Improving Success by Tailoring Ovarian Stimulation
36
Improving Success by Tailoring Ovarian Stimulation Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Center for Male Reproduction & Infertility Campinas, BRAZIL EOFF 2012, Dubai – Nov 22
Center for Male Reproduction & Infertility Campinas, BRAZIL
EOFF 2012, Dubai – Nov 22
Esteves, 2
Learn the primary factors affecting ovarian response to stimulation and the importance of knowing your patients’ profiles.
Learn the best OS strategies to minimize complications in “high responders” while maintaining sustainable pregnancy results.
Learn the best OS strategies to maximize pregnancy outcomes in “poor responders”.
What is in it for me?
Review this Lecture at: http://www.androfert.com.br/review
Improving Success by Tailoring Ovarian Stimulation
Esteves, SC – EOFF 2012
Esteves, 3
Factors Determining Response to Ovarian Stimulation
Demographics and anthropometrics (Age, BMI, Race) Genetic profile Cause of Infertility Years of Infertility Health status Nutritional status
Esteves, 4
Presenter
Presentation Notes
Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS). In fact, the patient is the main variable in ovarian stimulation response. There are multiple factors interacting mutually, such as demographics and anthropometrics, genetic profile, cause and duration of infertility, health and nutritional status. Therefore, the “feeling” of clinicians may be misleading because it is used empirically and has low reproducibility.
1930s 1950 1980 1995 2003
Pituitary FSH u-hMG
u-FSH
u-FSH HP r-hFSH
r-hFSH FbM
Intramuscular administration sc Injector pens
sc, subcutaneous; FbM, filled by Mass; HP, highly-purified
Safety, Quality, Consistency and Patient
Convenience
Esteves, 5
Long-acting
r-hFSH;
2010
Puriity and
SpecificActivity
Adapted from Lunenfeld. Hum Reprod Update 2004;10:453–67
r-hFSH +r-hLH FbM
2007
Horse PMSG
Presenter
Presentation Notes
At the same time, the therapeutic armamentarium for ovarian stimulation has increased over the last years and clinicians face the problem of which drug regimen to use.
Urinary vs. RecombinantThe endless debate…
Meta-analyses of rec-hFSH vs HMG/HP-HMG/uFSH
Number of RCTs included
Number of
couples
Statistical significance
Clinical significance
Coomarasamy et al, 2008
7 2,159
LBR (RR = 1.18, 95% CI: 1.02 to 1.38, P<0.03) in favor of HMG
4% difference in LBR in favor of HMG (CI: 1%-?)
Al Inany et al, 2009 6 2,371
Insufficient evidence of a difference in odds of pregnancy or live birth
None
Van Wely et al, 2011
28 7,339 Insufficient evidence of a difference in odds of live birth Subgroup analysis of r-hFSH vs HMG in favor of HMG (OR 0.84, 95% CI 0.72 TO 0.99; N=3,197)
None
For a LBR of 25%, use of rFSH rather than hMG would result in a LBR
19%-25%
Coomarasamy et al, Hum Reprod. 2008;23:310-5; Al Inany et al, Gynecol Endocrinol. 2009; 25:372-8; Van Wely et al. Cochrane Database Syst Rev. 2011; 2:CD005354 Esteves, 6
Presenter
Presentation Notes
A number of meta-analyses have compared the efficacy of different gonadotropin products. These meta-analyses have a number of limitations. There are various differences between the studies, such as the type of down-regulation protocol, inclusion and exclusion criteria, and gonadotropin product used. Despite these shortcomings the overall picture indicates that all available gonadotrophins are effective and safe. Coomarasamy et al., including seven randomized trial (2159 women) comparing hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles, have showed a significant increase with hMG in clinical pregnancy (RR = 1.17, 95% CI = 1.03 to 1.34) and live birth rate (RR = 1.18, 95% CI: 1.02 to 1.38, P < 0.03). No significant differences were noted for gonadotrophin use, spontaneous abortion, multiple pregnancy, cancellation and ovarian hyperstimulation syndrome rates. The observed difference was a 4% increase in live birth rate with hMG when compared with rFSH. However, the lower limit of the confidence interval was 1%, and thus the finding of this meta-analysis should not be over-interpreted (10). In 2009, Al-Inany et al, in another meta-analysis, with six randomized trials included (2371 participants), comparing HP-hMG vs. rFSH, have showed no diference in clinical pregnancy or ongoing pregnancy/live-birth. Separing only IVF cycles (not ICSI), it was demonstrated a better ongoing pregnancy/live-birth rate in favour of HP-hMG (O.R = 1.31, 95% CI = 1.02 to 1.68) (11). The most recent meta-analysis, published by Van Wely et al (Cochrane Database), in 2011, has compared rFSH to urinary gonadotropins (hMG, HP-hMG, FSH-P, FSH-HP) in IVF/ICSI cycles, including 28 trials (7339 couples), and have showed no diference in live birth or OHSS rate. Comparing only hMG/HP-hMG to rec-hFSH, they have showed significantly fewer clinical pregnancies after rFSH as compared to HMG (OR 0.85, 95% CI 0.74 to 0.99; I2 of 0%; 12 trials, N=3775) and fewer live birth (or ongoing pregnancy) (OR 0.84, 95% CI 0.72 TO 0.99; I2 OF 0%; 11 trials, N=3197). the majority of the included trials were industry sponsored and this may have introduced a bias in favour of the gonadotrophin produced by the sponsor. The subgroup analyses in which we grouped the primary outcomes for pharmaceutical sponsoring suggest that live birth and clinical pregnancy rate were lower for rFSH compared to urinary FSH in the Ferring sponsored trials. However, further analysis of the Ferring sponsored trials and the non-sponsored trials that compared HMG/HP-HMG with rFSH showed comparable summary OR and confidence intervals that overlapped. Hence, though they couldn’t rule out that a sponsor effect was involved in this finding the potential effect of this sponsor bias appears to be limited. The conclusion was that it appears that all available gonadotrophins are equally effective and safe (12). For a live birth rate of 25%, use of rFSH rather than hMG would result in a live birth rate between 19 and 25% (a). Another bias in the comparisons of hMG/HP-hMG and rec-hFSH is that rec-hFSH shows only FSH activicty, while the first have 1:1 FSH:LH ratio (1). This differrence can interfere in the results of specific groups of patients that could be beneficiated by LH activity.
Esteves, 7
Define your patient population and your results by “Data Mining” your own database.
What are the best strategies to individualize COS for my patient population? Search the literature for relevant studies that match your patient profile.
Presenter
Presentation Notes
These meta-analytic studies give us an overall idea but do not respond what we really want to know, that is,
Data Mining
Presenter
Presentation Notes
Data mining is the process that attempts to discover patterns in large data sets. The overall goal of the data mining process is to extract information from a data set and transform it into an understandable structure for further use.
1Reproductive Hormones Report - GCC Countries (Feb 2011) 2Bologna criteria: Ferraretti et al. Hum Reprod 2011. Esteves, 9
• Prevalence of Patients with Poor Response to Ovarian Stimulation2
05
10152025303540
< 30years
30-35years
36-39years
40-42years
>42years
Cancellation Rate < 4 oocytes
Up to 68%
Prevalence of Infertile Patients (WHO II) with PCO in Clinical
Practice1
Up to 45% Infertility Patients aged 35 or
above1
Presenter
Presentation Notes
With that, you will be able to understand the prevalence of certain subgroups in your patient population and whether these subgroups match the prevalence reported in the literature. In addition, you will be able to understand how your overall population, or subsets of them, perform in a particular regimen of ovarian stimulation, and even compare these results as we did in this large observational study ... Como os valores foram obtidos: The relationship between age and POR (cycles cancelled because of absent or low ovarian response or pick-ups with ≤3 oocytes) in 3825 women entering the first cycle in the Bologna S.I.S.Me.R unit and in the Modena IVF university unit between January 2004 and December 2009. All patients underwent conventional COS protocols with different FSH/HMG starting doses depending on age. As expected, the prevalence of POR increases with female age. (ferraretti et al, 2011) Patients with PCOS are at risk of hyperstimulation. This group of patients may account for about 40% of patients that we see in clinical practice, depending on the country studied. WHO group II: normogonadotropic anovulatory women; ;
Unselected group of 865 NG down-regulated women Group A (hMG; N=299) Group B (HP-hMG; N=330) Group C (r-hFSH; N=236)
Reproductive Biology and Endocrinology 2009; 7:111.
Presenter
Presentation Notes
In which we examined the clinical efficacy of different gonadotropin products used for ovarian stimulation in our clinical practice. We compared the efficacy of rec-hFSH (n=236), hMG (n=299) and HP-hMG (n=330) in a subset of normogonadotropic down-regulated women undergoing IVF/ICSI. UI (19).
Live birth rate per cycle (%) 24.4 32.4 30.1 NS Moderate/severe OHSS(%) 2.3 1.8 1.3 NS
Esteves et al. (observational study 2009)
Esteves et al, Reprod Biol Endocrinol. 2009; 7:111 Esteves, 11
Presenter
Presentation Notes
Overall, women who received the different gonadotropins had similar after IVF/ICSI. The clinical pregnancy and live birth rate per initiated cycle was not statistically different. However, the total dose of gonadotropin (in IU) administered to stimulate the ovaries was significantly lower in those who received rec-hFSH (2268±747) than those who received hMG (2685±720) or HP-hMG (2903±867) (p< 0.001).
Tota
l Dos
e per
Live
Birt
h (IU
)*
0
3,000
7,000
10,000
21.6%
r-hFSH HP-hMG
6,324*
7,739
hMG
9,690 52.2%
* Mean total dose per cycle/Live birth rate (≤35 years)
To achieve a live birth,
21-52% more HP-hMG and hMG was required
compared with r-hFSH
Esteves et al. (observational study 2009)
Esteves, 12
Presenter
Presentation Notes
This difference in favour of r-hFSH was reflected for the amount of gonadotropin used per live birth. To achieve a live birth significantly less r-hFSH was required than hMG (52% reduction) and HP-hMG (21% reduction). One practical implication of this observation is that this marked difference neutralizes part of the cost difference between r-hFSH and hMG preparations. We observed that it was far more common to step the rec-hFSH dose down during ovarian stimulation as compared to hMG.
18.7 20.3
53.4* % Cycles with “Step-down” during ovarian stimulation
HMG HP-HMG rec-hFSH (fbm)
*P<0.01
Esteves et al. (observational study 2009)
Esteves, 13
Presenter
Presentation Notes
We discovered that in our practice, it was far more common to step the rec-hFSH dose down during ovarian stimulation as compared to hMG. The clinicians stated that they felt comfortable with the pen device that allow small dose reductions of 37.5UI , after perceiving a better response with rec-hFSH compared to u-HMG using the same starting doses. The clinicians involved in this study stated that they felt comfortable with the pen device, which allowed more precise small dose reductions of 37.5 UI rather the 75UI reductions in the HMG preparations.
Improving Success by Tailoring Ovarian Stimulation
Key
Poi
nts
Patient variability excludes the possibility of a single approach to controlled ovarian stimulation.
Overall, recombinant and urinary gonadotropins have similar clinical efficacy. However, it is important to determine how a given protocol works for you by defining your patient population and data mining your experience.
Esteves, 14
Esteves, 15
What are the best strategies to individualize COS for my patient population? Search the literature for relevant studies
that match your patient profile.
High-quality oocyte yield
Cycle cancellation, OHSS, multiple
pregnancy
Central Paradigm
Minimize complications
and risks
Maximize beneficial effects
of treatment
Fauser et al., 2008 Esteves, 16
Presenter
Presentation Notes
It is beyond discussion that ovarian stimulation with gonadotropins have a key role in ART treatments. OS has been applied to compensate for inefficiencies in the IVF procedure by increasing the number of oocytes retrieved thus enabling the selection of the best quality embryos for transfer. Because of the variability in patient characteristics and OS response, today, the central paradigm of all ovarian stimulation protocols is to maximize the beneficial effects of treatment (relating to high-quality oocyte yield) while minimizing the potential risks associated with OHSS and multiple pregnancy.
Esteves, 17
Negative Predictors
Positive Predictor
van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589.
Female Age Duration of infertility Basal FSH Type of infertility Indication Fertilization method Number of oocytes retrieved Number of embryos transferred Embryo quality
All reflecting ovarian reserve
Level 1a
Presenter
Presentation Notes
9 common predictors evaluated; 14 studies included; The summary OR for pregnancy and female age was 0.95 (95% CI:0.94–0.96) indicating that increasing female age was associated with lower pregnancy chances in IVF. Negative predictors: pregnancy and female age [OR: 0.95, 95% confidence interval (CI): 0.94–0.96], duration of subfertility (OR: 0.99, 95% CI: 0.98–1.00) and basal FSH (OR: 0.94, 95% CI: 0.88–1.00). A positive association was found for the number of oocytes (OR 1.04, 95% CI: 1.02–1.07). Better embryo quality was associated with higher pregnancy chances. All significant factors were age related and reflect ovarian reserve, which is a major determinant of success.
●Genetic Biomarkers Single Nucleotide Polymorphisms for FSH-R/LH/LH-R/E2-R/AMH-R
Markers of Ovarian Response
Esteves, 18
Verberg M et al. Hum. Reprod. Update 2009;15:5-12
Pregnancy by number of oocytes retrieved after mild (♦ ) or conventional
(�) ovarian stimulation for IVF
⑤ ⑩
Level 1a
Presenter
Presentation Notes
Age and follicle-stimulating hormone (FSH) level remain the most commonly used single patient characteristics in clinical practice. These variables only provide a basic prognosis for success and indications for standard COS treatment based on gross patient categorization. In contrast, the anti-Müllerian hormone level appears to be an accurate predictor of ovarian reserve and response to COS, and could be used successfully to guide COS. The antral follicle count is a functional biomarker that could be useful in determining the dose of FSH necessary during stimulation and the success of treatment. Meta-analysis of Verberg et al: Three randomized controlled trials comparing the efficacy of the mild ovarian stimulation regimen (involving midfollicular phase initiation of FSH and GnRH co-treatment) for IVF with a conventional long GnRH agonist co-treatment stimulation protocol could be identified by means of a systematic literature search.These studies comprised a total of 592 first treatment cycles. Individual patient data analysis showed that the mild stimulation protocol results in a significant reduction of retrieved oocytes compared with conventional ovarian stimulation (median 6 versus 9, respectively, P < 0.001). Optimal embryo implantation rates were observed with 5 oocytes retrieved following mild stimulation (31%) versus 10 oocytes following conventional stimulation (29%) (P = 0.045).
AMH = AFC >Inhibin B >FSH >Age
Esteves, 19 Broer et al. Fertil Steril 2009
Predictor of Pregnancy
In ART
Predictor of Excessive Response
Predictor of Poor
Response
Broer et al. Hum Reprod Update 2011
● AFC studies AMH Studies
● AFC studies AMH Studies
Level 1a
Presenter
Presentation Notes
pmol/l = x140/1000 = ng/mL (AMH = 140 Kda) Systematic reviews and meta-analysis of the existing literature have shown that AMH and AFC have similar power to predict both poor and excessive ovarian response to stimulation. AMH (82% and 76%, respectively) and AFC ( 82 and 80%, respectively). Comparison of the summary estimates and ROC curves for AMH and AFC showed no statistical difference (BroerSL et al, Hum Reprod Update 2011).
*Bologna criteria: Ferraretti et al. Hum Reprod 2011; Broer et al. Hum Reprod Update 2011; Nelson et al. Hum Reprod. 2009; Broer et al. Fertil Steril. 2009; Hendricks et al. Fertil Steril 2007. Esteves, 20
Response to Ovarian
Stimulation
Anti-Mullerian Hormone (ng/mL)
Antral Follicle Count
False Positive
Rate
Risk of Excessive Response (≥15 oocytes or OHSS)
≥ 3.5
> 15
~15% Risk of Poor Response (≤ 4 oocytes)*
< 1.1
< 5
pmol/L X1000/140
AMH and AFC to Determine Who is Who Prior to OS
Level 2a
Presenter
Presentation Notes
The evaluation of ovarian reserve may enable the identification of patients who will have a better or worse response to gonadotropin stimulation than would be expected for their chronological age. This help clinicians to individualize patient management by selecting an appropriate treatment protocol. Nevertheless, a patient’s true ovarian reserve can be determined only after a cycle of ovarian stimulation. In terms of CUT-OFF, there is no homogeneity among studies. Best are the 2 meta-analyses (Boer 2009 e 2010). Aflatoonian, J Assist Reprod Genet 2009:. The sensitivity and specificity for prediction of high ovarian response were 89 % and 92 % for small AFC (≥ 16) and 93% and 78% for AMH (≥ 34.5 pmol/l) - 4,83 ng/ml La Marca Hum Rep. (2007): All the cancelled cycles due to absent response were in the group of the lowest AMH quartile ((<0.4 ng/ml)) , whereas the cancelled cycles due to risk of ovarian hyperstimulation syndrome (OHSS) were in the group of the highest AMH quartile (>7 ng/ml) . Lee et al, hum repro 2008: CUT OFF: 3,36,. The basal serum AMH level predicted OHSS with a sensitivity of 90.5% and specificity of 81.3%. Nardo et al fertile Steril. (2009) : cutoff of AMH >3.5 ng/mL would have 88% sensitivity in predicting overstimulation with a specificity of 70%. For poor response a cutoff of 1.0 ng/mL would have 87% sensitivity and 67% specificity Gnoth C, Hum Reprod 2008: When the calculated optimal AMH cut-off of ≤1.26 ng/ml was used to predict responses to COS, it was found to have a 97% sensitivity for predicting poor responses (< 4 oocytes retrieved) and a 98% accuracy in predicting a normal COS response.
Esteves, 21
High Responders
Poor Responders
Presenter
Presentation Notes
These meta-analytic studies give us an overall idea but do not respond what we really want to know, that is,
31.3% 31.1% 35.3%
50.0%
20.0%
0%
10%
20%
30%
40%
50%
60%
75 IU 112.5 IU 150 IU 187.5 IU 225 IU
Clinical pregnancy rates/cycle started
Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:95–204.
Individualized dosing in increments of 37.5 IU of folitropin alfa possible by FbM technology
Age (28-32)
Oocytes retrieved (8-12)
Esteves, 22
Low Starting Doses of r-hFSH for Ovarian Stimulation in
High Responders
Level 2a
Presenter
Presentation Notes
In this context, the CONsistency in r-hFSH Starting dOses for Individualized tReatmenT (CONSORT) approach represents a step towards personalized ART. 4 factors have been identified to be predictive of ovarian response to FSH stimulation in women aged <35 years. These factors have been combined into a model that predicts the optimum starting dose of rec-hFSH for individual patients. The availability of GONAL-f® FbM means that precise and accurate dosing can be achieved, allowing the opportunity to develop valid FSH daily dosing guidelines. The four most important predictive factors measured routinely are basal FSH level, body mass index (BMI), age and antral follicle count. These form the basis of the CONSORT calculator. An equation was created using a large database that described oocyte yield in terms of these four factors and FSH starting dose. By inverting the equation, a formula was created that enables calculation of the optimum FSH starting dose by entering values for the four factors and the desired oocyte yield (10). To validate the model, a prospective, open-label, multicentre study of ART at 18 centres worldwide was conducted. All cycles were stimulated using the GONAL-f® FbM prefilled pen, which provides precise and accurate dosing, and enables FSH dosing in relatively small increments. Patients enrolled had aged <35 and oocytes retrieved ranged from 8-12 (mean 10.2). Pregnancy rate were adequate by transferring an average of 1.8 embryos 1. Howles et al. Curr Med Res Opin 2006;22:907–916 2. F Olivennes, CM Howles, A Borini, M Germond, G Trew, M Wikland, F Zegers-Hochschild, H Saunders, V Alam. Reproductive BioMedicine Online 18: 195-204, 2009. The precision and accuracy of gonadotropin FbM preparations are so good that excellent clinical results are achieved even using low daily doses, as shown in this important study. In the CONSORT study, patients were included if they fulfilled the following criteria: between 18 and 35 years of age regular, spontaneous, ovulatory menstrual cycle, 21–35 days in length early follicular phase (days 2–4) serum levels of FSH (≤ 12 IU/L) and oestradiol (E2) within centre’s normal range both ovaries present. Patients were excluded if they had any of the following: previous poor response in two ART cycles (defined as ≤ 5 mature follicles and/or ≤ 3 oocytes collected) previous over response (> 24 oocytes) BMI > 30 kg/m2. All cycles were stimulated using the GONAL-f® FbM that enables FSH dosing in relatively small increments.
Esteves, 23
GnRH Antagonist Protocol in High Responders
9 RCT; 966 PCOS women Relative Risk
Duration of ovarian stimulation -0.74 (95% CI -1.12; -0.36)
Gonadotropin dose -0.28 (95% CI -0.43; -0.13)
Oocytes retrieved 0.01 (95% CI -0.24-0.26)
Risk of OHSS Mild
Moderate and Severe
20% vs 32% 1.23 (95% CI 0.67-2.26) 0.59 (95% CI 0.45-0.76)
Clinical PR 1.01 (95% CI 0.88; 1.15)
Miscarriage rate 0.79 (95% CI 0.49; 1.28)
Pundir J et al. RBM Online 2012; 24: 6-22.
40% reduction in moderate/severe OHSS by using antagonists rather than agonists
Level 1a
GnRH-a triggering (0.2-1.5 mg): antagonist protocol; Reduced if not eliminated risk for OHSS; Challenge is to rescue luteal phase:
Vitrification and FET (Garcia-Velasco, Fertil Steril, 2012) Modified LP support (Humaidan et al., 2011)
Esteves, 24
GnRH Agonist for LH Triggering in High Responders
Level 1a
11 RCT – 1,055 women (GnRH Agonist vs hCG triggering)
LBR OPR Moderate/ severe OHSS
Fresh autologous cycles (8 RCT)
OR 0.44 (0.29 - 0.68)
OR 0.45 (0.31 - 0.65)
OR 0.10, (0.01 to 0.82)
Donor recipient cycles (3 RCT)
OR 0.90 (0.57 - 1.42)
OR 0.91 (0.59 -1.40)
OR 0.06 (0.01 - 0.31)
Youssef et al. Cochrane Database Syst Rev. 2011
Presenter
Presentation Notes
Prevention of OHSS: 1st level prevention: use instead of GnRH agonists 2nd level prevention: in patients on antagonist protocols identified to be at risk of developing severe OHSS, replacing hCG with GnRH-a as a trigger for final oocyte maturation; it should be combined to cryopreservation of all embryos 3rd level prevention: In patients with early onset of OHSS, reinitiation of GnRH-ant in the luteal phase might lead to rapid regression of the syndrome; however, only limited data on this new concept are available in the literature Comments: Youssef (Cochrane 2011): GnRH agonist to trigger x hCG in antagonista cycle 11 RCTs (n = 1055) 8 RCT fresh autologous cycles / 3 studies assessed donor-recipient cycles In fresh-autologous cycles: GnRH agonist was less effective than HCG in terms of: live birth rate per randomised woman (OR 0.44, 95% CI 0.29 to 0.68; 4 RCTs) ongoing pregnancy rate per randomised woman (OR 0.45, 95% CI 0.31 to 0.65; 8 RCTs). For a group with a 30% live birth or ongoing pregnancy rate using HCG, the rate would be between 12% and 22% using an GnRH agonist. Moderate to severe ovarian hyperstimulation syndrome (OHSS) incidence per randomised woman was significantly lower in the GnRH agonist group compared to the HCG group (OR 0.10, 95% CI 0.01 to 0.82; 5 RCTs). For a group with a 3% OHSS rate using HCG the rate would be between 0% and 2.6% using GnRH agonist. In donor recipient cycles, there was no evidence of a statistical difference in the live birth rate per randomised woman (OR 0.92, 95% CI 0.53 to 1.61; 1 RCT). Houve alguns artigos criticando, como do Humaidan, dizendo que: debatable conclusions are drawn from early studies, when the concept was still under development. Vitrification and FET in subsequent natural cycle vs coasting and Fresh ET same cycle CPR: 50% vs 29% (P<0.05) Garcia-Velasco, Fertil Steril, 2012 Modified luteal support improved delivery rate: hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined. Delivery rates: 18% risk difference favoring hCG (before) X 6% (after modified luteal support).
Best Strategies to Maintain Sustainable Pregnancy Results and Minimize Complications in
“High” Responders
Evidence
Low Starting Doses of r-hFSH, preferably filled by mass preparations
2a
GnRH Antagonists 1a
GnRH Agonist for LH Triggering* 2b
Improving Success by Tailoring Ovarian Stimulation
Key
Poi
nts
Esteves, 25
*Lower PR in fresh transfers
Reduced oocyte quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increase Miscarriage Rates
Reduced ovarian
paracrine activity
Hurwitz & Santoro 2004
LH receptor poly-
morphisms
Alviggi et al., 2006
Androgen secretory capacity reduced
• Piltonen et al., 2003
Decreased numbers of functional
LH receptors
• Vihko et al. 1996
Reduced LH
bioactivity while
imnuno-reactivity
unchanged
• Mitchell et al. 1995; Marama et al 1984
Esteves, 26
Less
Sen
sitiv
e O
varie
s On the other hand…
Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002
• 15-20% of NG women have less sensitive ovaries
• Older patients (≥35 years)
• Poor responders
• Slow/Hypo-responders
• Deeply suppressed endogenous LH (endometriosis)
Presenter
Presentation Notes
The general consensus regarding LH is that most women have sufficient levels of endogenous LH and do not require supplementation. However, certain subgroups with low levels of LH may benefit from additional LH. The subgroups which may benefit from LH supplementation include women over the age of 35 years, those with a poor response to ovarian stimulation or women with highly suppressed levels of endogenous LH. The general consensus regarding LH is that most women have sufficient levels of endogenous LH and do not require supplementation, although certain subgroups with low levels of LH may benefit from additional LH (Alviggi et al. Reprod Biomed Online 2006;12:221–233; Tarlatzis et al. Hum Reprod 2006;21:90–94; Esteves et al. Reprod Biol Endocrinol 2009;7:111; Marrs et al. Reprod Biomed Online 2004;8:175–182). The subgroups which may benefit from LH supplementation include women over the age of 35 years, those with a poor response to ovarian stimulation or women with highly suppressed levels of endogenous. It has been suggested that a subgroup of women with adequate AFC and FSH levels with hypo-response to ovarian stimulation may also benefit from LH supplementation (Alviggi, et al. RBMOnline 2009). These patients harbor single nucleotide polymorphisms of FSH and LH receptors.
Esteves, 27
14 RCT (1,127 patients) Duration of stimulation
Number Oocytes retrieved
Cycle cancellation
Clinical Pregnancy
-1.9 days (-3.6; -0.12)
-0.17 (-0.69; 0.34)
1.01 (0.71; 1.42)
1.23 (0.92, 1.66)
Pu D et al. Hum Reprod. 2011; 26: 2742.
GnRH Antagonists in Poor Responders
Limited Clinical Benefit Shortcomings:
- Definition of poor responders - Different gonadotropins regimens for OS
Level 1b
Presenter
Presentation Notes
Liu et al performed this meta-analysis involving 566 IVF patients in a GnRH-ant protocol group and 561 patients in a GnRH-a protocol group. Fourteen eligible studies were included. GnRH-ant protocols resulted in a statistically significantly lower duration of stimulation compared with GnRH-a protocols (P = 0.04; WMD: -1.88, 95% CI: -3.64, -0.12), but there was no significant difference in the number of oocytes retrieved (P = 0.51; WMD: -0.17, 95% CI -0.69, 0.34) or the number of mature oocytes retrieved (P = 0.99; WMD: -0.01, 95% CI: -1.14, 1.12). Moreover, no significant difference was found in the cycle cancellation rate (CCR, P = 0.67; OR: 1.01, 95% CI: 0.71-1.42) or clinical pregnancy rate (CPR, P = 0.16; OR: 1.23, 95% CI: 0.92, 1.66).
Intervention Meta-analytic Studies Population Effect on
Pregnancy
Growth Hormone1
Kyrou et al,20091 Kolibianakis et al, 20092 Duffy et al, 20103
Poor responders
Higher LBR1,2,3 Higher PR2
Higher CPR3
Transdermal Testosterone2 Bosdou et al , 2012 Poor
responders Higher LBR Higher CPR
Kolibianakis et al, Hum Reprod Update 2009,15:613-22; Kyrou et al, Fertil Steril̀ 2009;91: 749–66; Duffy et al, Cochrane Database Syst Rev 2010;1:CD000099; Mochtar MH et al. Cochrane Database Syst Rev.
2007,2:CD005070; Bosdou JK et al, Hum Reprod Update 2012;8:127-45
Level 1a
Esteves, 28
GH: IGF-1 and 2; oocyte quality and response to OS 4-24 UI/day; SC; different protocols Testosterone: increase in intra-ovarian androgens ~1mg/d nominal delivery rate; pre-OS (15-21d)
Presenter
Presentation Notes
GH Duffy et al (Cochrane): Ten studies (440 subfertile couples) were included. In women who are not considered poor responders undergoing in IVF there is no evidence from randomised controlled trials to support the use of growth hormone. In women who are considered poor responders the use of growth hormone has been shown to significantly improve live birth (4 RCT- OR 5.39, 95% CI 1.89 to 15.35)and pregnancy rates (8 RCT - OR 3.28, 95% CI 1.74 to 6.20). Quality of the evidence; differences in participant number, cause of subfertility, treatment protocol and outcomes measured all varied considerably between the trials. There was no uniformity of dose and timing of the intervention. A large scale trial with a standardised treatment protocol and intervention protocol is required. Kolibianakis: 6 RCT (169) –only poor responder: clinical pregnancy (rate difference: +16%, 95% CI: +4 to +28; fixed effects model) (number-needed-to-treat (NNT) = 6, 95% CI: 4-25) and live birth rates (rate difference: +17%, 95% CI: +5 to +30; fixed effects model) (NNT = 6; 95% CI: 3-20). Furthermore, GH addition was associated with a significantly higher proportion of patients reaching embryo transfer (rate difference: +22%, 95% CI: +7 to +36; fixed effects model). Kyrou: Five eligible RCTs, poor responder (n = 128). Odds ratio for live birth: 5.22, confidence interval: 95% 1.09–24.99 Many different protocols of GH use: Owen et al. (1991) : 24 IU im/day on alternate days, starting simultaneously with hMG until the day of hCG administration Zhuang et al. (1994): 12 IU im/day on alternate days Suikkari et al. (1996): 4 or 12 IU/day, starting on cycle day 3 Tesarik et al (2005): 8IU of GH from day 7 of exogenous gonadotrophin administration till the day following the ovulation-triggering injection of hCG Bergh et al. (1994): 0.1 IU/kg body weight/day sc, starting simultaneously with FSH until the day of hCG administration Dor et al. (1995) 18 IU sc on cycle day 2, 4, 6, 8 Kucuk et al. (2008): 4 mg (12 IU) sc, from day 21 of the preceding cycle and until the day of hCG administration The grounds for supplementing GH in ART are multiple. Insulin-like growth factors 1 (IGF-1) and 2 (IGF-2) are both present in follicular fluid and believed to play a crucial role in the cytoplasmic maturation. In several animal models of in vitro maturation exogenous administration of GH increased follicular IGF-1 and IGF-2 in as well as oocyte competence. Growth hormone could possibly increase the DNA repair capacity in oocytes as shown in liver cells. In support of this hypothesis, Mendoza et al. showed a positive correlation between the oocytes’ ability to evolve in morphologically normal embryos and GH levels in follicular fluid. Furthermore, several reports looking at the function of Granulosa cells in vitro indicated that IGF-1 improved the response to gonadotropin stimulation. Testosterone 1 meta-analysis, Bosdou et al (2012): In two trials involving 163 patients, pretreatment with transdermal testosterone was associated with an increase in clinical preg- nancy [risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%] and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. Only 2 trials: Massin 2006 (human reproduction): prospective, randomized, double-blind, placebo-controlled study.The design was set up to perform a paired comparison of the ovarian parameters recorded in two consecutive cycles, each woman being used as her own control. And then, comparing testosterone to placebo. 25 women with placebo ans 24 with trasndermic testosterone ( testosterone 1%), Women applied once-daily 1 g of gel (10 mg of testosterone) on the external side of the thigh. Testosterone absorption with the gel is approximately 10%. Either testosterone or placebo gels were applied for 15–20 days in the period preceding the second stimulation for IVF or ICSI, i.e. during the period of pituitary desensitization in women treated with a long GnRH agonist protocol or during pill administration in women treated with another analogue protocol. Comparing to previous cycle, the both groups there was an increase in the number of oocytes on the second. Placebo group: 3,6 to 5 (p<0,02) / testosterone: 3 to 5,31(p<0,02). Placebo x testo: p=0,8, no difference: numbers of pre-ovulatory follicles, total and mature oocytes and embryos did not significantly differ between testosterone and placebo-treated patients.. Kim, 2011 (Fertility and Sterility): poor responders, 55 with placebo and 55 with trasndermic testosterone ( testosterone 1%), with a 1.25 mg/d nominal delivery rate of testosterone was started from sixth day of E-P pretreatment and continued for 21 days. All antagonist cycle. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the TTG pretreatment group. Embryo implantation rate and clinical pregnancy rate per cycle initiated also were significantly higher in the women pretreated with TTG. Explanations to use: It has been suggested that the accumulation of androgens in the micro milieu of the primate ovary, plays a critical role in early follicular development and granulosa cell proliferation. Androgen excess has been shown to stimulate early stages of follicular growth and increase the number of preantral and antral follicles. In addition, increased intraovarian concentration of androgens seems to augment follicle stimulating hormone (FSH) re- ceptor expression in granulosa cells and thus, potentially lead to enhanced responsiveness of ovaries to FSH. Besides these experimental data, further clinical observa- tions on women with polycystic ovary syndrome or testosterone-treated female transsexuals, suggest that exposure to exogenous androgens may lead to increased number of developing follicles, regardless of gonadotrophin stimulation Furthermore, it has been reported that inadequate levels of endogenous androgens are associated with decreased ovarian sensitivity to FSH and low pregnancy rates after IVF. Bosdou et al also evaluated other interventions such as use of aromatase inhibitors, androgens, etc.
LH Supplementation in Poor Responders…
Regimen Outcome Effect on Pregnancy
Mochtar et al, 2007 3 RCT (N=310) Poor responders
r-hFSH+rLH vs. r-hFSH alone* OPR OR 1.85
(95% CI: 1.10; 3.11)
Bosdou et al, 2012 7 RCT (N= 603) Poor responders
r-hFSH+rLH vs. r-hFSH alone*
CPR
LBR (only 1 RCT)
RD: +6%, (95% CI: -0.3; +13.0)
RD: +19%
(95% CI: +1.0; +36.0%)
Hill et al, 2012 7 RCT (N=902) Women advanced age ≥35 yrs.
Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4. Esteves, 29
Level 1a
Presenter
Presentation Notes
It has been shown, in retrospective studies, that low concentrations of circulating follicular phase LH in women undergoing GnRH-agonist long-protocol cycles might be associated with impaired oestradiol synthesis and/or a low oocyte yield as well as low fertilization rates, low pregnancy rates and high miscarriage rates (Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002). The beneficial effect of LH supplementation in down-regulated poor responders undergoing COH with rFSH has been demonstrated in these meta-analyses. The potential benefit of LH administration for older patients could be explained by two different mechanisms. On the one hand, the endocrine changes occurring with ovarian aging include an increase of the serum FSH levels in the early follicular phase, which are not accompanied by an LH increase but by a progressive decrease of the basal androgen levels. Moreover, the follicular capability for inducing androstenedione synthesis after rFSH administration is significantly impaired in older patients compared with younger reproductive-aged patients, whereas E2 secretion is preserved by increased aromatase function. Action of LH at the follicular level that increases androgen production for its later aromatization to estrogens in a dose dependent manner may restore the follicular milieu in these patients to recover oocyte quality and, therefore, embryo quality and implantation rates. Follicle-stimulating hormone acts on granulosa cells to promote the conversion of cholesterol into P, which is passed to the thecal cells to be converted into androgens under the influence of LH, therefore reducing circulating P. All in all, this could explain why stimulation with rFSH alone can produce poorer outcomes in older and low-responding patients because they usually receive higher FSH doses for COS, they show higher P levels at the end of stimulation, and, subsequently, their endometrium receptivity diminishes.
De Placido et al. studied the effects of LH supplementation in women showing a poor response to ovarian stimulation. ‘Poor responders’ were defined as those who had serum oestradiol levels below 180 pg/ml and no follicles over 10 mm on day 8. These women were randomized to a daily dose of either 75 IU or 150 IU r-hLH. Women classified as ‘good responders’ received no additional r-hLH (control group). They found that the high dose of r-hLH was significantly more effective in terms of oocyte development and maturation than the increasing FSH drive. Furthermore, there was no significant difference between the high-dose group and controls in terms of these outcomes.
Esteves, 31
What is the optimal LH supplementation protocol?
Existing studies give us some clues but the optimal LH protocol has yet to be established How much LH should be used? Should the dose be fixed or flexible? At what stage of the cycle should LH be
administered?
FSH
LH
2:1? 1:1? Fixed? Mimic of natural LH levels?
Presenter
Presentation Notes
Even if we are able to identify those women who may require LH supplementation, there is currently no consensus on the most suitable LH protocol. Indeed, the protocol used may even depend on the subgroup being treated. Some of the treatment parameters that still need to be established are below. How much LH should be used? Should the dose be fixed or flexible? At what stage of the cycle should LH be administered?
Esteves, 32
r-hFSH + r-hLH (2:1 fixed ratio) vs. urinary hCG-based LH
Buhler KF, Fisher R. Gynecol Endocrinol 2011; 1-6.
Matched case-control study; N=4,719 pts.; long GnRH-a protocol
31 26 25
0
5
10
15
20
25
30
35
2:1 r-hFSH+r-hLH
HMG rec-hFSH +HMG
Duration ofStimulation (days)
Mean No. oocytesretrieved
IR (%)
CPR per transfer(%)
P=0.02
Level 2a
Presenter
Presentation Notes
New fixed combination of rec-hFSH and rec-hLH filled by Mass at a 2:1 ratio; Pergoveris™: rec-hFSH (150 UI) + rec-hLH (75 UI); Bosch et al. Expert Opin Biol Ther 2010; 10: 1001-9.
LH activity derives from hCG in HMG; hCG is concentrated or added during purification;
ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20; Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod 2004; 70:861-866;
Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Esteves, 33
Lower gene expression (LH/hCG receptor, etc.) in granulosa cells of pts. treated with HMG: May reflect down-regulation of LH receptors by constant ligand exposure during the follicular phase due to longer half life and higher binding affinity of hCG to LHr.
Preparations used are important for granulosa cell function and may influence the developmental competence of the oocyte and the function of corpus luteum.
Presenter
Presentation Notes
Human chorionic gonadotropin (hCG) is similar in structural attributes compared with follitropin. A notable exception is the presence of a long carboxy terminal segment that is O-glycosylated (O-linked CHO). This segment is not visible in the hCG crystal structure (PDB files 1XUN and 1HCN), but it is shown here for illustrative purposes. Of importance is that this extension confers a long half-life to hCG; when grafted onto the hFSH beta subunit, this extension likewise confers a longer circulatory half-life to hFSH. The C-terminal extended hFSH is currently in clinical trials. Although the alpha subunits of LH and hCG are identical to that of FSH, the beta subunits are different. Luteinizing hormone has a beta subunit containing 121 amino acids that confers its specific biologic action and is responsible for its interaction with the LH receptor. This beta subunit of LH contains the same amino acids in sequence as the beta subunit of hCG, but the hCG beta subunit contains an additional 23 amino acids. The two hormones differ in the composition of their carbohydrate moieties which, in turn, affects bioactivity and half-life. The half-life of LH is 20 minutes, and that for hCG is 24 hours.
Best Strategies to Maximize Pregnancy Results
and Minimize Complications in “Poor” Responders
Evidence
Adjuvant Therapy 1a
LH supplementation Poor responders
Advanced age (≥35) Slow/Hypo responders
1a 1a 1b
Improving Success by Tailoring Ovarian Stimulation
Key
Poi
nts
Esteves, 34
A Final Word on LH Supplementation: OI/IUI
LH levels 1.2 UI/L (WHO group I) Higher follicular development pts. receiving LH (67% vs 20%; p=0.02): Shoham et al., 2008.
Similar follicular development HMG vs FSH+rLH; higher cumulative PR after 3 cycles in FSH+LH (56% vs 23%; p=0.01): Carone et al., 2012.
Level 1b
Esteves, 35
WHO group II Clomiphene-resistant: fewer intermediate-sized follicles and OHSS in
LH-supl. vs FSH group; similar ovulation rate (Plateau, 2006); Previous over-response: higher monofollicular development in LH group
(32% vs 13%; p=0.04): Hughes et al., 2005; IUI: higher monofollicular development in LH group without
intermediate-size (42% vs 11%; p=0.03); lower cycle cancellation due to risk OHSS (-7% difference): Segnella et al., 2011.
Presenter
Presentation Notes
Hypogonadotrophic hypogonadism Management options include exogenous replacement of gonadotropins and pulsatile GnRH agonist administration. In women with intact pituitary function, pulsatile gonadotropin releasing hormone (GnRH) therapy can be used. Exogenous gonadotropins administration is the alternative therapeutic option in hypothalamic dysfunction and the first line treatment if the defect is primary pituitary failure. Currently available evidence indicates that rFSH alone may not be sufficient to promote optimum follicular growth in severely gonadotropin deficient women. It has been suggested that a minimum threshold of serum LH is required to re-establish meiosis and final stages of growth of antral follicles. The European Recombinant Human LH Study Group, 1998: A dose finding trial included 38 WHO type I anovulatory patients, who were randomly assigned to receive either 0, 25, 75, or 225 IU rLH once daily in addition to 150 IU follitropin alpha once daily. None of the 8 patients who received follitropin alpha alone ovulated in the absence of rLH. Fourteen percent of patients who received follitropin alpha and 25 IU/L rLH ovulated compared to 66% and 80% of those who received 75 IU/L and 225 IU/L, respectively. Significant dose dependent increases in the rate of optimal follicular growth were observed in women receiving follitropin alpha with different doses of rLH varying from 0 to 225 IU/day. Shoham et al, 2008: Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries. Thirty-nine patients with LH < 1.2 IU/l and FSH < 5.0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa. With LHr: 66.7% achieved follicular development compared with 20.0% of patients receiving placebo (P = 0.023). Burgues et al, 2001: A case series from Spain included 38 hypogonadotrophic anovulatory (WHO group I) women undergoing 84 ovulation induction cycles where patients received 150 IU/day rFSH and 75 IU/day rLH. Sufficient follicular growth was observed in 79 (94%) out of 84 initiated cycles. The cumulative pregnancy rate following three cycles of stimulation with follitropin alpha and lutropin alpha was 39.5%. Kaufman et al, 2007: An open-label, noncomparative study with 31 hypogonadotrophic hypogonadal women. They receive Lutropin alfa 75 IU and follitropin alfa (75-225 IU). In a total of 54 cycles, 27 of 31 (87.1%) achieved follicular development within three cycles. Twenty of 27 patients (74.1%) who achieved follicular development and received hCG became pregnant; 16 (59.3%) continued to clinical pregnancy. Carone et al, 2012: Two-arm randomized open-label study, 35 women with hypogonadotropic hypogonadism, comparing: r-hFSH + r-hLH (2:1) X hMG-HP in women with. Following a total of 70 cycles, 70% of r-hFSH/r-hLH treated patients ovulated vs. 88% in hMG-HP group (p=0.11). However, PR in r-hFSH/rhLH group was 55.6% compared to 23.3% in hMG-HP group (p=0.01). OI in WHO group II anovulation The large majority of women with PCOS would have excess elevated LH concentrations when measured at the appropriate time. This may justify the potential advantages in preparations devoid of LH activity as follitropin alpha. Currently, there is no role of lutropin alpha in the management of women with PCOS. (conclusao de uma revisao de gibreel et al, 2009). Mas ha 2 estudos com inducao de ovulacao neste tipo de pacientes: Plateau et al, 2006: A randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized to stimulation with HP-HMG (n=91) or rFSH (n=93) using a low-dose step-up protocol. The ovulation rate was 85.7% with HP-HMG and 85.5% with rFSH (per-protocol population), and non-inferiority was demonstrated. Significantly fewer intermediate-sized follicles were observed in the HP-HMG group (P<0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with HP-HMG and 9.8% with rFSH (P=0.058). Hugues et al, 2005: 153 wHO group ii anovulation women that during ovulation induction had over-response (at least 3 follicles 11-15mm and no one >15) were randomized to receive, in addition to 37.5IU recombinant human FSH (rFSH), either placebo or different doses of rLH (6.8, 13.6, 30 or 60mg) daily for a maximum of 7 days. The proportion of patients with exactly one follicle ≥ 16mm ranged from 13.3% in the placebo group to 32.1% in the 30 mg rLH group (P =0.048). The pregnancy rate ranged from 10.3% in the 60 mg group to 28.6% in the 30 mg rLH group. Adverse events were similar between groups. CONCLUSIONS: In patients over-respond- ing to FSH during ovulation induction, doses of up to 30 mg rLH/day appear to increase the proportion of patients developing a single dominant follicle (≥ 16mm). Our data support the ‘LH ceiling’ concept whereby addition of rLH is able to control development of the follicular cohort. IIU 1 RCT comparing HP-hmg com FSHr Segnella et al, 2011: 523 patients with unexplained infertility or mild male infertility undergoing controlled ovarian hyperstimulation for IUI. Patients were randomized for treatment with rFSH (262 patients) or HP-hMG (261 patients). Insemination was performed 34-36 hours after hCG injection. The primary outcome was clinical pregnancy rate (PR). The secondary outcome was the number of interrupted cycles for high risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. -Regarding follicular development, there was a significantly lower average number of intermediate-size follicles (14–16 mm) at the end of stimulation in the HP-hMG group (0.73 ± 1.00 in HP-hMG and 1.96 ± 1.54 in rFSH; P=0.001); - furthermore, the number of follicles ≥17 mm was significantly higher in rFSH cycles (1.27 ± 0.45 in HP-hMG and 1.69 ± 0.84 in rFSH; P1⁄=0.03; -Development of one dominant follicle (≥17 mm) without intermediate-size follicles was achieved for 42.3% in the HP-hMG cycles versus 11.5% in the rFSH cycles (P1⁄=0.03). -On the hCG day, E2 levels were significantly higher in the rFSH group compared with HP-hMG (833.19 ± 385.80 pg/mL and 551.75 ± 240.06 pg/mL, respectively; P1⁄=0.004). -No significant difference in endometrial thickness were observed. -Higher P levels were observed in the rFSH cycles (37.77 ± 26.22 ng/mL in rFSH and 23.52 ± 13.39 ng/mL in HP-hMG; P=0.02) The clinical PR was 19.7% (95% confidence interval [CI] 15.3%-25.1%) in the HP-hMG group and 21.4% (95% CI 16.9%-26.8%) in the rFSH group [absolute difference -1.7% (95% CI -8.6% to 5.2%)]; The number of interrupted cycles for OHSS risk and multiple pregnancy was significantly higher in the rFSH group, 8.4% (95% CI 5.6%-12.4%) than in the HP-hMG group 1.2% (95% CI 0.4%-3.3%) [absolute difference -7.27% (95% CI -11.3 to -3.7)]. CONCLUSION(S): HP-hMG is not inferior compared with rFSH regarding clinical PR. Comments: Bi/multifollicular development was significantly higher in the rFSH cycles, contributing to the significantly higher estradiol concentration compared with HP-hMG cycles. In contrast, the develop- ment of a single dominant follicle without intermediate-size follicles was significantly higher in the HP-hMG cycles. The lower number of follicles obtained in HP-hMG cycles could reflect an LH effect during the follicular phase; the gonadotropin might induce follicular atresia. In the present study, despite significant differences between the two treatment groups regarding number of dominant follicles and hormonal environment, the endometrial thickness and the clinical pregnancy rate were similar between the two groups. We could hypothesize that exogenous LH/hCG activity might positively influence oocyte quality and development. This observation could explain the benefit regarding PR for those normo-ovulatory women with unexplained infertility who achieved pregnancy even though they developed a monofollicular response. Interesting data in the present study concern the different mean age of pregnant patients. Mean age of pregnant patients was higher in the HP-hMG group compared with the rFSH group. This observation led us to hypothesize that, in older women, the addition of LH/hCG activity could positively affect oocyte quality and steroidogenesis. This hy-pothesis is supported by data demonstrating that in poor responders, superimposing rLH on rFSH improves outcome data. Finally, because one of the main challenges for clinicians in- volved in ovulation induction is controlled ovarian hyperstimulation cycle cancellation, another end point of our work was to evaluate the frequency of interrupted cycles for high risk of OHSS and multiple pregnancy. We observed that the number of interrupted cycles was higher in the rFSH group; therefore, HP-hMG treatment might besafer in women who tend to a multifollicular response. References: The European Recombinant Human LH Study Group. Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J Clin Endocrinol Metab. 1998 May;83(5):1507-14. ShohamZ,SmithH,YekoT,O’BrienF,HemseyG,O’DeaL.Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study. Clin Endocrinol (Oxf). 2008;69(3):471–478. Burgues S. Spanish Collaborative Group on Female Hypogonadotrophic Hypogonadism. The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain. Hum Reprod. 2001;16(12):2525–2532. Kaufmann R, Dunn R, Vaughn T, et al. Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women. Clin Endocrinol (Oxf). 2007;67(4):563–569. Carone D, Caropreso C, Vitti A, Chiappetta R. Efficacy of different gonadotropin combinations to support ovulation induction in WHO type I anovulation infertility: clinical evidences of human recombinant FSH/human recombinant LH in a 2:1 ratio and highly purified human menopausal gonadotrophin stimulation protocols. J Endocrinol Invest. 2012 Oct 22. Platteau P, Andersen AN, Balen A, et al. Ovulation Induction (MOI) Study Group. Similar ovulation rates, but different follicular develop- ment with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study. Hum Reprod. 2006;21(7):1798–1804. Recombinant LH Study Group. Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study. Hum Reprod. 2005;20(3):629–635. Sagnella F, Moro F, Lanzone A, Tropea A, Martinez D, Capalbo A, Gangale MF, Spadoni V, Morciano A, Apa R. A prospective randomized noninferiority study comparing recombinant FSH and highly purified menotropin in intrauterine insemination cycles in couples with unexplained infertility and/or mild-moderate male factor. Fertil Steril. 2011 Feb;95(2):689-94. Epub 2010 Sep 25.
