REPRODUCTIVE SYSTEM: FEMALE GONADS Deanne G.

Asdala, MD Outline Structure of the Female Reproductive system Oogenesis Female hormones Hormonal Action and Regulation The Ovarian and Menstrual cycle The Female Sexual act Abnormalities of Ovarian function Female External Genitalia

Gonadal Drainage Venous drainage Left ovary/testis gonadal vein renal vein IVC Right ovary/testis gonadal vein - IVC Lymphatic drainage Ovaries/ testis para-aortic lymph nodes Most important principal organs of the female repro tract: ovaries, fallopian tube, uterus and vagina The Ovary

Germinal epithelium- outer surface of the ovary derived from the germinal ridges epithelium Primordial ova from the germinal epithelium Oogenesis Ovaries contain 7 million primordial follicles during fetal devt. At the time of birth: 2 million ova, 50% are atretic Uterine ligaments Suspensory ligament Contains ovarian vessels Transverse cervical ligament (Cardinal) Uterine vessels Round ligament No important structure Broad ligament Round ligament of uterus and ovaries and uterine tubules and vessels

Remaining ova undergo 1st part of Meiotic division until prophase stage Atresia continuous during development At puberty: less than 300,000 ova in both ovaries One ova matures per cycle In humans, no new ova are formed after birth. Ovaries contain 7 million primordial follicles during fetal development. Many undergo atresia(involution) before birth. Remaining ova undergo 1st part of Meiotic division and enter a stage of arrest until prophase stage in those that survive persist until adulthood Only one ova reaches maturity per cycle, the remainder degenerate Page 1 of 8

produced by granulosa cells ; if u see an antrum = secondary follicle granulosa cells on one side of follicle surrounds the oocyte to form = cumulus oophorus

Primordial Follicle Surrounded by single layer of follicular cells

Oocyte maturation- inhibiting factor keeps the ovum suspended in its primordial state in the prophase stage of meiotic division 400-500 primordial follicles develop during the reproductive years to expel an ova-one each month. The remainder degenerates or become atretic Primordial follicle- ovum(immature)surrounded by a single layer of follicular cells oocyte maturation-inhibiting factor that keeps the ovum suspended in its primordial state in the prophase stage of meiotic division

tertiary/ graafian follicle-Largest ones in slide, usualy closer to center of slide theca interna and theca externa are thicker cresent shapen antrum is now seen (formed by merging of previously seen vacuoles) corona radiata (communicates with gap junctions)

Primary Follicle Primary follicle -1st,2nd follicular cells enlarge and become cuboidal = now called granulosa cells,these cells later form the corona radiata ; zona pellucida starts to appear Granulosa cells- layer of spindle cells from the ovarian stroma Theca several layers of granulosa theca internaestrogen,progesterone theca externa-capsule of the follicle

Secondary Follicle

Dominant follicle-estrogen from the most rapidly growing follicle act onthe hypothalamus to depress further enhancement of FSH secretion by the anterior pituitary gland, in thisway blocking further growth of the less well developed follicles. becomes matured follicle at the time of ovulation. Outer wall of capsule protrudes(growth of new blood vessels into the follicle wall, and prostaglandins (vasodilation) and theca externa release lysosomes that dissolutes the capsule), the stigma releases fluid and the ovum surrounded by the corona radiata Oocyte Maturation Oocytes stay in primary follicle until prophase I of 1st Meiotic division

Before ovulation: 1st meiotic division is completed

2ndary follicle - antrum vacuoles start to appear with follicular fluid inside, that contains peptides Page 2 of 8

*Diminished liver function causes Hyperestrinism Secondary oocyte receives most of the cytoplasm; the other 1st polar body fragments and disappears Asymmetrical cell division (cytokinesis) leads to the production of polar bodies during oogenesis. To conserve nutrients, the majority of cytoplasm is segregated into the secondary oocyte during meiosis I, and the ovum during meiosis II. The remaining daughter cells generated from the meiotic events are small and contain relatively little cytoplasm and are referred to as polar bodies. Eventually, the polar bodies degenerate. There may be one or two polar bodies in the ovum. The first polar body is one of the two products in the first stage of meiosis and is considered haploid, with 23 chromosome pairs and 46 chromatids. The second polar body is haploid, with 23 chromosomes and 23 chromatids. Sometimes the first polar body undergoes the second meiotic cell division. Hormones Theca interna have LH receptors which acts via cAMP to increase conversion of cholesterol to androstenedione which is supplied to the granulosa cells Granulosa cells make estradiol when provided with androgens. FSH receptors in GC facilitates secretion of estradiol by acting via cAMP to increase their aromatase activity. GC also acquire LH receptors which stimulates estradiol production

GnRH hypothalamic releasing hormone, secreted in short pulses once every 90 mins. LH, FSH anterior pituitary sex hormone secreted in response to GnRH Estrogen, progesterone secreted by the ovaries in response to the anterior sex hormones (LH,FSH) Estrogen Naturally occurring estrogens

Functions: Maturation and growth of reproductive organs Follicular growth; feedback FSH inhibition Endometrial proliferation, Myometrial excitability Development of breast stroma Development of secondary female sexual characteristics Stimulates bone growth Female fat distribution HDL, LDL Ovaries, vagina, uterus,ft increase size. Ext genitalia enlarge- deposition of fat in the mons Changes vaginal epithelium cuboidal-stratified (resistant to trauma, infection) Growth of stromal tissue and ductile system and deposition of fat- 10 days preceding menstruation: breast swelling, tenderness, pain due to distention of ducts, hyperemia, and edema of interstitial tissue of breast Bone growth-causes uniting of epiphyses with the shafts osteoporosis- in menopause. No estrogen secreted. Increased Osteoclast activity, dec bone matrix, dec ca and po4 deposition tx: estrogen replacement also: inc BMR, fat deposition in SQ tissues, soft skin that is warm, more vascular, slight effect on na and h20 retention esp during pregnancy

17-Estradiol, Estrone, Estriol Secreted by the granulosa cells of ovarian follicles, corpus luteum, placenta Formed from Androgens and Androstenodione Aromatase enzyme catalyzes conversion of androstenodione to estrone and testosterone to estradiol( most potent) Estradiol(major secreted estrogen) -estradiol secreted by the ovaries Estrone secreted by adrenal cortex and thecal cell Estriol secreted by placenta, occurs in the liver *Diminished liver function causes Hyperestrinism

Estrogen Potency: Estradiol> Estrone > Estriol Bounded to Albumin (60%) and Gonadal steroid binding globulin (38%), rest free in the circulation (2%) Excreted in the urine, secreted in the bile and reabsorbed in the bloodstreams Estradiol(OVARY) most potent estrogen, estriol (PLACENTA)the least

Synthetic Estrogen Ethinyl derivative of Estradiol Active when given by mouth unlike naturally occurring estrogen Diethystilbesterol (DES) estrogenic Estradiol effects Reduces symptoms of menopause Prevents development of osteoporosis Reduces progression of atherosclerosis Stimulates growth of endometrium and breast Tamoxifen, Raloxifene bone preserving and cardiovascular effects of estradiol Resistant to hepatic metabolism vs. naturally occurringinactivated in the liver before reaching circulation DES estrogenic- converted to a steroid ring like structure. Teratogenic: vaginal clear cell ca Stimulates growth of endometrium and breast may develop Cancer of the uterus, breast Tamoxifen doesnt stimulate breast; Raloxifene doesnt stimulate the uterus, breast (both doesnt combat menopause sxs)

ER alpha is found primarily in the uterus, kidneys, liver, and heart, whereas ER beta is found primarily in the

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ovaries, prostate, lungs, gastrointestinal tract, hemopoietic system, and central nervous system (CNS). Progesterone Secreted by the corpus luteum, placenta, adrenal cortex, testes Bounded to Albumin (80%) and Gonadal steroid binding globulin (18%); 2% free in the circulation Intermediate in secreting steroid hormones, enter circulation from the testes and adrenal cortex Excreted in the urine synthetic steroid mifepristone (RU 486) binds to the receptor but does not release the heat shock protein, and it blocks the binding of progesterone- abortion Function: Promote secretory changes in the endometrium and spiral artery development Decreases uterine contractions Maintenance of pregnancy Development of lobules and alveoli of the breast Increase body temperature Inhibition of gonadotrophins Endometrium - Preparation for pregnancy Uterine smooth muscle relaxation inc temp 0.5F Gonadotrophins LH, FSH

2. CL involutes , FSH increases again then after a few days LH increases-initiates follicle growth and increase in E (11-12 days, dec FSH,LH bec of negative effect of E but after there is sudden increase in LH then FSH-this is the preovulatory surge followed by ovulation) Hormonal Regulation

1. 2. 5. 6.

Hormonal Control

Before LH surge, 2 days before: secretions of both FSH and LH by the anterior pituitary gland are at first slightly suppressed. Then secretion of LH increases abruptly sixfold to eightfold, and secretion of FSH increases about twofold. The greatly increased secretion of LH causes ovulation to occur After LH SURGE: Progesterone and estrogen, inhibin combined negative feedback effect on the anterior pituitary gland and hypothalamus, causing the suppression of both FSH and LH secretion and decreasing them to their lowest levels about 3 to 4 days before the onset of menstruation Puberty Puberty Onset of adult sexual life Caused by gradual increase in gonadotrophic hormone by age 8 Menarche onset of menstruation Female Secondary Sex Characteristics

Pulsatile release of GnRH occurs in the mediobasal hypothalammus(arcuate nuclei) every 1-2 hrs lasting 5-25 mins stimulates Ant.pituitary secretion of LH and FSH Estrogen inhibits LH, FSH in the ant.pituitary augmented by the presence of progesterone* Inhibin secreted along w/ the steroid sex hormones by the CL inhibits FSH>LH * *Negative feedback Estrogen** during the preovulatory stage cause LH secretion and lesser extent FSH. Progesterone** secreted b4 preovulatory LH surge stimulates LH secretion **positive feedback 1.Postovulatory (bet ovulation and beginning of menstruation) CL secretion of E,P and inhibin causes supression of LH,FSH

Pubic and axillary hair androgen Breast estrogen cream- systemic absorption causes enlargement Estrogen pigmentation of the areola Ovarian Cycle

Ovarian Cycle

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Primordial follicle- ovum w/ a single layer granulosa cell Granulosa cells provide nourishment for the ovum and secrete an oocyte maturation-inhibiting factor keeping ovum in primordial state in the prophase stage of meiosis Follicular Phase (Day 1-14) Primordial follicle develops LH and FSH receptors are up-regulated Estradiol levels increase proliferation of the uterus FSH and LH levels are suppressed Progesterone levels are low Ovarian Cycle

Corpus luteum lipid inclusions-yellow appearance; Secretes progesterone and estrogen (granulosa cells) and androgens (theca cells); depends on blood supply, VEGF; persist during pregnancy; Corpus albicans luteum degenerates 4 days before the next menses or after 12 days loses lipid; replaced by connective tissue and is absorbed over the next mos Luteal Phase (Days 15-28) Corpus luteum begins to develop Vascularity and secretory activity of the endometrium increases Corpus luteum regresses if no fertilzation happens Ovarian Cycle Involution of the corpus luteum Inhibin inhibits secretion by the anterior pituitary esp. FSH Corpus luteum degenerate (Involution) Cessation of Estrogen, Progesterone and Inhibin allows increase of LH, FSH again growth of new follicles and a new ovarian cycle begins Inhibin inhibits FSH - low FSH, LH corpus luteum degenerates 2 days before menstruation Uterine Cycle Uterine cycle/ menstrual cycle Day 1-5 = Menstruation Day 5-6 Regeneration Day 6-14 Proliferative/Estrogen phase Day 14-28 Secretory/Progesterone/Luteal phase Uterine Cycle

Follicle enlarge every cycle Mass of granulosa cells secrete a follicular fluid-containing high estrogen concentration. Accumulation of fluid causes formation of cavity around the Antrum Dominant follicle 1 of the follicle grow rapidly on the 6th day; depends on the ability of follicle to secrete estrogen. Injection of gonadotrophins , follicles develop simultaneously Atretic follicle Estrogen from the most rapidly growing follicle acts to depress FSH, blocking growth of other less developed follicles (apoptosis) Graafian mature follicle estrogen from theca interna Ovarian Cycle Ovum picked up by fimbria of oviducts transported to the uterus unless fertilization occurs out in the vagina Corpus hemorrhagicuum minor bleeding in the abdo.cavity mittleschmerz - lower abdo pain Ovulation (Day 15) Occurs 14 days before menses LH surge caused by burst of estradiol Estrogen levels decrease Cervical mucus increases in quantity Ovarian Cycle Outer wall of capsule protrudes(growth of new blood vessels into the follicle wall, and prostaglandins (vasodilation) and theca externa release lysosomes that dissolutes the capsule), the stigma releases fluid and the ovum surrounded by the corona radiata Ovarian Cycle

The Menstrual Cycle Rhythmical changes in the female hormone secretion and physical changes in the ovaries and sexual organs Averages 28 days (20-45 days) Single ovum released and uterine endometrium is prepared for implantation of the fertilized ovum

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Averages 28 days (20-45 days); abnormal cycle length assoc. w/ decreased fertility Significant events during the menstrual cycle: Single ovum is released normally each month and uterine endometrium is prepared for implantation of the fertilized ovum

Amenorrhea emotional stimuli, envt changes, hypothalamic and pituitary disorders, primary ovarian disorders, systemic diseases Secondary amenorrhea always rule out pregnancy Dysmenorrhea- disappears after 1st pregnancy caused by prostaglandins Premenstrual Syndrome (PMS)

Corpus luteum regress-hormonal support(prog,estrogen) is withdrawn endometrium thinner, coiling of the arteries-spasm necrosis of spiral arteries leads to spotty hemorrhage producing menstrual flow-leukocytes fibrinolysin released Endometrium layers: stratum functionale long, coiled spiral arteries stratum basale short straight basilar arteries

attributed to salt and water retention

Menopause

The endometrium is supplied by two types of arteries. The superficial two thirds of the endometrium that is shed during menstruation, the stratum functionale, is supplied by long, coiled spiral arteries (Figure 2523), whereas the deep layer that is not shed, the stratum basale, is supplied by short, straight basilar arteries. Menstruation Vasospasm of blood vessels produced by prostaglandins Menstrual blood predominantly arterial with tissue debris, prostaglandins and fibrinolysisn New endometrium regenerates from stratum basale Vasospasm- initiates necrosis in the endometrium lysosomal membranes breakdown w/ release of prostaglandins Desquamation of the tissue and blood in the uterine cavity + contractile effects of prostaglandins mens occurs (30 ml blood lost, >80 ml abnormal) Mens fluid is nonclotting bec of fibrinolysin.(unless excessiveblood clots) , leukocyte-protective value Re-epitheliazation occurs after 4-7 days, mens stop Menstrual Abnormalities

HAVOC in Menopause

Physiological Menopausal Changes Hot flushes Psychic sensations of dyspnea Irritability Fatigue Anxiety Psychotic states Decreased strength and calcifications of bones Anovulatory Cycle Page 6 of 8

Indicators of Ovulation Basal body temperature increase in progesterone Thin, stringy cervical mucus Spinnbarkeit, Ferning pattern Check urine for Pregnanediol Temperature in the a.m. before getting out of bed. Progesterone is thermogenic. Ovulation 9 hrs after peak of LH surge. Ovum lives 72 hrs after being extruded from the follicle, fertilizable much shorter time. Most fertile period- 48 hrs before ovulation Spinnbarkeit elasticity 8-12cm thin, alkaline mucus for survival of sperms (estrogen) ovulation thinnest mucus Ferning after ovulation and pregnancy thick and fails to form fern pattern Fertility 4-5 days before ovulation, few hrs after. Avoid copulation: 4 days before ovulation, 3 days after Pills - administration of either of these hormones can prevent the preovulatory surge of LH secretion by the pituitary gland, which is essential in causing ovulation. sudden depression of estrogen secretion by the ovarian follicles, and this might be the necessary signal that causes the subsequent feedback effect on the anterior pituitary that leads to the LH surge *Analyze the urine for Pregnanediol, the end product of progesterone metabolism - lack of this substance indicates failure of ovulation Failure to ovulate treated w/ HCG same effects w/ LH side effect: multiple births Female Sexual Act Stimulation Erection and lubrication Orgasm Resolution

Sexual act: Erection and Lubrication Parasympathetic signals Dilates the arteries of erectile tissue introitus tightens Pass thru the Bartholins glands- secrete mucus inside the introitus for climax Parasympathetic Ach, NO, VIP - vasodilation Mucus vestibular glands release fluid in the vaginal walls, prob. release of VIP from vaginal nerves Sexual act: Orgasm Maximum intensity of stimulation Analogous to emission and ejaculation in male Promotes fertilization Contraction of perineal muscles and increase uterine and fallopian tube motility Dilation of cervical canal Rhythmic contraction of vaginal wallstransports sperm upward toward the ovum Dilation of cervical canal Upto 30 mins easy sperm transport Perineal muscles-ischio,bulbocavernosus muscle

1. 2. 3.

Sexual act: Stimulation Successful performance depends on psychic stimulation and local sexual stimulation Depends on background training, level of sex hormones Transmitted through the pudendal nerve and sacral plexus to the sacral segments of the spinal cord Glans of clitoris, breast, vulva, upper part of vagina-highly infiltrated with smooth muscles and blood vessels which engorges during sexual arousal - sensitive to stretch , perineal region (labia minora) tactile stimulation adds to sexual excitement Limbic system (psychic center) transmit signal to the arcuate nuclei in the mediobasal hypothalamus modify GnRH stimulation-control sexual function

Sexual act: Resolution After culmination of the sexual act Period of satisfaction and relaxed peacefulness Abnormalities of Ovarian Function Hypogonadism Poorly formed ovaries, lacks ovaries, genetically abnormal ovaries that secrete wrong hormones E.g. Hypothyroidism amenorrhea occurs Kallmans syndrome (Hypogonadotropic hypogonadism) HYPOGONADISM DEC ESTROGEN SECRTED, OVULATION DOEsNT NORMALLY OCCUR KALLMAN- rare X-linked recessive disease characterized by reduced or complete absence of the sense of smell (anosmia), underdeveloped genitalia and sterile gonads. gynecomastia, bimanual synkinesis (one hand copying the movements of the other hand), shortened fourth metacarpal bone and an absent kidney. GnRH, FSH, LH resistance Defects in GnRH, FSH, LH receptors Aromatase deficiency

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Prevents estrogen formation McCune-Albright syndrome Associated with precocious puberty, amenorrhea, galactorrhea Female Eunuchoidism Absent ovaries from birth or nonfunctional before puberty Secondary sexual characteristics absent, infantile sexual organs, prolonged growth of long bones Estrogen closure of epiphysis

endometrium grows in areas of the body where it is not supposed to. This can cause significant pain, irregular bleeding, and quite possibly infertility. In most cases of endometriosis, the tissue tends to grow in the pelvic area, including the outside of the uterus, on the bowels, rectum, ovaries, bladder, and the lining of the pelvis. Occasionally the endometrium will grow in other parts of the body as well, although this is considered quite rare. Endometrial tissue almost identical to that of the normal uterine endometrium grows and even menstruates. fibrosis throughout the pelvis, and this fibrosis sometimes so enshrouds the ovaries that an ovum cannot be released into the abdominal cavity Symptoms of endometriosis may include menstrual periods that are increasingly painful, lower abdominal pain, pelvic cramping for a week or two prior to menstruation, Lower abdominal cramping and pain felt during menstruation, pelvic pain at any time during menstruation, back pain felt at any time during menstruation, pain during intercourse, pain after intercourse, pain with bowel movements, spotting before menstruation, or infertility. Most women have cramps during menstruation. Endometriosis is significantly painful beyond normal cramping associated with menstruation. TX: NSAIDS, SX, OCP, Danazol, Gonadotropin-releasing hormone analogs (GnRH analogs) have been effectively used to relieve pain and reduce the size of endometriosis implants. These drugs suppress estrogen production by the ovaries by inhibiting the secretion of regulatory hormones from the pituitary gland. As a result, menstrual periods stop, mimicking menopause SALPINGITIS Infection and inflammation of the fallopian tubes Fibrosis occludes the tubes preventing fertilization ABNORMALITIES OF THE CERVICAL MUCUS Low-grade infection or inflammation, or abnormal hormonal stimulation of the cervix - lead to a viscous mucous plug that prevents fertilization Suboptimal mucus conditions that effect sperm survival and penetration ("hostile mucus") include: * (1) very thick and viscous mucus, which limits sperm penetration * (2) antisperm antibodies (in semen or mucus) such that complement dependent inactivation of sperm within the mucus results in nonmotile sperm or sperm "wiggling in place" within 2 hours of intercourse * (3) low (acidic) mucus pH, which may inactivate or destroy sperm * (4) infection within the cervix with inflammatory cells in the mucus digesting the sperm since they are identified as "foreign material

Granulosa cell tumor Feminizing tumor that occurs after menopause Hypersecretion of estrogen causes: Hypertrophy of uterine endometrium Irregular bleeding from the endometrium INC ESTROGEN, DEC GONADOTROPHIN PRODUCTION (DEC LH, FSH) - excessive secretion of estrogens automatically decreases the production of gonadotropins by the pituitary, and this limits the production of ovarian hormones Failure to ovulate treated w/ HCG from placenta same effects w/ LH side effect: multiple births Human Chorionic Gonadotrophin Treatment for hyposecretion of gonadotrophic hormones Same function as the LH Excessive use: multiple births Lack of ovulation caused by hyposecretion of the pituitary gonadotropic hormones can sometimes be treated by appropriately timed administration of human chorionic gonadotropin,

Female Sterility Causes of infertility: Endometriosis Salpingitis inflammation of the fallopian tubes; this causes fibrosis in the tubes, thereby occluding them Cervical Mucus abnormalities low-grade infection or inflammation, or abnormal hormonal stimulation of the cervix can lead to a viscous mucous plug that prevents fertilization

ENDOMETRIOSIS The endometrium is the name of the tissue that lines the uterus. Endometriosis is the condition that occurs when the Page 8 of 8