Focus Points of Discussions WHO classification Basic concepts Monitoring Drugs Gonadotrophins Complications Take home messege

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3.  WHO classification
 Basic concepts
 Monitoring
 Drugs
 Gonadotrophins
 Complications
 Take home messege
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4.  Grp I - hypothalamic pituitary failure or
hypogonadotrophic hypogonadism, accounting for
around 10% of ovulatory disorders;
 Grp II - hypothalamic pituitary dysfunction or
eugonadotrophic, 85% of ovulatory disorders;
 Grp III - ovarian failure or hypergonadotropic
hypogonadism, 4-5% of ovulatory disorders.
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5.  Basic concepts…
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6. Early follicular development
….gonadotropin independent
Late follicular development..gonadotropin
dependent
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7.  Late follicle development stimulation by
FSH is an absolute requirement for
development of large antral preovulatory
follicles.
 Duration and magnitude of FSH stimulation
will determine the number of follicles with
augmented aromatase enzyme activity and
subsequent E2 biosynthesis.
 Subsequent development of this cohort
during the follicular phase becomes
dependent on continued stimulation by
gonadotropins.
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8.  The entry of FSH into follicular fluid at
cavitation is believed to provide the
induction stimulus that initiates the process
of graafian follicle growth and development.
 At the cellular level, it is the FSH receptor on
the granulosa cell that is the fundamental
player
 FSH is obligatory for graafian follicle
development, and no other ligand by itself
has the ability to induce follicular fluid
formation.
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9.  FSH has trophic effect on granulosa cells …..
…………recruitment of follicles.
 FSH stimulates transcription of several genes within
granulosa cells leading to synthesis of proteins like
 Aromatase
 Inhibin
 LH receptor………………follicle differentiation
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FSH has long plasma half life of 30-36
hrs.
Plateau of plasma level is obtained
after 5 days of continuous FSH
injections this fsh accumulation
determines the final size of the cohort
of follicles

11. “Two–cell, two-gonadotrophin Concept”
 FSH works on granulosa cells-stimulating their
proliferation and growth
 FSH is active in early follicular phase thus
stimulates small follicles
 LH-acts on theca cells.. to produce androgens –
 Importance lies in the mid-to late follicular phase
stimulates large–follicle growth
 Causing atresia of small follicles- prevent OHSS
Marco Filicori
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12.  Both FSH and LH are required for promoting
follicular growth and differentiation…
 FSH..principal stimulator and regulator of
antral follicular growth…
 Some LH ..preantral stage..to stimulate
secretion of androgens by thecal cells…then
mid follicular phase to nourish then late
follicular phase for surge
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13. For normal folliculogenesis,
LH has to be ‘just right’, neither
‘too much’ nor ‘too little’
-midfollicular phase..0.5IU/L or 1.0IU/L
decreased fertilization and clinical pregnancy rate
The Goldilocks principle:
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14. Three theories of follicle recruitment have been
postulated to date:
(i) the ‘continuous recruitment’ theory,
(ii) the ‘single recruitment episode’ theory and
(iii) the ‘wave’ theory.

15. To treat poor prognosis or oncological patients
through
 Duostim (dual stimulation),
 LPS-only
 Random-start ovarian stimulation approaches.

16.  The most striking change in LH secretion
occurs at the end of the follicular phase, when
there is an abrupt rise in its concentration.
 This is the preovulatory gonadotropin surge
that initiates the ovulatory process.
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17. LH surge:
 0hr…….GV with nucleolus
 +15 hours………… GV Break Down
 +20 hours………… first meiotic metaphase
 +35 hours………… second meiotic metaphase
 +38 hours………… ovulation
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18. FSH Threshold and Recruitment Window
Threshold
Window
Rekruitment Selection Dominance
The longer and higher FSH is above threshold the more follicles are recruitet
Atresia
The longer and higher FSH is above threshold the more follicles are recruitet.
Fauser and Heusden, Endocrine Rev. 1997; 18; 71-106
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21.  Age/AFC/AMH
 BMI
 Duration Of Infertility
 Previous h/o induction protocol/response
 Basal USG..Ut,Endo,AFC
 Basal Endocrine profile..FSH,LH,AMH
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22. Age and Fertility
Optimal
Fertility
Declining
Fertility
Menopause
End of
Fertility
Irregular
Cycles
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Optimal
Fertility

23.  Which Protocol
 Starting Dose
 Maintenance dose
 Monitoring
 Day of trigger.. selection criteria
 Which drug
 What dose
 Luteal support
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25.  Perifollicular and subendometrial
Hallo…oedema
 Cumulus presence..30-40%
 Follicular volume..3-7ml
 Flow Indices…PSV>10,RI<0.5
 Perifollicular Vasularity..3/4th
 Sub Endo vasularity..minimum 5 spiral vessels
reaching to zone 4,ant &post,RI<0.6
 Endo peristalsis 3to5/ min
 Uterine A..on dominent sidePI<3.2
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26. Endometerium
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27.  Multifollicular recruitment bring about a sudden
increase in estradiol (E2) serum levels that is enough
to induce an LH surge while follicular growth is still
in progress.
 24% of IUI cycles suffer from premature LH surge
and this can result in undesired premature
luteinization leading to IUI procedure cancellation.
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28.  The impact of ovarian stimulation on the integrity and
function of the endometrium the duration of the window of
implantation is dependent on levels of estrogen
administered in the luteal phase (Ma et al 2003).
 The move towards
milder stimulation regimens, increasing use of cryopreservation
of embryos and transfer in a natural cycle.
 Ma et al. PNAS 2003 100:2963
 Horcajadas JA et al. J Clin Endocrinol Metab. 2008
Nov;93(11):4500-10
 Boomsma CM, et al, Fertil Steril 2010 (e-pub ahead of print)
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29. Beneficial effect of LH supplementation inBeneficial effect of LH supplementation inpppp
different patient populationsdifferent patient populations
Humaidan et al. 2004
AGE (>35) Bosch et al. 2008
Marrs et al. 2004
elevated basal FSH levels Lisi et al. 2005
Follicular growth stagnation Ferraretti et al 2004Follicular growth stagnation Ferraretti et al. 2004
initial poor response Placido et al. 2004
Ruvolo et al., 2007Ruvolo et al., 2007
endogenous high LH levels after
GnRHa down regulation Humaidan et al. 2004
g
v ßLH mutation Alviggi et al. 2006
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30. Synchronus Follicular growth..small dose to start,early
follicular phase recruitment, small incremental dose
Critical time of trigger for adequate LH surge
Appropriate Choice of Injection for trigger
Right amount of doses
Avoid Premature LH surge
Avoid premature leutinization
Constant look for endometrial quality development to
have good functioning endo for implantaion
Appropriate and right amount of luteal support
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31.  The production of a viable embryo requires
ovulation of a competent oocyte, adequate
progesterone production by the CL, and an
adequate uterine environment.
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