What is new in our knowledge on Physiology of Ovarian
Reserve and Endocrine Function
Q.1. Is there any recent change in aassesing ovarian reserve which was so long popular for last 3 decades like AMH &
AFC: Ans:You will be surprised that many scientists have
recently questioned the validity of AMH & AFC imp assign
follicular stock ??
Q. 2. What was known to us?? :
Ans;
Ovary contains a stock of follicles number of which gradually declines as age
advances by a process of physiological apoptosis. Physiological atresia starts
from intrauterine life the process of atresia continues through childhoodà puberty-à adolescence à child bearing age till
the stock is exhausted by the time when woman reaches menopause. We also know
that from several millions of follicles appearing in intrauterine life the
number is reduced to two millions at birth and 3,00,000 at puberty.
Q.3 . As she enters in
reproductive life??
Ans:What
happens in each menst cycle?? Ans:-During reproductive years with each
menstrual cycle some 30 to 40 follicles are wasted.
Q. 5:-Which Follicles undergo apoptosis first??
Ans:-It should be noted that better quality
follicles’ are exhausted in the first half of reproductive years followed by
relatively interior quality follicles.
Q.
6 . Leave me alone: I am a Lady? Don’t you know manners?? Haven’t attend
classes of Dr Pal (how gentle he is to me
!!) For havens sake please don’t
disturb me. I shall communicate to my
body guard Prof Pal, if you drill me or do unnecessary stripping of my
cyst wall which are too small based on
USG ?? Prof Pal then, will sent to you Jail if U unnecessary touch me,
.Ans:- Dr. Pal has told me what is bad touch (
excess drilling too many holes, high current ., deep holes –the law of 4
forgotten ) & what is good touch(big
chocolate cyst) !! You must know that one President gently slapped Queen at
Brimming ham Palace but that was a good humorous touch.
Ans:-Therefore
no unnecessary ovarian surgery please: During this long journey from puberty to
menopause any trauma or insult to the ovary may lead to qualitative and
quantitative loss of follicles reducing ovarian reserve prematurely
Q.7:-What was the
parameter of Ov reserve so far?? What about FSH on day 3 of spont cycles ??
Ans:-
FSH does not indicate the quality of oocytes available.. One clinically useful
indicator was to predict ovarian reserve is to measure the level of baseline
follicle – stimulating hormone. Gradual rise of baseline FSH in consecutive
cycles indicates diminishing ovarian reserve. Now scientist has concluded that
FSH is a quantitative predictor of oocytes level of borderline elevated. FSH
does not indicate the quality of oocytes available. From that point of view
patient’s age and assessment of AMH are better qualitative predictors of
ovarian reserve than baseline FSH.
Q.8. Is this hold
good(Basal FSH) in cases of genital
Kochs induced affection of Ovary or T O mass ??
Ans:-As
genital tuberculosis affects women of younger age better quality eggs are still
available although ovarian reserve may be borderline. This fact provides a
favorable scope for treating infertility by ART for women with genital
tuberculosis. In genital Kochs there has been shown that demonstrates that
though numbers of eggs are less quality of eggs is better because of relatively
younger age of the patient affected with genital tuberculosis.
Q . 9. So FSH gone,
which parameter of Ov reserve next to
consider ? Which test will be the best
predictor of Ov reserve??
Ans:-A
better qualitative predictor for ovarian reserve namely anti mullerian hormone
has recently been identified. AMH is synthesized and released by granulosa
cells of the follicle. Unlike other biomarkers for ovarian reserve like FSH
inhibin or E2 estimation of AMH can be done on any day of menstrual cycle. This
is because levels of serum FSH, E2 and inhibin B depend on individual feedback
mechanism whereas production of AMH depends on health and integrity of granulosa
cells and is not dependent on feedback mechanism.
Q.10:-Physiology
of ovarian endocrine function : Ans:-What is our expectation , being under
gonadotropin control ovaries should be
able to respond to appropriate levels of
gonadotropin and in response should be able to generate optimum amounts of
ovarian steroids namely oestrogen and progesterone
Q. 11. What
are the 33 Autocrine factors which are continuously governing the action
of FSH in the Granulosa cells & theca cells and possibly on oolemma
as well?? What controls –Intracellular signaling in ovarian cortex?? ?? ??
NDA?? UPA –Govt of many political parties!!
What is not known by NASA about the universe?? Who is Megnadh -who
fights/ helps somebody himself
hiding behind the cloud ? Parde
pichhee kaea hai??
Ans:-to
Q. 11 :-In addition intraovarian
peptides play important roles in regulating gonadotropic consist of autocrines and paracrine. At least 33 putative Autocrine
– paracrine regulators for follicular growth have been identified. They play a
major role in follicular growth and atresia. The important members of Autocrine
paracrine family consist of inhibin Activin insulin like growth factor vascular
endothelial growth factor transforming growth factor alpha etc. They play
important role in modulating gonadotropic effects on ovarian function and
ovulation. These cordinate ovarian
endocrine functions are disrupted either directly through toxins produced by
NTB or indirectly by adverse immune modulatory
change in intra follicular environment
. The consequences may be gonadotropin response deficiency anovulation
endometrial hyperplasia luteal phase defect etc.
Q.12:
Genital Kochs ?? How is the Ovarian
function affected in genital
tuberculosis ?? Kochs may be adversely
affected in following ways
a. Morphological
involvement of the ovaries: Ovaries are involved in 20 to 30% cases of genital
tuberculosis . The degree of morphological involvement depends on the
severity and stage of the disease. There
may be either tubercles on the ovary or adhesion caseation tubo ovarian cyst or
mass formation. Rarely the ovaries may be completely destroyed by the disease.
These types of tubercular ovarian affection may lead to both follicular stock
depletion and endocrine disruption.
b. Tubercular
hydrosalpinx: TB hydrosalpinges may interfere with ovarian function either
directly or indirectly. Fallopian tubes are involved in almost all women with
genital tuberculosis involvement is usually bilateral. Tubercular hydrosalpinx
is not uncommon in India. Other causes of tubal dilation include pelvic inflammatory
disease adhesion and obstruction due to any cause. Scientists have observed tubal dilatation with or
without obstruction in 46% of their
patients with genital tuberculosis . Incidence
of tubo ovarian mass has been
reported to be 15.3%
Q.13:-Then?? Will full course of ATD I can’t
become mother –Why?? Ans:-a possible
link between LGTB and endometrial receptivity one of the key factors
determining implantation which has not been studied so far we therefore aimed
to evaluate the various biochemical and
morphological markers of endometrial receptivity during implantation window in endometrial
tissue of women with LGTB . The biochemical markers examined in th study
were the endometrial adhesion molecules mucin a and an interleukin – 6
class cytokine leukemia inhibitor factor
Q. 14 “: TB what else is now known?? A significant decrease
in a vB3 integrin . LIF, E cadherin, MECA- 79 and MUC-1 expression was observed
in women with LGTB as compared to controls.
Q. 15 : What is Bologna
criteria 2011 ?? Why that was frames?? I am sinking am drowning!! Please tell
my father for my marriage .I am already 34 yrs!!! Ans: Over the past few
decades DOR / POR has emerged as a challenge. The incidence in
a population undergoing assisted reproduction treatment is estimated to be
9-24% . Measures have been taken to identity
such patients at risk or during treatment for appropriate management Bologna criteria 2011 is one such crucial
step taken towards the introduction of a uniform definition of POR to guide the
management and intervention strategies. It states that presence of at last two
of the following three features are required for the diagnosis of POR:
1. Advanced maternal age (
> 40 years ) or other risk factors
2. Previous POR ( < 3
oocytes with conventional stimulation protocol )
3. An abnormal
Ovarian Reserve Test (AFC 5-7 follicles
or AMH 0.5 -1.1 ng/ml )
Q. Q.
16:- : New defn of por responders??
Ans:-Two episodes of POR after maximal stimulation
categories patient as poor responder in
absence of advanced maternal age or abnormal
ovarian reserve test. Poor response
can be expected from patients with age> 40 years and abnormal ORP. Then starts the quest for oocytes laying
out plans and hoping for a good response.
. Q.
17 : Then we, who are poor responders ,
have no hope to become biological mother ??
Ans: No. Not at all. Don’t lose your hope. I don’t mean that. Hope is always there
because Dr Pal is still typing personally at the age of 77 yrs, Then why I can’t
produce my own good quality fertilizable egg at 39 yrs with no post fertilization developmental
errors ? !! Ans: What are the steps so
long adopted for so called poor responders??
Ans ::
Various
strategies have been tried so far
Modification : 1) gonadotropin dose adjustments
Modification
: 2) use of antagonist Modification : 3 Use of
cofollitropin alfa, Modification 4:
Estradiol in luteal phase. Modification :5:Addition
of Growth hormone. Modification : 6 :Another such novel approach is the use of Androgel.
Modification :
7 :: Will DHEA work?? How much money is spent per day for DHEA by
couple?? What other modifications and deviation from Sc?? Ans: Pretreatment with androgen has been a hot
topic for debate for many years.
Androgen acts primarily during FSH
dependent early folliculogenesis.
Androgens act on granulose cells in early follicle maturation and increases the sensitivity of
the follicles to FSH via cANP mediated pathway. Androgen receptor protein then decreased with
advancing follicular maturation. Thus androgens and FSH work synergistically .
A positive correlation has been observed between serum testosterone
concentration and number of oocytes retrieved and the amount of FSH required.
Modification: 8: Other modalities of androgen
administration?? Ans:-Various modes of
testosterone administration are known
like DHEA, 1) testosterone patches and 2) testosterone gel or androgel. Although DHEA
has already found its way into the practice use of Androgel seems to be the most
promising due to acceptable safety profile and better convenience. Androgel 1%
gel contains 50 mg testosterone which is
biologically similar to testosterone which is biologically similar to
testosterone secreted by human body.
Modification: 9 :Information on drug and its
usage: Each 5 gm gel contains 50 mg of
testosterone. So the dosage is a quarter of a gel which makes approximately
12.5 mg testosterone.
Modification: 10 :: How to use : Androgel is to be used prior to ovarian stimulation. It has been used in studies for
a variable time period of 4-6 weeks. The feasible and systematic way to use it
would be from Day 6 of previous cycle to Day 2 of stimulated menstrual cycle.
Modification: 11 :: How to apply : Step 1:. The gel should be applied
preferably on inner upper arm or on shoulder or abdomen over a dry and clean
area with intact skin.
Step :. 2. Take full gel in a syringe, apply and discard the remaining gel. Step 3. Apply at night before bedtime Step 4. Leave it to dry for 3-5 minutes
.5.Cover with clothing 6. Wash hands thoroughly Step 7.
Nobody should come in contact with the
area the gel has been applied to . Take
bath after intimate contact.
Modification: 13: I don’t like be a male!! I am
a woman. I am proud of my woman hood though I am still unable to reproduce.
That is one aspect but believe me I am caring to my hubby and other family
members. .Then doc why you are
prescribing male hormones to me? Do U like to change me as transgender-which I
don’t like!! Ans:-Special warning from
Dr Pal about Safety profile of androgen ?
: Apart from possible local skin reaction such as irritation and dryness
at the site of application not much of side effects have been observed with such small dose used for short period of
time.
Take home message from Dr Pal : :
Various
studies have shown that use of Androgel in poor responders may result in the increase in the number of mature eggs, good quality embryos and better
implantation rates but a randomized controlled trial is much needed to put this
into practice. Few other studies state that although there is a definite
increase in the number of follicles retrieved but the quality remains the same.
This goes in consensus with the fact that in condition such as PCOS although there is hyperandrogenism and more
number of follicles may be retrieved but quality is inferior. This is the point
where the data falls short. With that said being said this simple approach has shown
promising results and has entered the vernacular as a viable option to treat
poor responders.
Q.1. How we can reasonably confirm /diagnose
Adenomyosis? Ans: -We know that
subjective symptoms of adenomyosis are like endometriosis e, g. dysmenorrhea
subfertility, pelvic pain and menometrorrhagia, but for confirmation there are
basically two modalities which help us to confirm the clinical diagnosis of
adenomyosis. Such are 1) MRI 2) USG.
Q2:
what are the sonological features? In USG we should look for:-
1) Heterogeneous myometrial area.
2) Globular asymmetric uterus.
3) Irregular cystic spaces.
4) Myometrial linear striae.
5) Poorly defined / demarcation of
endometrial – myometrial junction.
6) Myometrial anterior- posterior
wall asymmetry. Usually the post wall is thicker than the ant wall,
7)
Both the walls of myometrium may be thickened say anterior and posterior
wall.
8) Increased or decreased
echogenecity
Most of us use only USG for diagnosis
confirmation as a cost savings approach while others have used all two parameters
for diagnosis of adenomyosis like USG & MRI. This is truer when one
considers for ART. Regarding endoscopic diagnosis the diag remains uncertain
though hysteroscopy is more helpful in diagnosing than laparoscopy. In fact
in fair number of cases the laparoscopy may be negative inspite of moderate to
severe adenomyosis.
Q.3:-What is meant by Junctional Zone
& what is the role of JZ in the etiogenesis of adenomyosis. , The area of endomyometrial junction is known as junctional zone.
Junctional Zone consists of three layers as detailed below:
a. Innermost myometrial layer
B. and the sub vascular layer above
the endometrial cavity – also known as archi
myometrium
c. Including basal endometrial layer
We know that the normal thickness of
junctional zone is 7-8 mm. In adenomyosis the junctional zone thickness
increases to > 12mm.
Q.4: Why & how adenomyosis
develops? In case of adenomyosis this Jan zone play a vital part and in
most of the cases the disease initiates with the invagination of JZ into myometrium
due to various causes of which abnormal uterine peristalsis is mostly
attributed.
Why abnormal peristalsis causing high
intra uterine pressure??
The process of invagination of this JZ is thought to be suing either to
a) abnormal peristaltic function or wave of peristalsis originating in this JZ
or local structural abnormalities in the myometrial tissue. This structural
abnormality may be congenital or acquired. These two factors are the chief
causes of genesis of adenomyosis usually favour development of adenomyotic
uterus. Besides c) abnormal hormonal and d) immunological conditions also have
a commanding role to play in the normal functions of JZ and if any one goes
wild then this increased pressure induced by uterine peristalsis may cause invagination
of endometrium.
We know that
the normal thickness of junctional zone
is 7-8 mm. In adenomyosis the junctional zone thickness increases to > 12mm.
Q.5:-How adenomyosis cause
subfertility or enhances spont miscarriage rate?
Ans:-Impediments to conception is
brought about by A) increased uterine peristalsis, as mentioned earlier, which
is partly governed by junctional zone. In cases of adenomyosis there is primary
abnormality in junctional zone thickness à which leads to uterine
dysperistalsis and therefore B) impairment of sperm transport... In addition in adenomyosis there is also C)
increased colonization by macrophages’) Secretory products of these macrophages
have adverse impact on oocyte quality fertilization and implantation. These
noxious products released by macrophages
trickles down to F tubeàthen via fimbrial end to the surface of ovary and it is believed that the
said noxious agents / toxins liberated by endometrial macrophages is brought
about via utero ovarian countercurrent systemà impedes oocyte dev environemetyt.
Q 6: What is Junctional Zone?
Junctional Zone consists of three different components:-
a. On the outermost part is
“innermost myometrial layer”.
B. In the middle part is “sub
vascular layer deep to but adjoining the endometrial cavity – also known as archi myometrium “
C. and most inside close to uterine
cavity is the “basal endometrial layer”’
We know that the normal thickness of
junctional zone is 7-8 mm. But in adenomyosis the junctional zone thickness
increases to > 12mm.
Q.7. what is meant by normal uterine
peristalsis? How such peristlasis may go wild
and may become an etiologic factor of genesis of adenomyosis? Ans: Increased peristalsis
which creates increased intra uterine pressure – leading to invagination of
basal endometrium into the myometrium --Uterine myometrium has a regular
pattern of peristalsis regulated by endocrine
and paracrine stimuli. Junctional zone thickness causes increased
peristalsis which creates increased intra uterine pressure – leading to
invagination of basal endometrium into the myometrium. Invagination is more commonly found on posterior
wall of uterus. Invagination is also facilitated by weakness of smooth
muscle tissue of uterus .Weakness may be due to high estrogen concentration in the local area or impaired
immune related growth factor.
Q8. What are the other pelvic pathologies which may be
associated with adenomyosis? Apart from pelvic
endometriosis adenomyosis may be associated with other pelvic pathological
conditions like 1) leiomyomas 2) endometrial hyperplasia 3) endometrial polyp
4) atypical endometrial hyperplasia and rarely 5) adeno carcinoma. However
presence adeno myoma or adenomyosis has no adverse effect on the prognosis of
endometrial carcinoma.
Q.9. How we can confirm the clinical
diagnosis of adenomyosis? There are two modalities which help
us to confirm the diag of adenomyosis? Such are 1) MRI 2) USG.: In USG we
should look for:-
1) Heterogeneous myometrial area.
2) Globular asymmetric uterus.
3) Irregular cystic spaces.
4) Myometrial linear striae.
5) Poor definition of
endomyometrial junction.
6) Myometrial anterior- posterior
wall asymmetry.
7) Thickening of anterior and
posterior wall.
8) Increased or decreased
echogenecity
Most of us use only USG for cost
savings while others have used all both parameters for diagnosis of adenomyosis
.Hysteroscopy is more helpful in diagnosing than laparoscopy...
Q.10:
How best to treat adenomyosis?? A) If Uterus exceeds 10 cm
–presenting with menorrhagia and dysmenorrhea hysterectomy with preservation of
ovaries for future surrogacy is considered to be the rational /effective
treatment. Therefore Conservative surgery +- agonist (GnRH agonist) or one can
use Danazol loaded intra uterine device. In rest cases where the uterine length
is less than 10 Cm then following 7 options are available. Like 1)GnRH a for
six months 2) Wedge biopsy 3) Uterine artery embolization 4) High intensity
focused ultrasound
5) Ultra long GnRH followed by IVF
vs. conventional Ivf. 6)
Combination of conservative surgery
plus GnRH-a
7) LNG or danazol loaded IUs 8)
Conservative surgery alone .9) High intensity focused ultrasound & Uterine
artery embolization 10) Laparoscopic partial resection of uterus with uterine artery
occlusion.
Q.11: What will the Obstetric
Outcome in adenomyosis? Ans:-The obstetric outcome in an adenomyotic uterus
include 1) Increased risk of preterm premature rupture of membranes 2)
Uterine rupture or perforation -29
cases from 1904 to 1984 plus an ectopic pregnancy in adenomyotic area were
reported by Aziz et al 3) Rapid enlargement of adenomyotic uterus in pregnancy
conceived after controlled ovarian stimulation has been reported. In fact, ART
may lead to red degeneration during pregnancy and 4) PPH during and following
delivery.
Q. 12: If you like to moderate a
session in a CME on adenomyosis / endometriosis then may put such 11 questions
as Chair person. I firmly believe the Conference Hall will be vacant and all
the delegates including the panelists will be assembling there.
Be that as it may what are those tips which
will cause annoyance to audience?? :
Take
home message 1:-Diag modality: The best
method?? Apart from many diagnostic
markers as is imaged by MRI and or USG- a) thickened endomyometrial junctional,
b) anterior posterior uterine wall asymmetry c) heterogeneous myometrial areas
with irregular myometrial cystic spaces are the characteristics for diagnosis
of adenomyosis. It is believed that increased peristalsis which creates
increased intra uterine pressure – leads to invagination of basal endometrium
into the myometrium.
Take
home message 2:-
Etiology? What cause adenomyosis i.e.
formation of ectopic stromal tissues /glandular/surface epithelium of
endometrium to go inside the deep into myometrium? Apart from being a
diagnostic parameter through USG and MRI
– JZ thickness has a great impact on inducing normal myometrial contractility
which creates a favorable peristaltic movement of the myometrium for sperm and
embryo transport within the uterine cavity. This coordinated movement of JZ is
governed by many endocrine, neuronal & paracrine and growth factors. We
know that the normal thickness of junctional zone is 7-8 mm. In adenomyosis the
junctional zone thickness increases to > 12mm as it is overactive and in
most cases of adenomyosis the disease is initiated from this JZ.
Take
home message: 3:- Why subfertility?? 1) The myometrial peristalsis
of may misdirect sperm entry into the uterine cavity which may be an
independent cause of infertility in women with adenomyosis. 2) Other direct
cause of infertility due to adenomyosis only is migration of macrophages into
the uterine myometrium leading to production of local inflammatory exudates. 3)
Release of exudates within the myometrium produces adverse utero ovarian reflex
signal to the developing follicle in the ovaries resulting in liberation of
poor quality oocytes.
Take
home message 4:-Besides subjective symptoms of
dysmenorrhea and menometrorrhagia there are four other objective signs for
diagnosis of adenomyosis. These are A) laparoscopy or B) hysteroscopy with or
without directed myometrial biopsyà histology. C) Transvaginal
ultrasonography and 4) MRI. TVUS and MRI are non invasive and dependable
diagnostic procedures. Between the two, USG is easily available and least
expensive.
Take home message 5:-In initial years association of adenomyosis with pelvic endometriosis
was reported to be much less than what is being reported currently. This is
because of improvement of diagnostic facilities awareness of patient population
and perhaps late marriage of women.
Take home message 7: TR of
adenomyosis: Some without desire for babv: Currently with adenomyosis
infertility is the primary problem – conservative line of treatement is the
rational approach. Medical treatment with 1)GnRH a 2)danazol or 3)aromatase
inhibitors , 4) LNG-IUS and recently introduced 5) dienogest are effective but
not very popular for fertility restoration
Medical TR: - Adenomyosis has a
negative impact on ART outcome.
With conservative surgical treatment
or with ART may produce some positive outcome.
High intensity focused ultrasound or
uterine artery embolization are the alternative options with questionable
outcome.
Diffuse uterine adenomyosis measuring
10 cm or more with menometrorrhagia is beyond the scope of conservative
management:--Such patients require abdominal hysterectomy with preservation of
ovaries for future possibility of surrogacy.
Impact
of adenomyosis on obstetric outcome includes – miscarriage, ectopic
pregnancy within the adenomyotic foci, preterm labor, uterine perforation, and
postpartum hemorrhage.
Putting the Fetus at Risk