Dr. Ernesto Bosch Instituto Valenciano de Infertilidad Valencia, Spain Declared no potential conflict of interest
Is there a role for LH in elderly patients? Dr. Ernesto Bosch Instituto Valenciano de Infertilidad. Valencia, Spain www.ivi.es
Which is NOT the objetive? +
Which is NOT the objetive?
Objectives 1. To review the endocrinological features of the aging ovary 2. To understand the action of LH at the follicular level when given for COS and the potencial effect in older women 3. To analyse the current evidence-based knowledge on the use of LH in this population
Age of motherhood in EU
Age for IVF (IVI Valencia 2015)
Age for IVF (IVI Valencia 2015) 33% 24% 43% <35 35-39 >=40
Late Reproductive stage Hale et al,, et al. J Steroid Biochem Mol Biol 2014;142:121-31.
Ovarian aging Hale et al,, et al. J Steroid Biochem Mol Biol 2014;142:121-31.
LH (IU/L) FSH (IU/L) Ovarian aging Klein et al JCEM 1996;81:1038 45
24-Hour Mean Plasma Total Testosterone (ng/dl) Ovarian aging 75 50 Total Testosterone Levels in Women Decrease with Age n = 33 r = 0.54; P<0.003 25 0 0 20 25 30 35 40 45 50 Age (Years) Zumoff, et al. JCEM 1995;80:1429 30
Quienes son las Ovarian pacientes aging con respuesta subóptima? n = 1423 Total testosterone 55% DHEAS 77% Free testosterone 49% Androstenedione 64% Davison et al (2005) JCEM 90:3847 53
Ovarian aging Estradiol Androstenodione Hours after r-fsh Hours after r-fsh Old Young Welt et al (2006) Hum Reprod;21:2189 93
Objectives 1. To review the endocrinological features of the aging ovary Subtle changes in menstrual cycle Decrease of primordial, non growing and antral follicle count Variable-increasing levels of FSH in the early follicular phase Normal LH levels Decreasing AMH and Inhibin-B levels. Decrease of basal androgen levels (Te, A, DHEAS) with normal SHBG Decreased A synthesis in response to rfsh stimulation Preserved E2 synthesis in response to rfsh stimulation
LH during folliculogenesis in the natural cycle SEarly follicular phase Induction of androgens production in the theca cells Increase in follicular recruitment Paracrine activity From intermediate follicular phase Expression of LH receptors in the granulosa Jeppesen et al., JCEM, 2012 Sustain of FSH-dependent granulosa activities, including aromatase induction and growth factors release (IGF-1, EGF etc ) Optimization of steroidogenesis
Impact of LH administration in COS for IVF 30 oocyte donors (< 35 yrs, normogonadotrophic) Long protocol: GnRH agonist + intranasal nafarelin 300 225 150 rec FSH rec LH 75 0 FSH 300 FSH/LH 225/75 FSH/LH 150/150 Bosch, et al. Fertil Steril 2006;86:Suppl.2: S425
Impact of LH administration in COS for IVF Serum hormone determinations on day of hcg FSH 300 IU FSH/LH 225/75 IU FSH/LH 150/150 IU E2 (pg/ml) 2662 ±1239 2208 ±852 2700 ±1339 NS P4 (ng/ml) 1.1 ±0.7 0.6 ±0.3 0.6 ±0.5 NS FSH (miu/ml) 13.4 ±4.5 a 8.6 ±4.1 b 7.5 ±1.3 b p 0.009 (a > b) LH (miu/ml) 2.0 ±1.9 1.6 ±1.5 2.2 ±1.8 NS Te (ng/ml) 0.6 ±0.2 0.5 ±0.2 0.8 ±0.3 NS Δ4 (ng/ml) 2.7 ±0.7 2.4 ±0.4 2.9 ±1.1 NS DHEAS (µg/dl) 206 ±57 190 ±142 192 ±78 NS
Impact of LH administration in COS for IVF Follicular fluid hormone determinations LH E2 P4 Te Δ4 DHEAS
Impact of LH administration in COS for IVF Relationship between follicular esteroids levels and oocyte maturation Metaphase II Metaphase I GV p E2 (pg/ml) 165± 60 a 91 ± 79 b 175 ± 19 a 0.04 (a>b) P4 (ng/ml) 17.5 ± 6.3 15.0 ± 13.0 23.7 ± 15.1 NS LH (miu/ml) 1.4 ± 0.7 1.1 ± 0.8 1.3 ± 0.7 NS Te (ng/ml) 7.8 ± 6.2 b 21.6 ± 30.7 a 12.4 ± 0.6 0.007 (a>b) A (ng/ml) 94.1 ± 54.1 b 302 ± 281 a 161 ± 5.7 < 0.001 (a>b) DHEAS (µg/dl) 219 ± 94 270 ± 212 228 ± 10.6 NS
Impact of LH activity administration in COS for IVF Serum hormonal profile during stimulation Smitz et al (2007) Hum Reprod 22: 676-687
Impact of LH activity administration in COS for IVF Follicular fluid hormonal levels Smitz et al (2007) Hum Reprod 22: 676-687
Impact of LH activity administration in COS for IVF Ongoing pregnancy rate per started cycle transfer according to androgen levels FSH FSH+LH RR (95% CI) p Te 0.45 ng/ml 33.1 (25.4-41.7) 44.4 (36.1-53.2) 1.34 (0.98-1.85) 0.06 Te >0.45 ng/ml 50.0 (37.5-62.5) 40.0 (28.6-52.6) 0.80 (0.53-1.20) 0.28 DHEAS 156 mcg/l 32.4 (24.3-41.7) 38.2 (29.6-47.5) 1.18 (0.82-1.69) 0.37 DHEAS >156 mcg/l 47.3 (36.3-58.5) 43.4% (32.9-54.6) 0.92 (0.65-1.30) 0.63 Δ 4 1.90 ng/ml 39.1 (30.5-48.4) 46.0 (37.1-55.2) 1.18 (0.87-1.60) 0.30 Δ 4 >1.90 ng/ml 40.3 (29.7-51.8) 47.9 (36.9-59.2) 1.19 (0.82-1.72) 0.35 Bosch et al (2011), ESHRE.
Objectives 2. To understand the action of LH at the follicular level when given for COS and the potencial effect in older women LH administration is related to higher E2, Te and A serum levels at the end of stimulation, and lower P LH administration is positively related in a dose dependent manner to follicular E2, Te and A levels LH administration may be beneficial for patients with low basal androgen levels
LH administration in the elderly patient Hill et al (2012) Fertil Steril 97: 1108-1114
LH administration in the elderly patient Study Age Protocol LH administration Marrs 2004 >=35 GnRH agonist long 150 UI from day 6 Humaidan 2004 >=35 GnRH agonist long Ratio 2:1 from day 8 Fábregues 2006 >=35 GnRH agonist long 150 UI from day 6 NyboeAndersen 2008 >=35 GnRH agonist long 75 UI from day 6 Barrenechea 2008 >=40 or POR Flare up 150 UI from day 7 Matorras 2009 35-39 GnRH agonist long 150 UI from day 6 Bosch 2011 36-39 Antagonist 75 UI from day 1
Previous cycle: OC (0.030 mg of etinyl-estradiol + 3.0 mg of drospirenone) FSH alone GnRH antag 0.25 3x18mm rfsh: 300 IU rlh: Ø 1 2 3 4 5 6 7..8.. FSH + LH GnRH antag 0.25 3x18mm rfsh: 225 IU rlh: 75 IU 1 2 3 4 5 6 7 8 rfsh; 75 UI rlh; 75 UI Cetrorelix; 0.25 mg rcg; 6500 UI
35 E2 on day of hcg (pg/ml) P on day of hcg (ng/ml) FSH (n=172) FSH + LH (n=161) 1542 ±818 1625 ±905 0.436 0.85 ±0.40 0.69 ±0.41 0.002 Nº of oocytes 11.3 ±6.2 10.9 ±6.2 0.180 Nº of Metaphase II (ICSI) 7.8 ±4.7 7.3 ±3.8 0.255 Fertilization rate 67.4 ±23.4 67.4 ±25.5 0.998 Nº of transferred embryos 1.9 ±0.8 1.9 ±0.7 0.488 OHSS 5.3 (2.6-9.6) 7.0 (3.8-11.8) 0.493 P 36-39 E2 on day of hcg (pg/ml) P on day of hcg (ng/ml) FSH (n=142) FSH + LH (n=150) 1388 ±721 1560 ±806 0.064 0.89 ±0.44 0.67 ±0.38 < 0.01 Nº of oocytes 10.1 ±6.3 8.4 ±4.5 0.008 Nº of Metaphase II (ICSI) Fertilization rate Nº transferred embryos OHSS 5.0 (2.1-9.6) 7.0 ±4.3 6.6 ±3.1 0.303 61.2 ±27.3 68.0 ±25.0 0.027 1.7 ±0.7 1.9 ±0.8 0.109 3.0 (1.0-6.8) P 0.360 Bosch et al (2011) Fertil Steril 95; 1031-6 ; ASRM 2008 General Program Price Paper Award
Implantation rate Ongoing Pregnancy rate per Randomized patient (ITT analysis) p=0.84 OR: 1.03 (0.73-1.47) p=0.03 OR: 1.56 (1.04-2.33) OR: 1.0 (0.65-1.57); p=1.0 OR: 1.49 (0.93-2.38); p=0.09 40 40 30 30 20 20 10 10 0 27.8 28.6 18.9 26.7 0 37.3 37.3 25.3 33.5 <=35 36-39 <=35 36-39 FSH alone FSH + LH Bosch et al (2011) Fertil Steril 95; 1031-6; ASRM 2008 General Program Price Paper Award
Bosch et al (2011) Fertil Steril 95; 1031-6; ASRM 2008 General Program Price Paper Award
Different findings when LH is started on day 6 Konnig et al. Hum Reprod 2013;
Different findings when LH is started on day 6 (n=120) (n=120) Vuong et al. Hum Reprod 2015;
Different findings when LH is started on day 6
Objectives 3. To analyse the current evidence-based knowledge on the use of LH in this population Conflicting results across the RCT published so far Different design among the studies In antagonist cycles: Beneficial effect when LH given from day 1 of stimulation while no impact when given from day 6. Possible role of OCP pretreatment
Take-home messages Women in their late reproductive stage are the most frequent group of patients undergoing IVF The aging ovary shows a different endocrine basal situation, but also a different response to rfsh, suggesting a thecal insufficiency LH administration enhances follicular steroid-genesis, increasing the synthesis of androgens for their later aromatization to estrogens This function seems to be beneficial for women > 35 undergoing COS for IVF. To achieve this improvement, LH should be administered form the first day of stimulation