Menstruation --The dynamics in stromal cells & arachidonic acid interplay.

Posted in Young Group 3-3-20

What is the current concept on HMB? What goes wrong in  cases of menorrhagia  at endo level?? “It is the local mediators in particularly the Heavy Menstrual Bleeding:--is due to abnormalities of Arachidonic acid metabolism!!  Any idea??

It is the local mediators that paly a key role in cases of heavy menstrual bleeding which are mediated by hormones, Hormones usually do not act directly n the endometrial cells. Is that true??   Disturbances of arachidonic acid metabolism disturbances”” of angiogenic processes or alterations in factors such as “” matrix metallo- proteinases “.HMB does occur in the presence of ovulation and apparent absence of organic pathology & there are no differences in serum or endometrial conc. of steroid hormone concentrations or steroid receptor concentrations. However substantial evidence does exist implicating local mediators in particular disturbances of arachidonic acid metabolism disturbances of angiogenic processes or alterations in factors such as matrix metallo- proteinases. It appears that there may be a shift in endometrial prostaglandin signaling from the vasoconstrictor prostaglandins to the vasodilator prostaglandins. That is why Mefanamic acid has a great role in controlling AUB (HMB) as an initial step of therapy.

What exactly common people mean by the Term: The menstrual cycle?  Menstrual cycle is clinically described according to its 1)  regularly and 2) duration of bleeding. The average length between menses is between 21 and 35 days with duration of bleeding lasting 4-5 days.

Let us start the events about what changes occur at late luteal phase of previous cycle? Event No 1:- During the luteal stage of the menstrual cycle in the absence fertilization there is regression of the corpus luteum(C L): Event No 2:- leading to a decline of the steroid hormone progesterone. Event No 3:-During the secretory phase prior to this decline in circulating hormone levels there is already a decline of endometrial sex steroid receptor expression in the superficial layer of the endometrium.

What happens to glandular epithelium?? Declining levels of steroids can only be directly detected in the Stromal cells of the superficial layer-but why so??  Do U know that the epithelial glands within the superficial layer of the endometrium are negative in their immunostaining for progesterone and estrogen receptors? It is therefore considered that the declining levels of steroids can only be directly detected in the Stromal cells of the superficial layer which persistently stain for progesterone receptors.

How & in which way we can defer menstruation? Every one of us prescribes such drugs to postpone menst for social/ Exam/holiday / Tours or other domestic reasons. Having said that my point is “Have we ever closed our eyes and think what are the actions played in the system by progesterone after being getting absorbed by Gut or by Inj prog? “

When to ingest progesterone?   How late in cycle? It has demonstrated that menstruation can be blocked by progesterone add back up to 36 hours after steroid decline. It would therefore appear that menstruation specifically occurs in response to the decline of progesterone levels.

Dynamics of menst- - : To whom we owe so much?? In 1940 Marquee was able to perform classical studies into the mechanism of menstruation. By transplanting explants of human endometrial tissue into the anterior chamber of a Rhesus monkeys eye they were able to visualize direct events that occurred in response to progesterone withdrawal in response to steroid decline they observed. Decline of progesterone cause stromal shrinkage with increased coiling of spiral arterioles and vascular stasis. These changes were followed by a period of vasodilatation and perivascular bleeding and 24 hours later a subsequent intense vasoconstriction and tissue necrosis prior to menstruation itself.

Molecular mechanism of menstruation-:- In response to progesterone withdrawal a complex cascade of events follows that have yet to be fully elucidated.  It in part involves the production of prostaglandins that are able to induce vasoconstriction leading to a reduced blood flow to the endometrium. Subsequently there is increased expression of a range of locally acting mediators including cytokines, angiogenic factors, protease enzymes and further prostaglandins the cumulative endpoint of these changes in local mediators together with an influx of migratory leukocytes is the process of menstruation. 

-What are the two principal changes at premenstrual phase? -Progesterone withdrawal causes two changes:-Change No 1 “Vasoconstriction” & Change 2 : “Hypoxia of endo due to constriction of blood vessels at basal layers”: These are the two are the chief  known & documented   effects of progesterone withdrawal to initiate menstruation .

What happens if up regulation of matrix metalloproteinase production These two events result in an a) up regulation of inflammatory mediator’s production of matrix metalloproteinase’s and b) a leukocyte influx in the upper endometrial zones. There is coincident hypoxia and an up regulation of matrix metalloproteinase production in the same endometrial upper zone stromal cells.

Where from sloughing initiates?? Menstrual sloughing takes place from the superficial regions of the endometrium. Q.1. How we medical personnel classify menst aberration or disorders as we call it? Q.2: How do we classify the of abnormal uterine bleeding? However there were many classifications which were used and only two decades back a new classifications were introduced.

What is new in first decade of this century??  Etiology based classification-ignoring the hypo/hyper (meno) oligo/ Sec etc. A new classification system for causes of abnormal uterine bleeding in the reproductive years was developed by the International Federation of Gynaecology and obstetrics in November 2010.

What does this system imply?  The system is based on the acronym PALM- COEIN that covers the causes of abnormal menstrual bleeding polyp’s adenomyosis leiomyomas malignancy and hyperplasia coagulopathy ovulatory disorders endometrial causes iatrogenic. The novel classification was developed in response to concerns about the design and interpretation of basic science and clinical investigation that relates to the problem of abnormal uterine bleeding. This has led to much confusion when considering the results of clinical trials and also methods of treating a particular problem e.g. menorrhagia meant different things on the two sides of the Atlantic and has now been replaced with Heavy Menstrual Bleeding(HMB) .

A system of nomenclature for the description of normal uterine bleeding and the various symptoms that comprise abnormal bleeding has also been included. The new nomenclature also enhances education and communication between clinicians and scientists. Which should improve our understanding and management of this often perplexing clinical condition?

 what is meant by the abbreviation used at many OPD as “HMB,”??

 The term refers to excessive menst bleeding .For instance we don’t write  cancer Cervix in OPD ticket ,  Instead we write “Ca CX” so that pt herself don’t get hurt or feel much disappointed,. Similarly the word or abbreviation “HMB” has a social impact & also impact at chemist shop, & Lab people.

Is it always due to abnormal ovulation?? Always? Ans;-No. Earlier we considered that the commons cause of menorrhagia is due ovulatory dysfunction which typically leads to a combination of irregular bleeding and an unacceptable volume of menstrual flow which can lead to HMB. In the past this was the feeling of reproductive biologists and endocrinologist. But though anovulation or oligo ovulation is the chief cause of ovulatory dysfunction, but it is not the solo cause.

What sea changes have occurred in last three decades in deciding the etiology of HMB ?? Ans:- “Because now with the advent of 2D. 3 & 4-D USG, SIS & hysteroscopy we can establish with certainty that that many cases of meno are due to some organic lesions of endometrium or myometrium which used to remained  undiagnosed in 1980s. Clinically such anatomical cause of HMB can  be suspected by poor response to high dose OCP, in absence of systemic diseases like hypertension, coagulating disorders Blood sugar or thyroid disorder.

But with improved scanning more pathologies e.g. fibroids adenomyosis or polyps are being identified which can be sub classified further according to their position in the uterus. Most often the concerned woman is either not ovulating has infrequent ovulation. It so happens, in the late reproductive years such oligoovulation is frequent. that In the late reproductive years have deficiency of luteal function.

How to diagnose anovulatory disorders? This can be diagnosed by varying cycle lengths by keeping a record of last 6 months.   To be classified as having an ovulatory disorder the individual should have a cycle length in the previous 6 months that varies by at least 21 days although this may be subject to change with time.