FEMALE REPRODUCTUVE SYSTEM

Female reproductive organs Figure 81-1

Internal structures of the uterus, ovary and a Fallopian tube Figure 81-2

Fundamental reproductive unit = single ovarian follicle, composed of one germ cell (oocyte), surrounded by endocrine cells. Oogenesis : A developing egg (Oocyte) becomes Mature egg (Ovum) through series of steps.

Oogenesis: Oogonia produced by mitotic division (max # = 7 mil), Then during the last part (5 th month) of fetal life, prophase of 1 st meiosis starts but do not complete becomes primary oocyte (they contain diploid number of chromosomes 46 but do not separate). The primary oocytes stay in this meiotic arrest for years until prepare for ovulation. Number of primary oocytes decreases throughout childhood from 1-2 mil to 400,000 just before puberty. Before birth each oocyte surrounded by single layer of granulosa cells -- called primordial follicle -- complete about 6 mos after birth

Female hormonal system 1. Hypothalamic releasing hormone, gonadotropin releasing hormone GnRH 2. Anterior pituitary sex hormones,fst and LH 3. Ovarian hormones, estrogen and progesterone secreted in response to pituitary hormones 4. These hormones secreted at different rate during different parts of the female monthly sexual cycle.

Prior to birth first meiosis stops in prophase Pre-puberty MENARCHE 400,000 primary oocytes left 6-12 follicles develop One dominant follicle matures Ovulation -- end 1 st meiosis -- start 2 nd meiosis in fallopian tubes Figure 81-4

Differences between spermatogenesis and oogenesis 1. In females, mitotic proliferation of oogonia occurs prior to birth. In males, spermatogonia proliferate only after puberty. 2. In females, meiotic divisions of oocyte produces only one mature ovum. In males, meiotic divisions of primary spermatocyte produces 4 mature spermatozoa 3. In females, second meiotic division is completed only upon fertilization. In males, the products of meiosis (spermatids) undergo substantial differentiation in the maturing process.

The Basics Gametogenesis

Female sexual cycle: Menstrual cycle -- controlled by gonadotropins, gonadal hormones Ovarian cycle-- follicular phase -- avg 15 d (range, 9-23 days) ovulatory phase -- 1-3 d -- culminates with ovulation luteal phase 13 d -- less variable than follicular Endometrial cycle -- menstruation, proliferative and secretory phases

OVARIAN CYCLE In female child each ovum is surrounded by single granulosa cells sheath called primordial follicle. Granulosa cells provide nourishment to the ovum and secrete oocyte maturation inhibition factor that keep the ovum in suspended in its primordial state. After puberty LH and FSH increase and cause growth of the follicle to becomes primary follicle.

Some spindle cells derived from ovary interstitium Collect in several layers outside granulosa giving rise to mass of cells outside granulosa cells called theca cells. 1- Theca interna secrete estrogen and progesterone 2-Theca externa form capsule of the developing follicle

After expulsion of the ovum from the follicle the remaining granulosa and theca interna cells change into lutein cells and growth to form corpus luteum. Now 1-Granulosa cells form progesterone and estrogen 2-Theca cells form androgen androstenedion and testosterone which are change by aromatase enzyme in the granulosa cells to estrogen

Introduction: Ovarian cycle is a series of monthly repetitive physiological and developmental changes in the ovaries, which prepare the ovaries for ovulation and subsequent development of a C.L whose hormones will assist in regulating the uterine cycle and, if the implantation of a developing embryo occurs, assist in regulating the pregnancy. It is regulated by FSH and LH from the anterior pit.

The changes that occur in the ovary during each cycle can be divided into three phases: 1) Follicular phase (day 1-13 ) 2) Ovulatory phase (day 13-15) 3) The luteal phase (day 15-28). These phases run in parallel with the phases of the uterine cycle and together comprise the menstrual cycle.

1) The follicular phase: Starts from the first day of menstruation until ovulation. The primary goal: to develop a viable follicle capable of undergoing ovulation. The early events initiated by in FSH levels at the first day of the cycle To a in P and E levels at the end of the previous cycle and the subsequent removal of inhibition of FSH by these ovarian hormones Stages: A- Primordial follicle C- Antral follicle B- Primary follicle D- Vesicular follicle

1) Follicular Phase of the ovarian cycle A.Primordial follicle (7 millions): ovum with granulosa cell (GC)sheath (nourisment & oocyte maturation-inhibiting substance). B. Primary Follicle: after puberty 2-3 fold increase, several layers of GC. 300,000 follicles C.Antral Follicle: FSH causes proliferation of GC, development of theca interna & theca externa, GC secrete follicular fluid rich in estrogen leading to antrum formation.

1) Follicular Phase, cont D. Vesicular Follicle: Estrogen makes GC more sensitive to FSH, FSH & Estrogen promote LH R, LH & Estrogen cause proliferation & secretion. On the 6 th day one follicle becomes dominant F, while others regress, forming atretic follicles. High level of estrogen acts on hypothalamus to decrease FSH by ant. Pit. Only one Graafian F (mature F with 1-1.5 cm diameter) is formed each month.

A)Approximately 500 oocytes are ovulated over the course of a lifetime. B) At ovulation: The follicle ruptures releasing the secondary oocyte and corona radiata into the peritoneal cavity to be taken up by the oviduct. The zona granulosa and thecal cells remain in the ovary. Discharge of the ovum occur (with part of the cumulus) of the mature Graafian follicle from the surface of ovary at the middle of the cycle (14+2 days before the subsequent menstruation).

Chemical mechanics of ovulation: LH surge prostaglandin endoperoxide synthase in granulosa cells (sets up pseudoinflammatory response) FSH (some LH) stimulates release of plasminogen activator from granulosa cells (converts plasminogen to plasmin) Prostaglandins E and F release lysosomal enzymes that digest follicular wall -- not completely understood Stigma -- forms on surface of follicle, balloons out, forms vesicle and ruptures -- oocyte expelled Process facilitated by intrafollicular pressure and contraction of smooth muscle in theca

Corpus luteum (CL): Occur after ovulation, Morphological changes occur in the remaining part of the follicle within the next 2-3 days converting it to CL. Formed from: The zona granulosa granulosa lutein Theca cells theca lutein cells & some capilaries & c.t. } Cells become cuboidal with central nucleus

Corpus leutum 1-Granulosa cells secrete mainly progesterone and estrogen 2- Theca cells form androgen,androstenedione and testosterone and these converted by enzyme aromatase in the granulosa cells into estrogen 3-Local hormone in the follicular fluid called luteinization- inhibiting factor hold luteinization until after ovulation

3) Luteal phase (cont) corpus luteum (cont.) CL produces Progesterone if pregnancy occur promote required progesterone until formation of the placenta Some estrogen. NB: resulting in secretory endometrium in preparation for reception of fertilized ovum Corpus luteum life span In the absence of fertilization, 14 days apoptosis Corpus albicans. If pregnancy occur, The chorionic gonadotrophin having LH like action causes further growth of CL ( and its hormonal production ) CL of pregnancy (support the early embryo until placenta takes over the function of E & P production).

Involution of CL 1-Estrogen and progesterone inhibit the secretion Of ant Pit FSH & LH cause degeneration of CL 2- Lutein cells secrete small amount of inhibin hormone which inhibit FSH secretion cause degeneration of CL

H-P-O axis 1. Positive feedback Sex hormones (E) GnRH or LH/FSH E peak ( 200pg/ml) LH/FSH peak During ovulation only. 2. Negative feedback Sex hormones (E) GnRH or LH/FSH Follicular phase: E FSH Luteal phase: E P LH/FSH (formation) E P LH/FSH (regrescospyrigihto 201n1 by Sa)unders, an imprint of Elsevier Inc.

Indicators of ovulation: i. Mid-abdominal pain (irritation of the peritoneum). ii. elasticity of cervical mucus iii. Cervical mucus dries in Arborizing form iv. Cornified cells in the vaginal mucosa v. Basal body temperature ( 0.5 o C) vi. Urinary E, and pregnanediol or plasma progesterone level during luteal phase(day 21) Absolute proof of ovulation is pregnancy.

C.Luteal phase a. Interval between ovulation and menstrual flow (15 th - 28 th day). b. Duration is κ: 14±2d (t½ = corpus luteum). c. Day of ovulation = Length of the menstrual cycle - 14d d. Predominant Hormone: Progesterone nc.

Corpus luteum Provides necessary hormones for implantation of blastocyst and maintenance of zygote until placenta can take over 80% granulosa cells, 20% thecal cells If not fertilization, will regress in about 14 d Avascular scar = corpus albicans

Ovarian Cycle: follicular phase luteal phase ovulation (FORMAT FOR NEXT FEW SLIDES) Endometrial 1 Cycle: 4 14 menstrual proliferative phase (11 d) secretory phase (12d) 28

Ovarian Cycle:follicular phase LH surge ovulation FSH and LH in the Follicular phase LH surge lasts 48 h Inc GnRH bursts FSH LH Endometrial Cycle: menstrual 1 4 14 proliferative phase (11 d) secretory phase (12d) 28

Ovarian Cycle: follicular phase LH surge ovulation Increase in estradiol to stimulate LH surge. Then estradiol has negative feedback on GnRH to reduce LH, FSH. estradiol FSH LH Endometrial Cycle: 1 4 14 Proliferative phase neg feedback--g nrh Secretory phase (12d) 28

Ovarian Cycle: follicular phase Changes in activin and inhibin in follicular phase. ovulation + FSH _ Granulosa cells Activin inhibin FSH activin inhibin 1 4 14 Endometrial Proliferative phase Cycle: menstrual Secretory phase (12d)28 activin inhibin

Ovarian Cycle: follicular phase ovulation Changes in progesterone in follicular phase. progesterone activin progesterone 1 Endometrial Cycle:menstrual 4 14 Proliferative phase (11 d) 28 inhibin

The uterine cycle and normal menstruation: Because of the monthly cyclic production of estrogens and progesterone, the endometrial lining of the uterus passes into three phases. They are; Proliferative phase, Secretory (or luteal phase), and menstrual phase.

1-Proliferative phase It is about 9-11 days in duration. Estrogen secreted in increasing quantities by the developing follicle causes proliferation of the epithelial cells left after endometrial desquamation. Endothelial re-epithelialization occurs within 4-7 days after the beginning of menstruation (when bleeding ceases). The next 7-10 days the endometrial thickness increases greatly to about 3-5 mm (formation of new endometrial glands and blood vessels). The mucus strings secreted by the endometrial glands (especially these of the cervix), align in the cervical canal, forming channels that guide sperm in the proper direction from vagina into the uterus.

2. The secretory phase (progesterone phase, luteal phase) The length of this phase is remarkably constant at about 14 days. Occurs after ovulation (the second half of the cycle). Estrogens cause slight additional cellular proliferation, whereas progesterone causes marked swelling and secretory development with further increase in blood supply to the endometrium. Both blood vessels and glands become highly tortuous. Lipid and glycogen deposit greatly in the stromal cells. The peak of the secretory phase is about 1 week after ovulation. At this time, the endometrial thickness reaches to 5-6 mm. During the secretory phase, the endometrium provides appropriate conditions for implantation of a fertilized ovum. The fertilized ovum needs 3-4 days to enter the uterine cavity from fallopian tube and another 4-5 days for implantation. During this intervals uterine secretions (uterine milk) provide nutrition for the early dividing ovum. Once the ovum implants, trophoblastic cells of the blastocyst begin to digest the endometrium.

3. Normal menstruation Occurs when fertilization fails to occur during the secretory phase (involution of corpus luteum). The usual duration of the menstrual flow is 3-5 days (1-8 days range). Blood loss reaches up to 80 ml (average 30-40 ml). Bleeding can increase because of medications and diseases that affect the clotting mechanism. 24 hours before menstruation blood vessels leading to the mucosal layers become vasospastic, presumably because of vasoconstrictor types of prostaglandins. The vasospasm + nutrients + hormonal stimulation endometrial necrosis Hemorrhage + Sloughing of outer layers of the endometrium Prostaglandins and desquamated tissues initiate uterine contractions that expel the uterine contents. The menstrual fluid is normally non-clotting because of released fibrinolysin. Clots presence may indicate uterine pathology. Menstrual flow is rich in leukocytes. This outflow of leukocytes may explain the resistance of uterus to infection during menstruation despite the denuded endothelial surface.

Normal menstruation

The standard classification of abnormal bleeding for patterns (1)Menorrhagia (hypermenorrhea) is heavy or prolonged menstrual flow during regular period. The presence of clots may not be abnormal but may signify excessive bleeding. (2)Hypomenorrhea (cryptomenorrhea) is unusually light menstrual flow, sometimes only spotting, during regular period. An obstruction such as hymenal or cervical stenosis may be the cause.

(3) Metrorrhagia (intermenstrual bleeding) is bleeding that occurs at any time between menstrual periods. (4) Polymenorrhea describes periods that occur too frequently, usually associated with anovulation and rarely with a shortened luteal phase in the menstrual cycle. (5)Oligomenorrhea describes menstrual periods that occur more than 35 days apart. Bleeding usually is decreased in amount and associated with anovulation, either from endocrine causes (eg, pregnancy, pituitary-hypothalamic causes, menopause) or systemic causes (eg, excessive weight loss).

Cyclic changes in Cervix, vagina & breasts: 1-Cervix 2-Vagina 3-Breasts Estrogen:make mucus Thinner,more alkaline If spread on slide dries in fern like manner Estrogen:cornification of vaginal epithelium Estrogen:Proliferation of breasts ducts Progesterone:make mucus thick,tenaciuous,more cellular,if spread on slide doesn t fern Progesterone:thick mucus secretion,proliferation of vaginal epithelium and leucocytes infiltration Progesterone:growth of breast lobules & alveoli

2011 by Saunders, an imprint of Elsevier Inc.

Ovarian Cycle: ovulation + Corpus albicans Luteal phase + FSH _ Granulosa cells Activin inhibin FSH activin inhibin 1 Endometrial Cycle: 4 14 Proliferative phase menstrual (11 d) Secretory phase (12d) 28

Ovarian Cycle: + Luteal phase Corpus albicans ovulation Levels of estradiol in luteal phase + FSH _ Granulosa cells Activin inhibin estradiol Endometrial Cycle: 1 4 14 proliferative phase FSH secretory phase 28 inhibin

Ovarian Cycle: follicular phase ovulation Corpus luteum + _ Luteal phase Corpus albicans Changes in estradiol And progesterone in luteal phase. + Produces inhib GnRH _ progesterone estradiol 1 4 mens Endometrial proliferative phase Cycle: 14 secretory phase 28

Functions of estradiol Fat deposition: more subcutaneous fat in women than men Estrogens: hips and thighs fat deposition (prior to menopause) then more abdominal (Men: androgens: abdominal fat deposition) Skin: increase vascularization of skin, smooth and soft. Bones: estrogen inhibits osteoclastic activity, so height increases after puberty,but epiphyses and shafts of bones unite early and growth stops

Functions of estradiol External female sex organs: at puberty, increase in size of fallopian tubes, uterus and vagina, external genitalia deposition of fat in mons pubis change vaginal epithelia from cuboidal to stratified type endometrium: proliferation of cells and endometrial glands (important in nutrition of fertilized ovum) Breasts: fat deposition, development of stromal cells, ducts (progesterone, prolactin important in milk production)

Functions of estrogen and Progesterone: Estrogen Progesterone 1-Facilitate growth of follicles 1-Causes secretory phase of menstrual cycle 2-growth of ovaries, fallopian tubes, uterus, vagina and female external genitalia,breasts duct system and deposit of fat in the breast. 3-Produce female 2ry sex characters,body configuration,fat distribution & increase libido 4-Produce proliferative phase of Menstrual cycle,++uterine blood flow,musculature and make it more sensitive to oxytocin 5-produce cyclic changes in cervix & vagina 6-Control FSH&LH secretion & causes the LH surge at midcycle 7-Has metabolic anabolic effects, cause epiphyseal closure of bones(also ++bone density),decrease serum cholesterol level,++angiotensinogen secretion from liver,increase HDL,--LDL(Cardioprotective) Produce salt & water retention. Increase metabolism and fat deposition, slight increase protein deposition. 2-Stimulate developmentof breast lobules & alveoli 3-Essentia for maitenance of pregnancy and increase secretion of fallopian tubes essential for nutient of fertilized ovum. 4-Decrease sensitivity of uterus to oxytocin 5-Produce cyclic changes in cervix & vagina 6-Inhibit LH secretion during pregnancy (producing amenorrhea) 7-Thermogenic effect(++body temperature by 0.5 C at ovulation) ++respiratory rate Produce natriuresis No anabolic functions ---alveolar CO2

Female sexual act 1-Stimulation of female sexual act : Thinking lead to sexual desire and this desire change during the cycle reaching the peak near ovulation because of high estrogen. Physical stimulation as in male ( perineal region). Same nerve signals. 2-Female erection and lubrication (clitoris): as the penis control by parasympathetic nerves, same mechanism as in male 3-Female orgasm (female climax):analog to emission and ejaculation in male.

Female sexual response -- process is similar in males and females: 1) Excitement phase:caused by psychological or physical stimulation; engorgement and erection of clitoris, vaginal congestion -- due to NO, secreted by parasympathetic nerves 2) Plateau phase:intensification of these responses, increased HR, BP, respiratory rate, muscle tension 3) Orgasmic phase:culmination of sexual excitement, intense physical pleasure 4) Resolution phase:returns genitalia and body systems to pre-arousal state

Male and female sexual response Differences: Women don t require refractory time before beginning excitation again No ejaculation in the female

Female sexual dysfunction may be as high as 45% in women aged 16-50 yrs mechanisms: psychological illness unknown

Menopause Defn:obsolescence of ovaries, no estradiol production, ova only occasional secondary follicle, few primary follicles Occurs at 51.4 yr of age (average) Due to reduction in estrogen, low levels of inhibin, no negative feedback of LH and FSH; therefore, high levels LH and FSH Can occur naturally, due to surgery or as a result of chemotherapy

Women s Health Initiative Increased risk of CHD, stroke, pulm embolis (3x), breast cancer HRT regimen should not be initiated or continued for primary prevention of CHD JAMA 2002

pppp Physiological changes in the body during menopause 1-Hot flushes 2-Irritability 3-Anxiety 4- Fatigue 5- Psychic dyspnea 6-Decrease strength of the bones 7-Vaginal dryness 8-Gradual atrophy of genital organs Small dose of estrogen reverse these symptoms

Polycystic ovary syndrome Affects 10% of reproductive age women Characteristics: hyperandrogenemia oligomenorrhea obesity hirsutism infertility enlarged cystic ovaries Rx: metformin, anti-androgens?

Abnormal secretion of the ovaries: 1-Hypogonadism reduce secretion A- Before puberty cause infantile sexual organs, no secondary sexual character and tall female B- After puberty cause infantile sexual organs include the uterus, small vagina, breast atrophy C-Irregularity of menses and amenorrhea. 2-hypersecretion rare (granulosa cell tumor) and mainly cause irregular bleeding.

Female fertility: 1-Fertile period of each cycle (4-5 days), before ovulation 2-Rhythm method for contraceptive (75%). 3- Hormonal suppression of fertility (the pills) : use of estrogen or progesterone in the first half of the cycle prevent ovulation by prevent preovulatory surge of LH secretion by pituitary gland (90%). 4- Female sterility : A-Failure of ovulation mainly reduce gonadotropin hormone B-Endometriosis, salpingitis,