Female Reproductive System

• The female reproductive system is overviewed

Structure of the Female Reproductive System

• Key components are the fundus of the uterus, corpus of the uterus, fallopian tube, myometrium, endometrium, ovarian ligament, fimbria, ovary, perimetrium, cervical canal, cervix, and vagina

Functions of the Female Reproductive System

• Responsible for the development and transport of female sex cells (ovum)
• Secretes hormones
• Enables coitus
• Involved in fertilization of ovum
• Facilitates pregnancy and parturition

Menstrual Cycle Overview

• Regular cyclic changes occur in the female reproductive period and include the ovarian and endometrial cycles, as well as other cyclic changes
• Regulated hormonally, involving the hypothalamus (GnRH), pituitary gland (FSH and LH), and ovary (estrogen, progesterone, inhibin)
• The average duration of the cycle is 28 days

Oogenesis

• Oogonia (46) undergo mitosis prior to birth
• After birth, the 1st phase of the 1st meiosis occurs, inhibited by oocyte-maturation inhibiting factor
• Before ovulation, the end of the 1st meiosis takes place
• Metaphase of the 2nd meiosis occurs
• The end of the 2nd meiosis occurs when sperm enters
• The number of oocytes decreases due to atresia, starting from 7 million and reducing to around 500 mature oocytes

Folliculogenesis

• Folliculogenesis is the maturation of the ovarian follicle
• This process terminates in menopause
• Folliculogenesis stages include primordial, primary, secondary (vesicular), and Graafian (mature) follicles

Ovarian Cycle

• Before puberty, oocyte maturation inhibiting factor is present

Follicular Phase

• The cycle begins with recruitment and growth of 6-12 secondary follicles
• On the 6th day, a dominant follicle transforms into a mature follicle
• Involution, or atresia, leads to atretic follicles
• On the 14th day, ovulation occurs with the rupture of the mature follicle
• The released ovum is picked up by fimbria and transported to the uterus and then to the vagina

Ovulation Hormonal Process

• LH influences progesterone and estrogen levels
• Proteolytic enzymes in the theca externa lead to dissolution of the follicular wall
• Follicular hyperemia and PG cause plasma transudation into the follicle
• The follicle swells and ruptures

Luteal Phase of the Ovarian Cycle

• The follicle fills with blood, becoming the corpus hemorrhagicum
• Granulosa and theca cells proliferate into luteal cells (lipids), forming the corpus luteum
• The corpus luteum produces estrogens and progesterone through luteinization
• Four days before menstruation, the corpus luteum degenerates into the corpus albicans (cicatrix)
• If pregnancy occurs, the corpus luteum persists as the corpus luteum graviditatis

Endometrial Cycle

• The endometrial cycle involves changes to the endometrium to prepare for implantation

Menstruation (Days 1-5) of the Endometrial Cycle

• Most of the endometrium is desquamated during menstruation

Proliferative (Estrogen) Phase (Days 5-14) of the Endometrial Cycle

• Estrogen stimulates proliferation of stromal and epithelial cells and growth of endometrial glands and new vessels
• This leads to increased endometrium thickness and springy mucus secretion
• The epithelium regenerates

Secretory (Luteal) Phase (Days 15-28) of the Endometrial Cycle

• Estrogen and progesterone induce swelling, tortuous glands with clear secretion, lipid, and glycogen deposition in stromal cells
• Blood supply increases through tortuous vessels
• The endometrium prepares for fertilized ovum implantation

Menstruation

• If the ovum is not fertilized, the corpus luteum involutes, reducing estrogen and progesterone secretion
• This leads to endometrium involution, vasospasms (PG), and necrosis (mainly vessels), resulting in hemorrhages, menstruation, and endometrium desquamation
• Uterine contractions (PG) cause uterine content expulsion

Endometrial Arteries Structure

• Superficial 2/3 arteries are long spiral arteries that desquamate
• Deep 1/3 arteries are short and straight basal arteries that do not desquamate

Menstrual Blood Composition

• Blood is mainly arterial (75%)
• Contains debris, prostaglandins, and plasmin (endometrial tissue) to prevent clots unless bleeding is excessive
• Leucocytes are released to protect the denuded endometrium against infection
• The average blood loss is 30 ml, and duration is 3-5 days

Other Cyclic Changes in the Uterine Cervix

• No cyclic desquamation occurs
• Estrogens increase thinner and alkaline mucus
• Progesterone thickens mucus making it more tenacious During ovulation the mucus is thinnest creating arborizing, fern-like patterns during fertile days

Other Cyclic Changes in the Vagina

• Estrogens cause cornification of epithelial cells
• Progesterone leads to proliferation of epithelial cells and leucocytes infiltration

Other Cyclic Changes in the Breasts

• Estrogens stimulate ducts proliferation
• Progesterone stimulates lobules and alveoli growth
• Before menstruation, swelling and pain occur due to distension of ducts, hyperemia, and edema of interstitial tissue

Ovarian Hormones, Types

• Estrogens (C18 steroids) include 17β-estradiol, estrone, and estriol
• Progestins (C21 steroids) include progesterone
• Inhibin is a peptide with a regulatory function in granulosa cells and the corpus luteum
• Hormones transported in blood via albumin, estrogen and progesterone-binding globulins

Ovarian Estrogens Synthesis

• Synthesized in granulosa cells, corpus luteum, and placenta
• Produced from androgens via aromatase

Ovarian Progesterone Synthesis

• Corpus luteum, placenta, and follicles synthesize progesterone Occurs through intermediate steps in steroid synthesis
• Degradation occurs in the liver (estriol, pregnanediol) through conjugation, resulting in bile and urine

Estrogens Hormonal Peaks and Action

• Two peaks of secretion occur, before ovulation and during the mid-luteal phase
• Estrogens action is transcription and proteosynthesis

Theca Interna (LH) and Membr. Granulosa (FSH) on Estrogens

• In the theca interna (LH), cholesterol is converted to androstenedione, which turns into estradiol via aromatase
• In the membr. granulosa (FSH), androstenedione is converted to estradiol via aromatase

Effects of Estrogens on Female Sex Organs

• Estrogens cause growth and changes of internal and external genitalia during puberty, including increased Fallopian tubes motility (and cilia)

Effects of Estrogens on Breasts

• Estrogen is responsible for the development of stromal tissue
• Contributes to the growth of ducts
• Responsible for the deposition of fats

Secondary Sex Characteristics Due to Estrogens

• Narrow shoulders, broad hips, fat distribution, high-pitched voice, female pubic hair

Other Effects of Estrogens

• Controls skeleton epiphyseal closure; deficiency leads to osteoporosis
• Promotes protein deposition and positive nitrogen balance
• Leads to soft and smooth skin (decreased acne)
• Causes sodium and water retention
• Increases libido
• Decreases cholesterol
• Causes vasodilatation (local formation of NO), known as "female advantage"

Progesterone Production

• Progesterone is produced in small amounts by follicles and in big amounts by the corpus luteum which peaks during the luteal phase
• The action of progesterone is transcription and proteosynthesis

Theca Interna and Membr. Granulosa on Progesterone

• In the theca interna, cholesterol becomes pregnenolone
• In the membr. granulosa, pregnenolone turns into progesterone

Effects of Progesterone on the Uterus

• Induces the secretory phase of the cycle
• Is antiestrogenic
• Decreases uterine contractions and sensitivity to oxytocin which is causes ovum expulsion is prevented

Effects of Progesterone on Fallopian Tubes

• Increases mucous secretion → improves nutrition of fertilized ovum

Effects of Progesterone on Breasts

• Leads to development of lobules and alveoli
• Supports secretory function during lactation
• Causes swelling before menstruation

Thermogenic Effect of Progesterone

• Progesterone increases body temperature

Hypothalamus Control of Ovarian Function

• Gonadotropin-releasing hormone (GnRH) hormone is released
• GnRH Stimulates of FSH and LH secretion in a pulsatile secretion
• Frequency and amplitude changes cause cyclic hormonal changes
• Estrogen increases frequency while progesterone decreases the frequency

Effects of Mid-Cycle

• Mid-cycle sees increased gonadotropes sensitivity to GnRH & increased GnRH production which results in maximum LH production

Anterior Pituitary Control of Ovarian Function

• Follicle Stimulation Hormone (FSH) and Luteinising Hormone (LH) are key to ovarian function
• FSH and LH are glycoproteins
• cAMP → PK formation → phosphorylation of enzymes to make E+P
• FSH is needed for early maturation of follicles
• FSH + LH facilitates final maturation of follicles and ovulation

Luteinising Hormone (LH)

• Results in ovulation and the initial formation of corpus luteun
• Leads to the Stimulation of E + P secretion by corpus luteum

Early Follicular Phase of Ovarian Function

• Low inhibin plus estrogen and progesterone stimulate FSH resulting in follicles growth and estrogen
• LH secretion inhibited by estrogen (- feedback)

Preovulatory Phase (36 h before ovulation)

• LH and FSH secretion is is stimulated by estrogen (+ feedback, kisspeptin),
• Follicles continue to mature until ovulation

Ovulation Occurs After ~ 9 h after LH peak

Postovulatory Phase

• Estrogen, progesterone and inhibin are secreted by the corpus luteum, which reduces FSH and LH

Premenstrual stage

• FSH and LH levels drop and the corpus luteum degrades resulting in decreased levels of estrogen, inhibin and progesterone
• This decrease results in menstruation, which results in increased FSH and new follicles

Feedback Effects on Hormone Release

• Limbic system and nutrition stimulate the release of GnRH via the hypothalamus
• Estradiol and progestrone stimulate the release of LH and FSH via the pituitary

Ovarian Cycle Events and Matching Days

• Day 1: Endometrium is desquamated by menstruation
• Day 7: One follicle becomes dominant
• Day 14: Estrogen positive feedback is peaking
• Day 23: Progesterone from corpus luteum peaks
• Day 28: Estrogen and progesterone both are decreasing

Puberty Overview

• Puberty is the onset of adult sexual life
• Menarche and physical changes occur
• Puberty occurs between ages 11-16
• Insufficient secretion of GnRH during childhood
• Results in gradual increase of LH and FSH secretion around age 8

Menopause Overview

• Menopause occurs generally around 40 – 50 yr. and means few primordial follicles exist in the ovaries
• Decreased estrogen production leads to irregular or ceased cycles, hot flushes, psychic dyspnea
• Irritability, anxiety and fatigue is common
• Decreased calcification and strength of bones can result in osteoporosis and can increase the risks of the cardiovascular diseases

Menstrual Abnormalities Overview

• Anovulatory cycles: After menarche and before menopause
• Amenorrhea: Primary and secondary types exist
• Hypomenorrhea: Scanty, or menorrhagia (profuse) exist
• Metrorrhagia: Abnormal bleeding between periods can occur
• Oligomenorrhea: Reduced frequency of cycles can present
• Dysmenorrhea: Painful menstruation
• Premenstrual syndrome: Shown by increased irritability, depression, decreased concentration, headache, constipation and edema

Aspects of Menopause

• Primary ovarian failure defines menopause
• Loss of estrogen from the ovary is due to a decrease in LH and/or FSH
• A decrease in FSH and LH is due to a decrease in GnRH pulses