The Normal Menstrual cycle L1&2
Introduction :The external manifestation of a normal menstrual cycle is the presence of regular vaginal bleeding . This occurs as a result of the shedding of the endometrial lining following failure of fertilization of the oocyte or failure of implantation . The cycle depends on changes occurring within the ovaries and fluctuation in ovarian hormone levels , that are themselves controlled by the pituitary and hypothalamus , the hypothalamo-pituitary-ovarian axis ( HPO ) .
Hypothalamus :
The hypothalamus in the forebrain secretes the peptide hormone gonadotrophn-releasing hormone ( GnRH ) , which in turn controls pituitary hormone secretion . GnRH must be released in a pulsatile fashion to stimulate pituitary secretion of luteinizing hormone ( LH ) and follicle stimulating hormone ( FSH ) . If GnRH is giving in a constant high dose , it desensitizes the GnRH receptor and reduces LH and FSH release .Clinical view :
Drugs that are GnRH agonists ( e.g. buserelin and goserelin ) . Although they mimic the GnRH hormone , when administered continuously , they will downregulate the pituitary and consequently decrease LH and FSH secretion . This has effects on ovarian function such that oestrogen and progesterone levels also fall . These preparations are used as treatments for endometriosis and to shrink fibroids prior surgery .Pituitary gland
GnRH stimulation of the basophil cells in the anterior pituitary gland causes synthesis and release of the gonadotrophic hormones , FSH and LH . This process is modulated by the ovarian sex steroid hormones oestrogen and progesterone ( see Figure 1 ) . Low levels of oestrogen have an inhibitory effect on FSH production ( negative feedback ) , whereas high levels of oestrogen will increase LH production ( positive feedback ) . The mechanism of action for the positive feedback effect of oestrogen involves an increase in GnRH receptor concentrations , while the mechanism of the negative feedback effect is uncertain .The high levels of circulating oestrogen in the late follicular phase of the ovary act via the positive feedback mechanism to generate a periovulatory LH surge from the pituitary .
The clinical relevance of these mechanisms is seen in the use of the combined oral contraceptive pill , which artificially creates a constant serum oestrogen level in the negative feedback range , inducing a correspondingly low level of gonadotriphin hormone release .
Figure (1) Hyothalamo-pituitary-ovarian axis .
Unlike oestrogen , low levels of progresterone have a positive feedback effect on pituitary LH and FSH secretion ( as seen immediately prior to ovulation ) and contribute to the FSH surge . High levels of progesterone , as seen in the luteal phase , inhibit pituitary LH and FSH production . Positive feedback effects of preogesterone occur via increasing sensitivity to GnRH in the pituitary . Negative feedback effects are generated through both decreased GnRH production from the hypothalamus and decreased sensitivity to GnRH in the pituitary . It is known that progesterone can only have these effects on gonadotropic hormone release after priming by oestrogen ( Figure 2 ) .
There are other hormones which are involved in pituitary gonadotrophin secretion . Inhibin inhibits pituitary FSH secretion , whereas activin stimulates it .
Ovary
Ovaries with developing oocytes are present in the female fetus from an early stage of development . By the end of the second trimester in utero , the number of occytes has reached a maximum and they arrest at the first prophase step in meiotic division . No new occytes are formed during the female lifetime . With the onset of menarche , the primordial follicles containing oocytes will activate and grow in a cyclical fashion , causing ovulation and subsequent menstruation in the event of non-fertilization .In the course of a normal menstrual cycle , the ovary will go through three phases :
Follicular phase .
Ovulation .
Luteal phase .
Follicular phase :
The initial stages of follicular development are independent of hormone stimulation . However , follicular development will fail at the preantral stage and follicular atresia will ensue if pituitary hormones LH and FSH are absent .FSH levels rise in the first days of the menstrual cycle , when oestrogen , progesterone and inhibin levels are low . This stimulates a cohort of small antral follicles on the ovaries to grow .
Within the follicles , there are two cell types which are involved in the processing of steroids , These are the theca and the granulosa cells , which respond to LH and FSH stimulation , respectively . LH stimulation production of androgens from cholesterol within theca cells . These androgens are converted into oestrogens by the process of aromatization in granulose cells , under the influence of FSH . The roles of FSH and LH in follicular development are demonstrated by studies on women undergoing ovulation induction in whom endogenous gonadotrophin production has been suppressed . If pure FSH alone is used for ovulation induction , as ovulatory follicle can be produced , but oestrogen production is markedly reduced . Both FSH and LH are required to generate a normal cycle with adequate amounts of oestrogen .
As the follicles grow and oestrogen secretion increases , there is negative feedback on the pituitary to decrease FSH secretion . This assists in the selection of one follicle to continue in its development towards ovulation the dominant follicle . In the ovary , the follicle which has the most efficient aromatase activity and highest concentration of FSH induced LH receptors will be the most likely to survive as FSH levels drop , while smaller follicles will undergo atresia . The dominant follicle will go on producing oestrogen and also inhibin , which enhances androgen synthesis under LH control .
Figure (2) Changes in hormone levels , endometrium and follicle development during the menstrual cycle .
Clinical view :
Administration of exogenous gonadotrophins is likely to stimulate growth of multiple follicles which continue to develop and are released at ovulation ( and can lead to multiple gestations at a rate of around 30 per cent ) .This situation is used to advantage in patients requiring in vitro fertilization ( IVF ) , as many occytes can be harvested from ovaries which have been stimulated as described above .
There are other autocrine and paracrine mediators playing a role in the follicular phase of the menstrual cycle .
These include : Inhibin and activin . Inhibin participates in feedback to the pituitary to downregulate FSH release , and also appears to enhance ongoing androgen synthesis . Activin is structurally similar to inhibin , but has an opposite action is structurally similar to inhibin , but has an opposite action . It is produced in granulosa cells and in the pituitary , and acts to increase FSH binding on the follicles .
Insulin-like growth factors ( IGF I , IGT II ) act as paracrine regulators .
In the follicular phase , IGF-I is produced by theca cells under the action of LH. IGF-I receptors are present on both theca granulosa cells . Within theca , IGF-I augments LH-induced steroidogenesis . In granulosa cells , IGF-I augments the stimulatory effects of FSH on mitosis , aromatase activity and inhibin production .
In the preovulatory follicle , IGF-I enhances LH-induced progesterone production from granulosa cells .
Following ovulation , IGF-II is produced from luteinized granulosa cells , and acts in an autocrine manner to augment LH-induced proliferation of granulosa cells .
Kisspeptins are proteins which have more recently been found to play a role in regulation of the HPO axis , via the mediation of the metabolic hormone leptin's effect on the hypothalamus , Leptin is thought to be key in the relationship between energy production , weight and reproductive health . Mutations in the kisspeptin receptor , gpr-54 , are associated with delayed or absent puberty , probably due to a reduction in leptin-liked triggers for gonadotrophin release .
Ovulation
By the end of the follicular phase , which lasts an average of 14 days , the dominant follicle has grown to approximately 20 mm in diameter . As the follicle matures :
FSH induces LH receptors on the granulosa cells to compensate for lower FSH levels and prepare for the signal ovulation .
Production of oestrogen increases until they reach the necessary threshold to exert a positive feedback effort on the hypothalamus and pituitary to cause the LH surge .
This occurs over 24 36 hours , during which time the LH-induced luteinization of granulosa cells in the dominant follicle causes progesterone to be produced , adding further to the positive feedback for LH secretion and causing a small periovulatory rise in FSH .
Androgens , synthesized in the theca cells , also rise around the time of ovulation and this is thought to have an important role in stimulating libido , ensuring that sexual activity is likely to occur at the time of greatest fertility .
Clinical view :
The LH surge is one of the best predictors of imminent ovulation , and this is the hormone detected in urine by most over-the-counter 'ovulation predictor' tests .The LH surge has another function in stimulating the resumption of meiosis in the occyte just prior to its release . The physical ovulation of the oocyte occurs after breakdown of the follicular was occurs under the influence of LH , FSH and progesterone-controlled proteolytic enzymes , such as plasminogen activators and protaglandins . There appears to be an inflammatory-type response within the follicle wall which may assist in extrusion of the oocyte by stimulating smooth muscle activity .
Thus , women wishing to become pregnant should be advised to avoid taking prostaglandin synthetase inhibitors .
Luteal phase :
After the release of the oocyte , the remaining granulosa and theca cells on the ovary form the corpus luteum . The granulosa cells have a vacuolated appearance with accumulated yellow pigment , hence the name corpus luteum ( ' yellow body ' )Ongoing pituitary LH secretion and granulosa cell activity ensures a supply of progesterone which stabilizes the endometrium in preparation for pregnancy . Progesterone levels are at their highest in the cycle during the luteal phase . This also has the effect of suppressing FSH and LH secretion to a level that will not produce further follicular growth in the ovary during that cycle .
The luteal phase lasts 14 days in most women , without great variation . In the absence of beta human chorionic ganadotrophin ( BHCG ) being produced from an implanting embryo , the corpus luteum will regress in a process known as luteolysis .
The withdrawal of progesterone has the effect on the uterus of causing shedding of the endometrium and thus menstruation . Reduction in levels of progesterone , oestrogen and inhibin feeding back to the pituitary cause increased secretion of gonadotrophic hormone , particularly FSH . New preantral follicles begin to be stimulated and the cycle begins anew .
Endometrium :
The specific secondary changes in the uterine endometrium give the most obvious external sign of regular cycles .Menstruation :
The endometrium is under the influence of sex steroids that circulate in females of reproductive age .
During the ovarian follicular phase , the endometrium undergoes profileration ( the ' proliferative phase ' ) ; during the ovarian luteal phase , it has its ' secretory phase ' , Decidualization , the formation of a specialized glandular endometrim , is an irreversible process and apoptosis occurs if there is no embryo implantation . Menstruation (day 1) is the shedding of the 'dead' endometrium and ceases as the endometrium regenerates ( which normally happens by day 5 6 of the cycle ) .
The endometrium is composed of two layers , the uppermost of which is shed during menstruation . A fall in circulating levels of oestrogen and progesterone approximately 14 days after ovulation leads to loss of tissue fluid , vasoconstriction of spiral arterioles and distal ischaemia . This results in tissue breakdown , and loss of the upper layer along with bleeding from fragments of the remaining arterioles is seen as menstrual bleeding . Enhanced fibrinolysis reduces clotting .
Clinical view :
The effects of oestrogen and progesterone on the endometrium can be reproduced artificially , for example in patients taking the combined oral contraceptive pill or hormone replacement therapy who experience a withdrawal bleed during their pill-free week each month . Vaginal bleeding will cease after 5 10 days as arterioles vasconstrict and the endometrium begins to regenerate .In rare cases , the tissue breakdown and vasoconstriction does not occur correctly and the endometrium may develop scarring which goes on to inhibit its function . This is known as ' Asherman's syndrome ' . The endocrine influences in menstruation are clear . However there is also paracrine mediators influence in menstruation ,include : prostaglandin F2 a , endothelin-1 and platelet activating factor ( PAF ) are vasoconstrictors which are produced within the endometrium . They may be balanced by the effect of vasodilator agents , such as prostaglandin E2 , prostacyclin ( PGI ) and nitric oxide (NO) , which are also produced by the endometrium .
Recent research has shown that progesterone withdrawal increases endometrial prostaglandin ( PG ) synthesis and decreases PG metabolism . The COX-2 enzyme and chemokines are involved in PG synthesis and this is likely to be the target of non-steroidal anti-inflammatory agents used for the treatment of heavy and painful periods .
The proliferative phase :
Once endometrial repair is complete . After this time , the endometrium enters the proliferative phase , when glandular and stromal growth occur . The epithelium lining the endometrial glands changes from a single layer of columnar cells to a pseudostratified epithelium with frequent mitoses .Endometrial thickness increases rapidly , from 0.5 mm at menstruation to 3.5 5 mm at the end of the proliferative phase .
Figure (3) Tissue sections of normal endometrium during proilferative and secretory phases of the menstrual cycle .
The secretory phase
After ovulation ( generally around day 14 ) , there is a period of endometrial glandular secretory activity . following the progesterone surge , the oestrogen-induced cellular proliferation is inhibited and the endometrial thickness does not increase any further . However , the endometrial glands will become more tortuous , spiral arteries will grow , and fluid is secreted into glandular cells and into the uterine lumen . Later in the secretory phase , progesterone induces the formation of a temporary layer , known as the decidua . Stromal cells show increased mitotic activity , nuclear enlargement and generation of a basement membrane .Recent research into infertility has identified apical membrane projections of the endometrial epithelial cells known as pinopodes , which appear after day 21-22 and appear to be a progesterone-dependent stage in making the endmetrium receptive for embryo implantation ( Figure 4 ) .
Figure (4) photomicrograph of endometrial pinopodes from the implantation window .
Immediately prior to menstruation , three distinct layers of endometrium can be seen .
The basalis is the lower 25 per cent of the endomtrium , which will remain throughout menstruation and shows few changes during the menstrual cycle .
The mid-portion is the stratum spongiosum with oedematous stroma and exhausted glands .
The superficial portion ( upper 25 per cent ) is the stratum compactum with prominent decidualized stromal cells . On the withdrawal of both oestrogen and progesterone , the decidua will collapse , with vasoconstriction and relaxation of spiral arteries and shedding of the outer layers of the endometrium .
New developments :
Measurement of ovarian reserve :Female reproductive potential is directly proportionate to the remaining number of oocytes in the ovaries . This number decreases from birth onwards .
It is desirable to be able to quantify the residual ovarian capacity of women of older age or after undergoing treatment in order to give prognostic information and management advice to patients , and also to compare different forms of treatment . Research using :
Altrasound markers has looked at measurements of ovarian volume , mean ovarian diameter and antral follicle count to calculate ovarian reserve .
Biochemical markers include FSH . oestrodiol , inhibin B , anti-Mullerian hormone ( AMH ) . AMH is produced in the granulosa cells of ovarian follicles and does not change in response to gonadotrophins during the menstrual cycle . As a result , it can be measured and compared from any point in the cycle .