hormone therapy, immunotherapy, hysterectomy … Female – Endometrial neoplasia Type I Type II Female – Endometrial neoplasia Type 1 endometrial (endometroid) adenocarcinoma Grade 1: Well-differentiated with preserved glandular architecture and infiltration in myometrium (B) Grade 2: Moderately differentiated with glandular architecture but mixed with solid areas (C) Grade 3: Poorly differentiated with a predominantly solid growth pattern (D) Female – Endometrial Hyperplasia and Neoplasia Type II endometrial neoplasia A. Early stage of type II endometrial intraepithelial carcinoma, the precursor to serous carcinoma Strong, diffuse expression of altered p53 in endometrial intraepithelial carcinoma. B. Serous endometrial carcinoma with papillary growth pattern consisting of malignant cells with marked cytologic atypia including high nuclear-tocytoplasmic ratio, atypical mitotic figures, and hyperchromasia. Accumulation of altered p53 protein Learning Objectives/Outline or Reproductive Diseases • Male and female reproductive system anatomy and biology • Male reproductive diseases o Cryptorchidism o Testicular tumor • Female reproductive diseases o Premature ovarian insufficiency / failure (POI/POF) o Polycystic ovarian syndrome (PCOS) o Ovarian cancer o Endometriosis o Endometrial hyperplasia neoplasia