The female Reproductive -Physiology 17 -18
The complex and highly regulated sequence of events that manifests as regular monthly menstruation exists to ensure that only one oocyte is ovulated in any one cycle and that implantation of an early embryo can arrest the process of endometrial shedding and ensure its survival Monthly menstruation is an obvious marker that the various levels of interaction between hypothalamus, pituitary, ovary and uterus are functional.Menstruation Menstruation refers to the shedding of the superficial layers of the endometrium, with subsequent repair in preparation for regrowth from the basalis layer. Menstruation is initiated by a fall in circulating concentration of progesterone that follows luteal regression(leutolysis of corpus leuteum) because failure of implantation of early pregnancy. . Luteal progesterone synthesis is dependent on LH from the pituitary gland
The pituitary secretes the gonadotropin hormones LH and FSH in response to pulses of gonadotropin releasing hormone (GnRH) from the hypothalamus, which travel to the anterior pituitary via the hypothalamohypophyseal portal tract. LH secretion appears to be closely regulated by GnRH pulsatility, while secretion of FSH is co-regulated by hypothalamic GnRH and the inhibins and activins. In the normal follicular phase, GnRH pulse frequency is approximately once per 90 min. GnRH pulses are less frequent in the luteal phase,occurring approximately once in 4 h.
Hypothalamus anterior pituitary LH FSH
Estrogen progesteroneovary
endometrium
mensturation
GnRH
The menstrual cycle
The selection and growth of the dominant follicle leads to increasing concentrations of oestrogens in the blood, stimulating endometrial growth. Later, following the luteinizing hormone (LH) surge, ovarian oestrogens and progesterone from the corpus luteum induce endometrial secretory changes and the decline in luteal steroid production in the absence of pregnancy leads to the onset of menstruation.
Theca cells/LH
Granulosa/FSHThe Menstrual Cycle
The normal menstrual cycle is characterized by the presence of regular menstrual period, as the endometrium is shed following failure of fertilization & implantation of the oocyte. Each menstrual cycle represents a complex inter- Action between hypothalamus, pituitary gland, ovaries & endometrium.In The Ovary
The menstrual cycle is divided into 3 phases: Follicular phase Ovulation phase Luteal phaseThe Follicular Phase
The ovary contains thousands of primordial follicle (intial stages) that are in continuous development from birth & they are independed of hormonal timulation (preantral stage). Development beyond this stage is stimulated by the hormones, FSH & LH in a delicate balance & in their absence follicular development will fail ensuing follicular atresia.At the start of the menstrual cycle, FSH levels begin to rise as the pituitary is released from the negative feedback effects of progesteron, oestrogen & inhibin.Rising FSH levels rescue a cohort of follicles from atresia,& intiate steroidogenesis. The basis of hormonal activity in preantral to pre-ovulatry follicle is described as the( two cell, two gondotrophin) hypothesis.
LH stimulate the theca cells to produce androgen FSH stimulate granulosa cells to convert this androgen to estrogen (aromatization) & stimulate granulosa cells proliferaton.These gondotrophin rescue a cohort of preantral follicle from atresia, however, only one follicle is destined to grow to preovulatry follicle & released at ovulation , that’s dominant follicle is the largest & has the highest concentration of FSH-induced LH receptors.
At the time of follicular selection,FSH levels are declining in response to the negative feedback effects of oestrogen. The dominant follicle isTherefore the only follicle that is capable of development in the face of low FSH. FSH also stimulate inhibin production by the granulosa cell which by itself attenuates FSH production & enhanced LH induced androgen synthesis.
LH induces luteinization Of the granulosa cells, so that progesterone produced, which is further amplifies the positive Feedback effect of oestrogen
Leading to LH surge. Ovulation occurs 36 hr after the onset of LH surge. The periovulatory FSH surgeis probably induced by positive feedback of progesterone.
In contrast, in a conception cycle,the increasing block to progesterone synthesis is overcome by the rapidly increasing concentrations of hCG which act on the corpus luteum through its LH receptors
In The Ovary
The menstrual cycle is divided into 3 phases: Follicular phase Ovulation phase Luteal phaseFollicular Phase At birth, the human ovaries contain approximately 1,000,000 primordial follicles, arrested at prophase of the first meiotic division. This number already reflects considerable attrition from the maximum size of about 7,000,000 at 5 months of fetal life ,Further depletion will continue throughout reproductive life. follicle depletion occurs before and after menarche, during use of the oral contraceptive pill and during pregnancy and whether or not regular menstruation occurs. The early stages of follicle development in the human are independent of gonadotropins.
oogenesis
The primordial follicle is composed of primordial germ cell surrounded by mesenchymal cells derived from endodermal tissue.it undergoes mitotic division to form primary oocyte this in turn has first meiotic division 1at birth.then it arrest at metaphase of 2nd meiotic division until puberty At puberty,few follicles grow daily(the largest is 2-5cm&one of them will be selected for next ovulation Contiuation of meiosis start after LH surge &completed at sperm pentrationOogenesis&maturation of eggs
The primordial germ cell devide to produce oogonia(46) 1ry oocyte Mature ovum(23) 2ry oocyte And 2ed polar body &1st polar body.Follicular phase The temporary elevation in circulating concentration of follicle stimulating hormone (FSH) seen in the early follicular phase of the ovarian cycle allows a limited number of pre-antral follicles to reach this stage of maturity, creating synchronously developing follicles. However, only one ‘lead’follicle will acquire significant aromatase enzyme activity within its granulosa cells, leading to increased synthesis and secretion of oestradiol from androgenic precursor.
ula
Folliclar phase Once the concentration of serum oestradiol begins to rise in the mid-follicular phase, there is a rapid suppression of pituitary FSH production by negative feedback which is co-mediated by rising serum concentrations of inhibin B, a glycoprotein secreted by the granulosa cells of the developing dominant follicle. & about the10-12 th day ostrogen also triggersLH-Rfwhich stimulate pitutaryLH. LH stimulate the theca cells to produce androgen
Theca cells/LH
Granulosa/FSHOvulation Phase
Late in the follicular phase, FSH induces LH receptors on the granulosa cells. Oestrogen is an obligatory co-factor in this effect. the production of oestrogen is eventually to exert a positive feed-back effect on the pituitary LH secretion. LH levels increase, at first slowly(day8-12) &then more rapidly(day12 onwards).Prior to the release of the oocyte , the LH surge stimulates the resumption of meiosis(only completed after the sperm enter the egg).The increase in FSH LH,progesterone stimulate the activity of proteolytic enzymes & PG which promote an inflammatory response in the follicular wall & by stimulation of smooth muscle activity may lead to extrusion ofthe oocyte.
follicular phase LH induces luteinization Of the granulosa cells, so that progesterone produced, which is further amplifies the positive Feedback effect of oestrogen leading to LH surge. Ovulation occurs 36 hr after the onset of LH surge. The periovulatory FSH surgeis probably induced by positive feedback of progesterone
.
Ovulation phase
Prior to the release of the oocyte , the LH surge stimulates the resumption of meiosis(only completed after the sperm enter the egg). The increase in FSH, LH,progesterone stimulate the activity of proteolytic enzymes,cytokines & PG which promote an inflammatory response in the follicular wall & by stimulation of smooth muscle activity may lead to extrusion of the oocyte. Achemotactic effect of ovarian cytokines draws the fimbria of the Fallopian tube to within close proximity to the rupturing follicle. A thin mucus strand seems to join the mouth of the Fallopian tube to the ovular follicle, forming a bridge for transit of the oocyte into the tube.The leuteal phase
The ‘empty’ follicle rapidly fills with blood andthe theca and granulosa cell layers of the folliclewall luteinize, with formation of the corpus luteum (accumulation of yellow pigment within thecells).A rapid synthesis of progesterone, along with oestradiol, follows. Concentrations of progesterone in serum rise to above 25 nmol/l.These concentrations rise still further if pregnancy follows.Leuteal phase The low level of gonadotrophin means that the initiation of new follicular growth is inhibited for the duration of the luteal phase. The duration of the luteal phase is fairly constant 14 days in most women. In the absence of pregnancy & hCG production from embryo, the corpus luteum regress by luteolysis &oestrogen &progesterone &inhibin levels decline.
The pituitary is released from their negative feedback effect & gonadotrophin(FSH) start to rise, & a cohort of follicles at the preantral phase are rescued from atresia & a further menstrual cycle is initiated.
hypothalamus
GhRHpitutary
LH FSH
theca
granulosa
Endometrium
P p
E E
In The Endometrium
The endometrium undergoes cyclic changes during the menstrual cycle. These can be divided into three phases: Menstruation The proliferative (follicular) phase The secretory (luteal) phaseMenstruation
In an ovulatory cycle, where the endometrium is exposed to oestrogen & progesterone in an orderly manner, the endometrium become decidualized(2nd half) to allow implantation of the embryo. Decidualization is irreversible & if implantation does not occur , programmed cell death(apoptosis) ensues. Menstruation is initiated by the withdrawal of oestrogen & progesterone.menstruation
Immediately prior to menstruation, the endometr- ium regress, endometrial venous drainage is inhibited & vasodilatation ensues then a sequence of intense spiral artery vasoconstriction followed by relaxation is generated. These event lead to ischemia & tissue damage, shedding of the functional endometrium (stratum compactum &spongiosum) & bleeding from fragments of arterioles remaining in the basal Endometrium.. The PGs of the E and F series are present in high concentrations in the endometrium and their synthesis is regulated by the ovarian steroids. Increased production of PGF2∞ produces the myometrial contractions and vasoconstriction seen at menstruation, while E series PGs increase pain and vasoconstriction in turn leads to localized tissue hypoxia;so constriction of the spiral arterioles with contraction of the uterine muscle,leading to expulsion of the shed tissue
menstruation
Homeostasis in the endometrium is secured by spiral artery vasoconstriction & scarring is reduced by enhanced fibrinolysis, which breaks down blood clots Later, repair of the endometrium & new vessel formation (angiogenesis) lead to complete cessation of bleeding within 5-7 days from the start of the menstrual cycle.normal cycle evry 28days &normal blood loss is 30-80mlProlifetrative phase
An increasing amounts of oestradiol in the circulation, acts on the basalis layer of endometrium, which persists from cycle to cycle in contrast to the monthly shedding of the more superficial layers of endometrium. The new, proliferative endometrium grows rapidly under the influence of oestradiol, The epithelial lining the endometrial gland change from single layer of low columnar to pseudostratified with frequent mitosis in synchrony with the growth and maturation of the oocyte and its follicle. The endometrial thickness increased from 0.5mm To 3.5-5mm at the end of the proliferative phaseformation of new blood vessels (endometrial angiogenesis),which seems to occur by elongation and expansion from pre-existing small vessels in the basalis.
The secretory Phase
Its characterized by progesterone (secreted from corpus luteum) induced glandular secretory activity with inhibition of proliferation.Subnuclear intracytoplasmic granules appear in the cells & their content are released into the endometrial cavity . The gland become tortuous & the stroma becomes edematous & the spiral arteries continue to extend into the superficial layer of endometrium & become convoluted.