R lh supplementation to rfsh in gnrh antagonist cycles

rLH SUPPLEMENTATION TO rFSH IN GnRH ANTAGONIST CYCLES:
EFFECTS ON IMPLANTATION AND PREGNANCY RATE
A. Nazzaro, A Salerno

Physiology of follicular growth and differentiation

Pre-gonadotrophic folliculogenesis
KIT Ligand expression
It remains to be determined if activation can be
influenced by gonadotrophins but it certainly seems to
proceed normally in their absence

Paracrine connectivity in ovarian follicles.
Hillier S G Mol. Hum. Reprod. 2009;15:843-850
© The Author 2009. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oxfordjournals.org
The follicle responds to FSH and LH as a functional
syncytium integrated by paracrine signalling

Primary
Secondary
• oocyte expansion
• granulosa cell proliferation
• LH responsive Techa cells
Secondary
FSH
TGF-β

Gonadotrophin dependence
1) enhance granulosa cell sensitivity and
responsiveness to FSH
2) suppress LH-responsive thecal androgen
synthesis
FSH
1) promote androgen synthesis
2) Androgens in turn synergize with FSH
to augment inhibin synthesis
The principle requirement for LH
is to sustain androgen synthesis, without which there is no estrogen synthesis
Follicular antrum formation and antral expansion are absolutely dependent on FSH.

Late follicular phase
Huang Z , and Wells D Mol. Hum. Reprod. 2010;16:715-725

Follicular activation
Meiotic resumption
in late follicular phase
Zhang M et al. Mol. Hum. Reprod. 2009;15:399-409
LH stimulated paracrine signals are thereby able to
impact oocytes even in follicles whose granulosa
cells do not express LH-R

• costly
• time consuming
• potentially unhealty

Gonadotrophic manipulation of paracrine signalling
Paracrine signalling explains how gonadotrophins are potentially able
to benefit oocyte function
and by extension how inappropriate use of
exogenous gonadotrophins might be deleterious

closely mimic physiology
controlled ovarian stimulation regimes might be reverse engineered from the natural
follicular life cycle

Understanding the role of LH:
myths and facts

Too much or too little LH activity
can have negative outcomes
LH window

Gynecol Endocrinol. 2012 Sep;28(9):674-7. doi: 10.3109/09513590.2011.652716. Epub 2012 Feb
8.
Recombinant luteinizing hormone priming in multiple follicular stimulation for in-vitro
fertilization in downregulated patients.
Lisi F, et al.
follicular priming with LH
J Clin Endocrinol Metab. 1999 Aug;84(8):2951-6.
Androgen and follicle-stimulating hormone interactions in primate ovarian follicle
development.
Weil S, et al.
Li M et al. Mol. Hum. Reprod. 2009;15:149-154

Granulosa cells express androgen receptor (AR) through which theca-derived
testosterone amplifies FSH-stimulated PKA signalling
LH-driven thecal androgen production may be a component of the natural mechanism
through which antral follicles initially acquire sensitivity to FSH.

LH priming
Durnerin C I et al. Hum. Reprod. 2008;23:421-426
revealed increased developmentof small antral
follicles due to LH priming
a statistically significant increase in the number of normally
fertilized embryos obtained after subsequent FSH treatment
no clinically important outcomes were significantly altered in the LH group versus controls

Evidence that LH priming can improve oocyte quality.

Evidence that follicular coasting with LH can promote mono-ovulation: a double-blind,
placebo-controlled, multicentre pilot study in patients undergoing ovulation induction.

OSF regulation of CC function and oocyte quality Model depicting oocyte–CC interactions
and their impact on subsequent oocyte developmental potential.
Gilchrist R B et al. Hum. Reprod. Update 2008;14:159-177
Oocyte quality is assured by LH-driven nutritional and informational signals
emanating in cumulus cells

biphasic stimulation regimes using FSH followed by LH activity to target the gold standard
oocyte and its nearest neighbours (in developmental terms) could have potential clinical
merit

Schematic overview of expected FSH and LH concentrations in various GnRH analogue regimens a and b
are regimens without oral contraceptive pill (OCP) pretreatment: (a) long GnRH agonist protocol and (b)
fixed day 6 GnRH antagonist protocol.
Huirne J et al. Hum. Reprod. 2007;22:2805-2813
© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human
Reproduction and Embryology. All rights reserved. For Permissions, please email:

P. Platteau MD, MRCOG
Centre for Reproductive Medicine
Brussels Free University
Belgium
Antagonist study
A.Nazzaro, MD
A.Salerno MSc, PhD
AORN “G. Rummo
Italy

Ideal antagonist protocol
• Estroprogestin till Wednesday (last pill)
• GnRh-antagonist started on Monday for 3 days
• Blood test (E2 + P4 + LH)
• rFSH oh Thursday
• GnRh-antagonist added-back
on the 6th day of COH
• Blood test (E2 + P4 + LH) + US Tuesday and
Thursday
• OPU between Monday and wednesday
if P4 >1 ng/ml one more
antagonist ampule (rFSH
started one day later)

Ideal antagonist protocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
rFSH (Tailored)
GnRh-ant
HCG OPU ET
GnRh-ant
Menses
EP
rLH
rLH

Partially presented and awarded with first prize for scientific comunication at
2012 ASRM Annual Meeting – San Diego, Ca, 2012

Baseline characteristics of the two
study groups.
rFSH (n=211) rFSH + rLH (n=211) P-value
Age (years) 36.7 ± 1.5 36.6 ± 1.6 NS
BMI (kg/m2) 22.6 ± 2.7 22.7 ± 2.8 NS
Infertility duration (years) 4.4 ± 2.3 4.7 ± 2.4 NS
Basal plasma FSH (mIU/ml) 5.7 ± 2.4 5.1 ± 1.9 NS
Basal plasma LH (mIU/ml) 5.5 ± 2.3 4.0 ± 1.9 NS
Basal plasma oestradiol (pg/ml) 73.0 ± 29.1 66.9 ± 31.0 NS

r-FSH (n = 211) rFSH + rLH (n=211)
GnRH antagonist (days) 10.6 (1.8) 9.8 (1.3)
Duration of ovarian
stimulation (days)
11.7 (0.9) 11.4 (1.1)
Cumulative r-HFSH dose (IU) 2562 (1187) 2453 (1884)
Plasma oestradiol (pg/ml) 2254 (989) 2325 (723)
follicle size (mm)
10 and <14 4.6 (2.8) 3.8 (1.6)
14 and <16 mm 3.4 (1.6) 4.6 (2.1)
16 and <18 mm 4.4 (1.2) 4.3 (1.1)
>18 mm 3 (1.2) 3 (1.1)

r-HFSH (n = 211) rFSH + rLH (n=211) P-value
Retrieved oocytes 8.9 + 4.9 11.8 + 4.3 0.036
Metaphase II oocytes 4.2 + 2.1 7.8 + 2.3 0.014
Fertilization rate 0.58 + 0,26 0.87 + 0.32 0.017
Embryos/cycle 5.4 + 2.1 9.6 + 1.2 0.092
Grade I-II
embryos/cycle
4.3 + 0.8 7.6 + 1.3 0.086
Frozen embryo/cycle 1.0 + 0.4 4.3 + 1.2 0.008
Implantation rate (%) * 13 (105/829) 18 (148/826) 0.04
Clinical pregnancy rate
(%) **
22 (84/380) 32 (98/305) 0.03
•GS/Embryo transferred
• Pregnancy/Embryo Transfer

LH, endometrium and embryo implantation

This scanning electron micrograph of a sample taken on day 7 after HCG administration from an oocyte
donor in the ganirelix 2 mg group shows that the high-dose ganirelix treatment can produce the required
epithelial response.
Simon C et al. Hum. Reprod. 2005;20:3318-3327
© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human
Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oupjournals.org

Exogenous LH protects the endometrium from
exposure to premature progesterone rises

Percentage of genes in common between stimulated and natural cycles during the receptive
endometrium.
Haouzi D et al. Biol Reprod 2010;82:679-686
©2010 by Society for the Study of Reproduction

CONCLUSION
• The apparent beneficial effect of r-LH on implantation and
pregnancy outcomes in our study could be explained by
two different mechanisms:
1. Firstly, the embryo quality could be superior in the group
supplemented with r-LH.
2. Secondly, there may be an effect of LH supplementation
on the endometrium, which could promote implantation.
r-LH supplementation in GnRH-a cycles seems to improve implantation and pregnancy
rates via an improvement in oocyte quality and/or uterine receptivity

Translational implications
• The current emphasis on oocyte quality over quantity in ART procedures calls for a more
intelligent approach to ovarian stimulation based on sound physiological principles
• Follicular responses in standard FSH/hMG alone regimes are inevitably asynchronous,
yielding many oocytes that do not fertilize or are unable undergo normal embryonic
development.
• We have highlighted paracrine pathways emanating in thecal cells and granulosa cells
that potentially impact oocytes and which can be manipulated by sequential and/or
combined use of FSH and LH
• We have to designe tactics to increase follicular responsiveness to FSH/LH, synchronize
oocyte competence and maximize oocyte quality
There can be no one-size-fits-all approach to ovarian stimulation
Factors such as age, genotype and general health will always affect individual responses
However, treatment tailored to personal needs based on paracrine principles will
always be more likely to achieve the desired outcome.

R lh supplementation to rfsh in gnrh antagonist cycles

R lh supplementation to rfsh in gnrh antagonist cycles

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