Normal menstrual cycle TheProcess: The menstrual cycle is a complex process affecting multiple systems whose core regulation

is hypothalamic, but whose effects produce 28-day variations in ovarian, endometrial, breast, and behavioural function. Under CNS control and peripheral regulation by the neuroendocrine system (NPY, Leptin, opioids, noradrenaline, GABA), hypothalamic secretion of pulses of GnRH allows the gonadotropes of the pituitary to secrete gonadotropin (FSH and LH) in amounts which are appropriate for the degree of ovarian steroid and inhibin secretion they perceive. Gonadotropin secretion regulates ovarian follicular development and steroid secretion, ovulation of the mature follicle, and maintenance of the corpus luteum after ovulation. Eventually ovarian support ceases, the corpus luteum undergoes atresia, steroid secretion fails, and the endometrium becomes apoptotic and is lost during the subsequent menses. Females of reproductive age (anywhere from 11-16 years) experience cycles of hormonal activity that repeat at about one-month intervals. (Menstru means "monthly"; hence the term menstrual cycle.) With every cycle, a womans body prepares for a potential pregnancy, whether or not that is the womans intention. The term menstruation refers to the periodic shedding of the uterine lining. The average menstrual cycle takes about 28 days and occurs in phases: the follicular phase, the ovulatory phase (ovulation), and the luteal phase. Phases: 1.Follicular phase: Ovarian Recruitment, selection and domination of a single mature oocyte. This process is mediated by the secretion of FSH in inverse proportion to the production of estrogen and inhibin by the growing follicle, and the induction of a positive stimulus to LH secretion when the follicle is mature, resulting in ovulation. During the follicular phase the GnRH pulses occur at 90 minute intervals until the ovulatory LH peak occurs.

Follicular growth. The adult mammalian ovary contains a pool of germ cells arrested in meiotic prophase and surrounded by a single layer of granulosa cells, a basement membrane and a thin thecal cell layer. These units are the primordial follicles, which subsequently mature into primary follicles by a gonadotropin independent event. This final stage in preparation lasts about three months. When the menstrual cycle begins a population of sufficiently mature follicles come under gonadotropin .When the menstrual cycle begins a population of sufficiently mature follicles come under gonadotropin control ("recruitment"). This group of follicles then undergo a process of selection, most undergoing atresia until one dominant follicle remains. It is this dominant follicle that is ovulated. During this process the initial phase of follicular growth consists of the enlargement and maturation of the oocyte. As this maturation is completed, an acellular glycoprotein zona pellucida surrounds the oocyte, and the primitive granulosa cell layer begins to enlarge under the direct control of FSH and autocrine (self-)regulation by estrogen. Under the influence of LH, the thickening thecal cell mass secretes androgen (androstenedione and testosterone) which is aromatized to estrogen within the granulosa cells under the control of FSH. As this occurs, the granulosa cell mass also secretes inhibin, a member of the TGF-beta family of peptides. Inhibin is secreted in two forms depending on the beta chain present - Inhibin A which is increased in the luteal phase by the corpus and inhibin B which is secreted by the granulosa cells in the follicular phase. During this process the granulosa cells function as a syncytium, making contact with one another through tight junctions. Additional gap junctions connect the granulosa cells with the oocyte. As selection occurs, the "successful" follicles produce more FSH receptors, thus becoming more sensitive to FSH stimulation, and producing more estrogen as their granulosa cell mass grows. The elevated estrogen and inhibin levels which cause a fall in FSH secretion, and the other, less sensitive follicles become atretic. Eventually only one highly FSHsensitive follicle remains for ovulation. This dominant follicle grows rapidly in size, as the thickening granulosa cell layer begins to develop fluid filled spaces which eventually fuse to form a fluid filled antrum This is termed a secondary or antral follicle. The antrum swells, the mature follicle reaching 24 mm in diameter at the time of ovulation. LH receptor

induction on the granulosa cells abutting the basement membrane prepares the follicle for its response to the LH surge. The granulosa cells surrounding the oocyte mature into a specialized cumulus oophorus, and the mature follicle is termed a Graafian follicle. Ovulatory phase: During the follicular phase increasing estrogen secretion by the dominant follicle suppresses FSH release by negative feedback, but enhances LH release by the gonadotropes (positive feedback). When mature estrogen levels are sensed by the pituitary a pulse of high frequency high amplitude LH secretion occurs, causing ovarian maturation, inhibiting meiotic arrest and ultimately causing the follicle to rupture. The oocyte reenters meoisis possibly through LH-inhibition of a meiotic inhibitory factor. At the same time the zona pellucida changes its nature and the gap-junctions between the granulosa cells and the oocyte are lost. About 36 hours after the LH surge the follicle rupures, releasing the oocyte and its attached cumulus cells into the peritoneum. The mechanism of rupture is uncertain, but may be mediated in part by local prostaglanding production, and the release of proteases within follicular fluid. Clinical indicators of ovulation: i. Secretory pattern in endometrium seen on biopsy. ii. Rise in basal body temperature (BBT). BBT is the temperature taken on awakening and before activity. Persistent elevation of 0.5 1 reflects ovulation

3. Luteal Phase The ruptured follicle is converted to a corpus luteum, whose function is the secretion of progesterone and estrogen in order to finally mature the endometrium. The cells of the corpus luteum derive in part from thecal tissue, and in part from remaining granulosa cells. During this phase both steroids have negative feedback effects on gonadotropin secretion. Progesterone also slows the GnRH pulse generator, which declines to 2 hourly or even more as the luteal phase ends. As this slowing occurs the secretion of steroids declines, and the corpus

undergoes apoptotic atresia. The mechanism is poorly understood, since prolonged LH administration will only avoid atresia for a limited additional time. If pregnancy occurs, the fetus is able to preserve luteal function until the placenta becomes self-sufficient in steroid production. Endometrial cycle: During the follicular phase the endometrium undergoes hyperplasia under the control of estrogen, mediated by the secretion of growth factors such as IGF-1 (insulin-like growth factor-1) aided by vascular inducing angents such as VEGF (vascular endothelial growth factor).

At endometrial level the production of progesterone inhibits the estrogen induced hyperplasia, stabilizing endometrial thickness, but causing the development of a glandular secretory endometrium favourable for implantation. When follicular steroid secretion fails, the endometrium becomes atretic, and apoptosis leads to its being shed as the mentrual loss. Uterine response a. Menstrual phase (Days 1-5) i. Physiologic changes: endometrial and degenerative changes cause tissue necrosis at the end of the secretory phase. 1. Basalis layer remains 2. About 2/3 of endometrium are lost with each ovulatory cycle and by the time brisk flow ceases, most tissue loss has occurred from shedding of the superficial or functionalis layer. b. Proliferative phase (Days 6-14) i. Physiologic changes: under the influence of estrogen 1. Regeneration of surface and glandular epithelium 2. Thickness increases as phase continues. a. Ovulatory: no appreciable change seen in endometrium in the 24-36 hours following ovulation. Changes become noticeable after progesterone levels increase with the evolution of the corpus luteum. c. Secretory (Progestational) phase i. Physiologic changes: progesterone secretion induces maturational changes in endometrial lining. 1. Presence of glycogen rich fluid in the basal portion. 2. Fluid secretions into glandular lumens.

3. Increasing stromal edema to its maximum which is reached at about 22nd day of cycle when corpus luteum activity reaches its maximum level. 4. In the absence of fertilization and implantation, corpus luteum activity regresses; estrogen and progesterone levels drop; rapid regressive changes in the endometrium occur. Menstrual cycle would be influenced by 3 groups of factors: hormonal, enzyme and vascular. Now I am going to tell about them. There are four major hormones involved in the menstrual cycle: folliclestimulating hormone, luteinizing hormone, estrogen, and progesterone. Hormonal regulation Pituitary hormones 1. Follicle stimulating hormone: stimulates growth and development of ovarian follicles. As follicles grow, increasing estradiol levels within the follicles help them respond to LH with eventual ovulation. The follicles also produce estrogen, which stimulates endometrial growth. 2. Luteinizing hormone: stimulates maturation and ovulation of the Graffian follicle and subsequent development of the corpus luteum. Stimulates progesterone production which peaks after ovulation. When implantation of a conceptus occurs in the endometrium, hCG production signals the corpus luteum to continue secreting progesterone to prevent shedding of the endometrial lining. When implantation does not occur, decreasing progesterone levels permit sloughing of the uterine lining. Ovarian hormones: 1. Estrogen: steroids secreted by the ovaries that prepare the endometrium for implantation; increase motility of fallopian tubes and have other effects on the breasts, behavior and pituitary secretions. a. Estradiol is the major secreted estrogen. Other types are estrone and estriol. b. Inhibits FSH and LH secretion during the early follicular phase. c. Rise in estrogen 24 hours prior to ovulation initiates the LH

surge that produces ovulation. 2. Progesterone: a steroid secreted in large amounts by the corpus luteum. Effects: a. Induces progestational effects on the endometrium. b. Stimulates development of lobules and alveoli in the breast. c. Provide feedback to the hypothalamic and pituitary regulation of the hormonal feedback mechanism. d. Causes rise in BBT at time of ovulation Enzyme Factors: estrogen focuses enzymes to help form the basement membrane of the endometrium. Enzymes also participate in the biochemical process that results in glycogen stores in the endometrium and alter the microvasculature to allow nutrients to flow more easily between cells and blood vessels. Vascular factors: coiled arterioles which supply blood to the outer functionalis layer constrict 4-24 hours prior to beginning of menstruation. Cause ischemic changes to the endometrium and eventually sloughing off.