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  1. 1. <ul><li>Female reproductive physiology </li></ul><ul><li>Tianjin Medical University General Hospital </li></ul><ul><li>Obstetrics and Gynecology Department </li></ul><ul><li>Bai Xiaohong </li></ul>
  2. 2. <ul><li>Fetal period </li></ul><ul><li>Neonatal period </li></ul><ul><li>Childhood </li></ul><ul><li>Adolescence(puberty) </li></ul><ul><li>Sexual maturity (Child –bearing period) </li></ul><ul><li>menstrual cycle </li></ul><ul><li>pregnancy </li></ul><ul><li>Perimenopause </li></ul><ul><li>Senility </li></ul>
  3. 3. Puberty menopause Child –bearing period menstruation pregnancy
  4. 4. <ul><li>After birth, the gonads are quiescent until they are activated by gonadotropins from pituitary to bring about the final maturation of the reproductive system. </li></ul><ul><li>This period of final maturation is known as puberty. </li></ul><ul><li>Puberty is the period when the endocrine and gametogenic function of the gonads first develop to the point where reproduction is possible. </li></ul>
  5. 5. <ul><li>Menopause : The human ovary gradually becomes unresponsive to gonadotropins with advancing age , and its function decline, so that sexual cycles and menstruation disappear. </li></ul>
  6. 6. <ul><li>Menstrual cycle : The reproductive system of adult women shows regualr cyclic changes . </li></ul><ul><li>Periodic preparation for fertilization and pregnancy. </li></ul>
  7. 7. Menstrual cycle <ul><li>Hypothalamic-Pituitary Axis  </li></ul><ul><li>Ovarian Cycle  </li></ul><ul><li>Histophysiology of the Endometrium  </li></ul><ul><li>Spermatogenesis, Sperm, Capacitation </li></ul><ul><li>and Fertilization </li></ul><ul><li>Cleavage, Morula, Blastocyst </li></ul>
  8. 8. PURPOSE & REQUIREMENT <ul><li>Master the follicle development and steroid hormone secretory patterns </li></ul><ul><li>Know cyclic changes in the ovary and endometrium </li></ul><ul><li>Know the regulation of the menstrual cycle </li></ul>
  9. 9. menses
  10. 10. <ul><li>Normal pattern of menses </li></ul><ul><li>75% menstrual blood is of arterial ,only 25% is of venous origin. </li></ul><ul><li>It contains tissue debris, prostaglandins,and fibrinolysins. </li></ul><ul><li>Mean interval is 28 days +/- 7 days. </li></ul><ul><li>Mean duration is 3~5 days (1~8 days). </li></ul><ul><li>Average blood loss with menstruation is 35-50 ml . More than 80 ml is abnormal . </li></ul>
  11. 11. <ul><li>Each menstrual cycle represents a complex interaction between the hypothalamus, pituitary gland, ovaries and endometrium. </li></ul><ul><li>Cyclic changes in gonadotropin and steroid hormones induce functional as well as morphologic in the ovary, resulting in follicular maturation,ovulation, and corpus luteum formation. </li></ul><ul><li>Similar changes at the level of the endometrium allow for successful implantation of the development embryo. </li></ul>
  12. 12. Hypothalamus Pituitary Ovary endometrium
  13. 13. Hypothalamic- Pituitary Axis
  14. 14. <ul><li>The pituitary gland lies below the hypothalamus at the base of the brain within a bony cavity and is separated from the cranial cavity by a condensation of dura mater overlying the sella turcica. </li></ul><ul><li>The pituitary gland is divided into two portions: neurohypophysis and adenohypophysis </li></ul>Pituitary gland
  15. 15. Pituitary Hormones <ul><li>Ovarian secretion depends on the action of hormones secreted by the anterior pituitary. </li></ul><ul><li>The anterior pituitary contains different cell types that produce 6 established protein hormones: FSH, LH , TSH, prolactin, GH, ACTH. </li></ul><ul><li>The gonadotropins, FSH and LH, are synthesized and stored in cells in anterior pituitary, called gonadotrophs </li></ul><ul><li>FSH: follicle-stimulating hormone </li></ul><ul><li>LH: luteinizing hormone </li></ul>
  16. 16. <ul><li>FSH </li></ul><ul><li>LH </li></ul><ul><li>TSH </li></ul><ul><li>Prolactin </li></ul><ul><li>GH </li></ul><ul><li>ACTH </li></ul>Pituitary hormones gonadotropins
  17. 17. <ul><li>FSH ,LH, and TSH are glycoproteins, consisting of  and  subunits. </li></ul><ul><li>The  subunits of FSH, LH,and TSH are identical. The same  subunits is also present in human chorionic gonadotropin(hCG). </li></ul><ul><li>The  subunits are individual for each hormone. </li></ul>Gonadotropins
  18. 18. Ganodotropin secretory pattern
  19. 19. <ul><li>Follicular phase begins with the onset of menses and culminates in the preovulatory surge of LH. </li></ul><ul><li>Luteal phase begins with the onset of the preovulatory surge of LH and ends with the first day of menses. </li></ul>
  20. 20. <ul><li>Decreasing levels of estradiol and progesterone from the regressing corpus luteum of the preceding cycle initiate a rise of FSH by a negative feedback mechanism , which stimulates follicular growth and estradiol secretion. </li></ul>Negative feedback
  21. 21. <ul><li>At lower levels of estradiol there is a negative effect on the ready-release form of LH from the pool of Gonadotropins in the pituitary gonadotrophs. </li></ul><ul><li>As estradiol levels rise later in the follicular phase, there is a positive feedback on the release of storage gonadotropins, resulting in the LH surge and ovulation. </li></ul>negative effect positive feedback
  22. 22. positive feedback negative effect negative effect During the luteal phase, both LH and FSH are significantly suppressed through the negative feedback effect of elevated circulating estradiol and progesterone levels.
  23. 23. positive feedback negative effect negative effect <ul><li>This inhibition persists until progesterone and estradiol level decline near the end of the luteal phase as a result of corpus luteal regression, should pregnancy fail to occur. </li></ul><ul><li>The net effect is a rise in serum FSH, which initiates follicular growth for the next cycle. </li></ul><ul><li>The duration of the corpus luteum’s functional regression is such that menstruation generally occurs 14days after the LH surge in the absence of pregnancy. </li></ul>
  24. 24. prolactin <ul><li>Prolactin is secreted by lactotrophs. </li></ul><ul><li>Serum prolactin levels do not change strikingly during the normal menstrual cycle. </li></ul><ul><li>Prolactin may participate in control of ovarian steroidgenesis. </li></ul><ul><li>The physiologic role of prolactin during the normal menstrual cycle has not been established. </li></ul><ul><li>Hyperprolactinemia may alter gonadotropin secretion. </li></ul>
  25. 25. Hypothalamus
  26. 26. <ul><li>The secretion of the anterior pituitary hormones is regulated by the hypothalamic hypophysiotropic hormones. </li></ul><ul><li>Five peptides or biogenic amines that affect the reproductive cycle have been isolated from the hypothalamus: </li></ul><ul><li>GnRH gonadotropin-releasing hormone </li></ul><ul><li>PIF prolactin release-inhibiting factor </li></ul><ul><li>TRH thyrotropin-releasing hormone </li></ul><ul><li>SRIF somatotropin release-inhibiting factor </li></ul><ul><li>CRF corticotropin-releasing factor </li></ul>
  27. 27. GnRH ( gonadotropin-releasing hormone)
  28. 28. <ul><li>GnRH is a decapeptide that is synthesized primarily in the arcuate nucleus . It is responsible for the synthesis and release of both LH and FSH . </li></ul><ul><li>It usually causes the release of more LH than FSH, it is commonly called LH-releasing hormone(LH-RH) or LH- releasing factor(LRF) </li></ul>
  29. 29. <ul><li>Both FSH and LH appear to be present in two different forms within the pituitary gonadotrophs--releasable form and storage form. </li></ul><ul><li>GnRH reaches the anterior pituitary via the hypophyseal portal vessels and stimulates the synthesis of both FSH and LH, which are stored within gonadotrophs. </li></ul>
  30. 30. <ul><li>Subsequently, GnRH activates and transforms these molecules into releasable forms. </li></ul><ul><li>GnRH can also induce immediate release of both LH and FSH into the circulation. </li></ul><ul><li>GnRH may have a direct effect on ovarian function as well. </li></ul><ul><li>GnRH is secreted in a pulsatile fashion throughout the menstrual cycle. </li></ul>
  31. 31. Several mechanisms control the secretion of GnRH <ul><li>Estradiol appears to enhance hypothalamic release of GnRH and may help induce the midcycle LH surge by increasing GnRH release or by enhancing pituitary responsiveness to the GnRH. </li></ul><ul><li>Gonadotropins have an inhibitory effect on GnRH release. </li></ul>
  32. 32. <ul><li>The hypothalamus produces PIF, which exerts chronic inhibition of prolactin release from the lactotrophs. </li></ul><ul><li>A number of pharmacologic agents that affect dopaminergic mechanism influence prolactin release. Dopamine itself inhibits prolactin release directly within the adenohypophysis. Based on these observations, it has been proposed that hypothalamic dopamine may be the major PIF. </li></ul>PIF
  33. 33. Ovarian cycle
  34. 34. <ul><li>Steroid hormone </li></ul><ul><li>estrogens </li></ul><ul><li>progestins </li></ul><ul><li>androgens </li></ul><ul><li>Follicle development </li></ul>
  35. 35. Estrogens <ul><li>During early follicular development, circulating estradiol levels are relatively low . </li></ul><ul><li>About 1 week before ovulation, levels begin to increase , at first slowly, then rapidly. The levels generally reach a maximum 1 day before ovulation. </li></ul>
  36. 36. Estrogens <ul><li>After this peak and before ovulation, there is a marked and precipitous fall. </li></ul><ul><li>During the luteal phase, estradiol rises to a maximum 5 to 7 days after ovulation and returns to baseline shortly before menstruation. </li></ul>
  37. 37. Estrogens <ul><li>The naturally occuring estrogens are 17 β -estradiol, estrone, and estriol. </li></ul><ul><li>They are secreted primarily by the granulosa and the thecal cells of the ovarian follicle,the corpus luteum,and the placenta. </li></ul>
  38. 38. Effects on female genitalia <ul><li>Ovary : facilitate the growth of the ovarian follicles </li></ul><ul><li>Uterine :increase blood flow </li></ul><ul><li>increase muscle amount </li></ul><ul><li>myometrium more active </li></ul><ul><li>endometrium proliferation </li></ul><ul><li>tubes : increase the motility </li></ul><ul><li>cervix : mucus thinner and more alkaline </li></ul><ul><li>Vaginal :epithelium becomes cornfied </li></ul>Estrogens
  39. 39. Cervix mucus
  40. 40. Progestins <ul><li>During follicular development, the ovary secrets only very small amounts of progesterone and 17-hydroxyprogesterone. </li></ul>
  41. 41. Progestins <ul><li>Just before ovulation, the unruptured but luteinzing graafian follicle begins to produce increasing amounts of progesterone. </li></ul><ul><li>At about this time, a marked increase also occurs in serum 17-hydroxyprogesterone. </li></ul>
  42. 42. <ul><li>As with estradiol, secretion of progestins by the corpus leteum reaches a maximum 5 to 7 days after ovulation and returns to baseline shortly before menstruation. </li></ul>Progestins
  43. 43. Progestins <ul><li>The elevation of basal body temperature (BBT)is temporally related to the central effect of progesterone . </li></ul>
  44. 44. <ul><li>Should pregnancy occur, progesterone levels, and therefore basal body temperature, remain elevated. </li></ul>Progestins
  45. 45. Effects on female genitalia <ul><li>Uterine :inhibit uterine contraction, </li></ul><ul><li>endometrium secretory </li></ul><ul><li>cervix : mucus thick , tenacious. </li></ul><ul><li>Vaginal :secreted thick mucus ,epithelium proliferates </li></ul>Progestins
  46. 46. Androgens <ul><li>Both the ovary and the adrenal glands secrete small amounts of testosterone, but most of the testosterone is derived from the metabolism of androstenedione, which is also secreted by both the ovary and the adrenal gland. </li></ul>
  47. 47. Androgens <ul><li>Near midcycle, an increase occurs in plasma androstenedione, which reflect enhanced secretion from the follicle. </li></ul><ul><li>During the luteal phase, a second rise occurs in androstenedione, which reflects enhanced secretion by the corpus luteum. </li></ul>
  48. 49. Follicular development
  49. 50. <ul><li>Primordial follicles undergo sequential development, differentiation, and maturation until a mature graafian follicle is produced. The follicle then ruptures, releasing the ovum. Subsequent luteinization of the ruptured follicle produces the corpus luteum. </li></ul>
  50. 51. <ul><li>Primordial follicle </li></ul><ul><li>At approximately 8 to 10 weeks of fetal development, oocytes become progressively surrounded by precursor granulosa cells , which then separate themselves from the underlying stroma and oocyte by a basal lamina. </li></ul>Primordial follicle
  51. 52. <ul><li>Primary follicle </li></ul><ul><li>at between 20 and 24 weeks’s gestation </li></ul><ul><li>in response to gonadotropin and ovarian steroid </li></ul><ul><li>the follicular cells become cuboidal and the stromal cells around the follicle become prominent. </li></ul>
  52. 53. <ul><li>Secondary follicle </li></ul><ul><li>As granulosa cells proliferate, a clear gelatinous material surrounds the ovum, forming the zona pellucida. </li></ul>
  53. 54. <ul><li>the innermost three or four layers of rapidly multiplying granulosa cells become cuboidal and adherent to the ovum (cumulus oophorus) </li></ul><ul><li>a fluid-filled antrum forms among the granulosa cell </li></ul><ul><li>primary oocyte migrates eccentrically to the wall of the follicle </li></ul>Graafian follicle
  54. 55. <ul><li>The granulosa cells of the cumulus,which are in close contact with the pellucida become elongated and form the corona radiata </li></ul><ul><li>Covering the granulosa cells is a thin membrane:the theca interna and the theca externa. </li></ul>
  55. 56. <ul><li>During each cycle, a cohort of follicles is recruited for development. Among the many developing follicle, only one usually continues differentiation and maturation into a follicle that ovulates. </li></ul><ul><li>The remaining follicles undergo atresia. </li></ul>?
  56. 57. <ul><li>Follicular maturation is dependent on the local development of receptors for FSH and LH. </li></ul><ul><li>FSH-R are present on granulosa cells . </li></ul><ul><li>Under FSH stimulation , granulosa cells proliferate and the number of FSH receptor increases. </li></ul><ul><li>Estrogens, particularly estradiol, enhance the induction of FSH receptors and act synergistically with FSH to increase LH receptors. </li></ul>
  57. 58. <ul><li>During early stages of folliculogenesis, LH receptors are present only on the theca interna layer. </li></ul><ul><li>FSH also enhances the induction of LH receptors on the granulosa cells of the follicle that is destined to ovulate. </li></ul>
  58. 59. <ul><li>The presence of greater numbers of FSH-R and granulosa cells and increased induction of aromatase enzyme and its receptors may differentiate between the follicle of the initial cohort that will develop normally and those that will undergo atresia. </li></ul>
  59. 60. <ul><li>Growth factors such as insulin , insulin-like growth factor( IGF ), fibroblast growth factor( FGF ), and epidermal growth factor( EGF ) may also play significant mitogenic roles in folliculogenesis , including enhanced responsiveness to FSH. </li></ul>
  60. 61. ovulation <ul><li>The ovulation occurs 36 to 44 hours after onset of the preovulatory surge of LH. </li></ul>Follicle
  61. 62. <ul><li>The preovulatory LH surge initiates a sequence of structural biochemical changes that culminate in ovulation. </li></ul><ul><li>Before ovulation, a general dissolution of the entire follicular wall occurs, particularly the portion that is on the surface of the ovary. </li></ul>ovulation
  62. 63. <ul><li>With degeneration of the cells on the surface, stigma forms, and the follicular basement membrane finally bulges through the stigma. </li></ul><ul><li>When this ruptures, the oocyte and corona radiata are expelled into the peritoneal cavity, and ovulation takes place. </li></ul>
  63. 64. ovulation
  64. 65. Human oocyte-corona-cumulus complex
  65. 66. <ul><li>Ovulation is a gradual phenomenon, with the collapse of the follicle taking from several minutes to as long as an hour or more. </li></ul><ul><li>The oocyte adheres to the surface of the ovary, allowing an extended period during which the muscular contractions of the tube may bring it in contact with the tubal epithelium. </li></ul>
  66. 68. Luteinization and corpus luteum <ul><li>After ovulation and under the influence of LH, the granulosa cells of the ruptured follicle undergo luteinization. </li></ul><ul><li>Corpus lutuem: the luteinized granulosa cells, plus the surrounding theca cells, capillaries, and connective tissue. </li></ul><ul><li>Corpus lutuem produces copious amounts of progesterone and some estradiol. </li></ul>
  67. 69. <ul><li>The normal functional life span of the corpus luteum is about 14 days. </li></ul><ul><li>After this time it regresses, and unless pregnancy occurs, menstruation ensues and the corpus luteum is gradually replace by corpus albicans. </li></ul>
  68. 70. Histophysiology of the Endometrium
  69. 71. Endometrium <ul><li>The endometrium is uniquely responsive to the circulating estrogens , progestins. </li></ul><ul><li>It is this responsiveness that gives rise to menstruation and makes implantation and pregnancy possible. </li></ul>
  70. 72. <ul><li>The endometrium is divided into two zones: </li></ul><ul><li>Functionalis : undergoes cyclic changes in morphology and function during the menstrual cycle and is sloughed off at menstruation . </li></ul><ul><li>Basalis : relatively unchange during each menstrual cycle and after menstruation provides stem cells for the renewal of the functionalis. </li></ul>
  71. 73. Cyclic changes in histophysiology <ul><li>Menstrual phase </li></ul><ul><li>Proliferative phase </li></ul><ul><li>Secretory phase </li></ul>
  72. 74. Menstrual phase <ul><li>The first Day of menstruation is taken as day 1 of the menstrual cycle. </li></ul><ul><li>The first 4 days of cycle are defined as the menstrual phase. </li></ul><ul><li>During this phase, there is disruption and disintegration of the endometrial glands and stroma, leukocyte infiltration, and red blood cell extravasation. </li></ul>
  73. 75. <ul><li>Despite these degenerative changes, early evidence of renewed tissue growth is usually present at this time within the basalis of the endometrium. </li></ul>
  74. 76. Proliferative phase <ul><li>The proliferative phase is characterized by endometrial proliferation or growth secondary to estrogenic stimulation. </li></ul>
  75. 77. <ul><li>The bases of the endomatrial glands lie deep within the basalis, these epithelial cells are not destroyed during menstruation. </li></ul><ul><li>As menstruation ends each month, they provide and migrate through the stroma to form a new epithelial lining of the endometrium and new endometrial glands. </li></ul>Proliferative phase
  76. 78. <ul><li>During this phase of the cycle, the large increase in estrogen secretion causes marked cellular proliferation of the epithelial lining, the endometrial glands, and the connective tissue of the stroma. </li></ul><ul><li>The endometrium increasea in thickness,the glands are drawn out. . </li></ul><ul><li>Numerous mitoses are present in these tissues. </li></ul><ul><li>There is an increase in the length of the spiral arteries, which traverse almost the entire thickness of the endometrium. </li></ul>Proliferative phase Endometrium of proliferative phase
  77. 79. Proliferative phase <ul><li>By the end of this phase, cellular proliferation and endometrial growth have reached a maximum, the spiral arteries are elongated and convoluted, and the endometrial glands are straight, with narrow lumens containing some glycogen. </li></ul>
  78. 80. Secretory phase <ul><li>Following ovulation, progesterone secretion by the corpus luteum stimulates the glandular cells to secrete glycogen, mucus, and other substances. The glands become tortuous and the lumens are dilated and filled with these substances. </li></ul>
  79. 81. <ul><li>The stroma becomes edematous. </li></ul><ul><li>Mitoses are rare. </li></ul><ul><li>The spiral arteries continue to extend into the superficial layer of endometrium and become convoluted. </li></ul>
  80. 82. Secretory phase <ul><li>By day 23, the corpus lutuem begins to regress, secretion of progesterone and estradiol declines, and the endometrium undergoes involution. </li></ul><ul><li>About 1 day prior to the onset of menstruation, marked constriction of the spiral arterioles takes place, causing ischemia of the endometrium followed by leukocyte infiltration and red blood cell extravasation. </li></ul><ul><li>The resulting necrosis causes menstruation or sloughing of the endometrium. </li></ul>
  81. 83. Spermatogenesis, sperm capacitation, and fertilization
  82. 84. <ul><li>Fertilization normally takes place in the fallopian tube. </li></ul><ul><li>Fertilization or conception is the union of male and female pronuclear elements. </li></ul>
  83. 85. <ul><li>Spermatogenesis requires about 74 days. Together with transportation, a total of about 3 months elapses before sperm are ejaculated. </li></ul><ul><li>The sperm achieve motility during their passage through the epididymis. </li></ul><ul><li>Sperm capacitation occurs,which renders them capable of fertilization in vivo, when they removed from the seminal plasma after ejaculation. </li></ul>sperm
  84. 86. <ul><li>The average ejaculate contains 2 to 8 ml of semen </li></ul><ul><li>40 to 300 million sperm may be deposited in vagina </li></ul><ul><li>more than 50% of which are move forward </li></ul>
  85. 87. More than 15% of which should be morphologically normal.
  86. 88. <ul><li>Fewer than 200 sperm achieve proximity to the egg. Only one sperm fertilizes a single egg released at ovulation. </li></ul><ul><li>Capacitation is the physiologic change that sperm must undergo in the female reproductive tract before fertilization. </li></ul>
  87. 89. sperm oocyte <ul><li>The acrosome , a modified lysosome, lies over the sperm head as a kind of “chemical drill-bit” designed to enable the sperm to burrow its way into the oocyte. </li></ul><ul><li>The acrosome reaction is one of the principal components of capacitation </li></ul>corona First PB ovum zona
  88. 90. The overlying plasma membrane becomes unstable and eventually breaks down, releasing Hyaluronidase corona-dispersing enzyme.
  89. 91. <ul><li>After traversing the zona, the postacrosomal region of the sperm head fuses with the oocytes membrane, and the sperm nucleus is incorporated into the ooplasm. </li></ul><ul><li>This process triggers the cortical reaction that results in changes in the oocyte membrane and zona . The cortical reaction prevent the entrance of further sperm into oocyte. </li></ul>
  90. 92. <ul><li>Following penetration of the oocyte, the sperm nucleus decondenses to form the male pronucleus, which approaches and finally fuses with the female pronucleus at syngamy to form the zygote. </li></ul><ul><li>Fertilization restores the diploid number of chromosomes and determines the sex of the zygote. </li></ul>
  91. 93. Intracytoplasmic sperm injection (ICSI)
  92. 94. Cleavage, morula, blastocyst
  93. 96. 4-cell 8-cell blastocyst Implanted blastocyst