More than 100 years knowledge on hypothalamic involvement in reproduction a tribute to bernhard aschner Bernhard Aschner 1883-1960 W.Feichtinger Aschner, 1912 postulated that ovarian function was influenced by higher centers. world s first publication Section or disease of the pituitary stalk led to hypopituitarism and gonadal distrophy He also hypothesized that pituitary extracts may affect genital organs and postulated that they may have practical applications. On relationships between the pituitary gland and the genitals (male and female) 1912 observations on pituitary glands observations on hypophysectomised animals Before and after castration Male and female dogs 1
male dogs Male dogs A normal dog s sexual organs A hypophysectomised dog s sexual organs female dogs female dogs Ovaries of a normal female versus ovaries of a hypophysectomised female Ovaries and uterus of a hypophysectomised female female dogs his later research Ovaries and uterus of a normal female Aschner published more than 170 scientific articles including 14 books that were translated into all civilised languages and published all over the world Bernhard Aschner. In: Judith Bauer-Merinsky: Die Auswirkungen der Annexion Österreichs durch das Deutsche Reich auf die medizinische Fakultät der Universität Wien im Jahre 1938: Biographien entlassener Professoren und Dozenten. Wien: Diss., 1980, S. 9-11. http://ub.meduniwien.ac.at/edocmed/?f_ac=ac06621696&f_file=1 2
1947 http://gedenkbuch.univie.ac.at Translation of Paracelsus to modern German Language 1926 60 years Gonadotropinswhat did we learn? B, LUNENFELD, MD, PhD 16 1780 Pallanzani Management of the infertile couple Till 1949 we only had autologous or donor insemination for male fertility problems and Surgical procedures to manage infertility due to blocked tubes were introduced by Smith in 1849 In 1949 Stein and Lewental introduced wedge resection for PCO. These techniques helped about 2 % of childless couples to have their genetic child. 1884 Pancoast William Tyler Smith In 1954 Frank Stabler * wrote : I think I can say that I know of no hormone available to me that will make a woman ovulate naturally, In 2012, 60 years later J Mouzon calculated that the use of Gonadotropins in Ovulation induction, IUI, IVF and ART has helped couples to deliver more the 12 Million Children**(5 ART & 7 OI+IUI) Ninety percent of infertile couples may today have their genetic offspring if we educate them to seek treatment before the age of 40 and make optimal use of methods' available. What we learned in the last 60 years. 17 *A Criticism of the Present-day Management of the Barren Woman, Ulster Med J, 1954 May; 23(1): 14, 15-20, 21-22 **J Mouzon 2012 18 3
Injection of a kaolin extract of urine from menopausal women to hyphysectomised infantile mice Beginnings of Commercial hmg (Pergonal) 21-22 day old Sacrifice day 4 rats injected sc 3 days and collect ovaries Ovaries and uteri or and uteri or VP VP are weighed and data processed M.Sindona Pietro Bertarelli P Donini 1958 Rome Pacelli 1952-1969 1906 Cesaro Serono founded Istituto Farmalogico Serono S,p,A F Bertarelli Borth R, Lunenfeld B, de Watteville H, Activité gonadotrope d un extrait d urines de femmes en menopause, Experientia 1954; 10 : 266 70 19 5 B, Lunenfeld 20 Steps In Production Process Lunenfeld, B., Menzi, A. and Volet, B. 1960 1 st International Congress of Endocrinology Copenhagen, p. 587. donors Collection Pooling Transportation Mixing 21 22 Lunenfeld B, et al. Soc Fr Gynecol. 1962;5:346 351 Agents stimulating ovarian function 1980 The availability of hmg, urinary FSH, clomiphene citrate, ergot derivatives such as bromocriptine and gonadotropin releasing hormone (GnRH) analogues contributed to the conquest of hormone dependent infertility in both men and women, For mechanical causes of childlessness only surgical and microsurgical procedures were available. But 1978 -R,Edwards & P,Steptoe reported the birth of the 1st test tube baby, a fulfillment of a dream by Leopold Schenk in 1887 23 24 4
The Fathers of in vitro Fertilisation In 1880 Leopold Schenk noted that cell division occurred in cultures after sperm were added to ova 1934-G Pincus Attempted IVF in Rabbits 1944- Menkin & John Rock IVF of human egg 1959 M,C, Chang Rabbit (IVF + birth) 1973 -LB Shettles ( 1973- Lancet De Kretzer et al attempts IVF) 1981 Howard W, and 1978 -R,Edwards & P,Steptoe 1st test (Alex Lopata, Ian Johston Georgeanna Jones introduced tube baby natural cycle First IVF pregancy ended in abortion IVF using hmg 26 Intracytoplasmatic Sperm injection (ICSI) In the Conquest of male infertility Palermo, Joris, Devroey, Van Steirtghem; Lancet, 1992 Jul 4; 340 (8810):17-8 28 Un-ovulatory women Serum Gonadotropins & Serum Estradiol levels Classification Ovulatory women with infertility Success in ART improved since 1981 1980 1990 5 10 % LBR 1990 2000 FSH & LH & Estradiol FSH ~ & Estradiol ~ FSH & LH & Estradiol 2000 2009 10 24 % LBR WHO I & WHO II with LH deficiency WHO II Hyper PCOS Prol,* WHO III Tubal factor Male factor 2010 24 40 % LBR Ovulation Induction FSH + LH Ovulation Induction CC FSH Egg Donation IVF FSH** ICSI FSH** * ergoline derivatives eg, Bromocryptine ** Add LH in cases of induced LH deficiency 29 World IVF Database - SART database 2003-2009and CDC 2011 30 5
Live-birth (%) 24.02.2015 All IVF cycles performed in the UK from April 1991 to June 2008 Rate of live-birth delivery per initiated cycle 40% 30% 30,2% 30,0% 28,5% Fresh cycle (IVF + ICSI) Frozen cycle 25,3% 20% 18,1% 16,7% 18,0% 16,5% 19,8% 19,6% 10% 9,9% 6,6% 0% UK Germany Australia/ N. Zealand * Canada USA * Japan * Sunkara et al Hum Reprod. 2011 Jul;26(7):1768-74. 31 Sources: Europe, UK, Germany: 2007 results from ESHRE (De Mouzon et al 2012) Canada:2009 results from Canadian ART register (2011) USA: 2009 results from US CDC report (2011) Japan:2008 results from Japan Society of Obstetrics &Gynecology Australia / New 32 Zealand:2009 results from Australian Institute of Health and Welfare report (2011) * : GIFT and ZIFT included in the calculation LBR rates in JP, UK, Australia USA Cumulative term live-birth rate after starting IVF treatment Heijnen et al Lancet 2007 Age JAPAN LBR/ITT UK LBR/ITT Australia/NZ LBR/ITT USA LBR/ITT Conventional ttm protocols <35 15% 33.1% 37.8% 41% 35-39 10% 23.25% 18.0% 27% Mild ttm protocols 40-44 4% 8.5% 6.8% 12,6% J, De Mouzon European registry by ESHRE 2008 - SART 2010 JISART 2008 Assisted reproductive technology in Australia and New Zealand 2009 33 34 Conventional IVF Mild IVF Modified natural Cycle (IVF) Natural cycle Protocols for women < 35 (10-20 pmol AMH AFC 5-15) 9-15 00cytes LBR= 20-41% 2-7 Oocytes LBR = 15-25% 1 oocyte LBR= 5-10% 1 oocyte LBR =3-6% GnRH agonist/ antagonist FSH/hMG 150-300 IU FSH/LH 150-300 IU CC/FSH/hMG low dose hcg only +GnRH antagonist with FSH/hMG or FSH/LH add back What s the optimal number of oocytes to harvest in a stimulation cycle? The German experience 1997-2010 > 230,000 cycles between 1997 and 2010 Only treatment cycles with a minimum of 5 oocytes collected at pick up were analysed No poor responders Clinical Pregnancy rate/et optimised 9-15 oocytes 35 (DIR Report for 2010) 6
Sources: Europe, UK, Germany: 2007 results from ESHRE (De Mouzon et al 2012) Canada:2009 results from Canadian ART register (2011) USA: 2009 results from US CDC report (2011) Japan:2008 results from Japan Society of Obstetrics &Gynecology Australia / New Zealand:2009 results from Australian Institute of Health and Welfare report (2011) 24.02.2015 Number of ET transferred and resulting multiple deliveries Rate of OHSS per ART cycle initiated 70 100 60 90 80 50 40 30 EU Australia USA 70 60 50 40 EU Australia USA 1.1% 1.4% 0.3% 20 30 20 Not available Not available 10 10 0 1 2 3 4 0 Singletons multiples triplets+> Embryo transf, EU Australia USA EU Australia USA OHSS Rate 1 22,5% 65% 12% 2 52,8% 33,7% 50% 3 22,5% 0,9% 25% 4 2,2% 0 14% Singletons 78.9% 91.6% 69.5% multiples 20.1% 8.4% 30.5% triplets+> 0.8% 0.2% 1.6% During the 13 years (1997 2009) in Europe multiple European delivery registry by rates ESHRE 2008- declined CDC 2010 Assisted by reproductive 32% technology and triplets in Australia and by New Zealand 78% 2009 37 <50,000 cycles 50,000 < cycles < 100,000 100,000 < cycles < 150,000 >150,000 cycles 0.6% 38 0.6% Reduction of Hyperstimulation Syndrome hcg has been used as a surrogate for the mid-cycle surge of LH for several decades however its luteotropic effect, facilitates ovarian hyperstimulation syndrome, Recently GnRH antagonist protocols to prevent a premature LH surge allowed final oocyte maturation and ovulation to be triggered with a single bolus of a GnRH agonist. This method helped to significantly reduce OHSS Prospective randomized studies, however, reported a poor clinical outcome in IVF/ICSI patients. This appeared to be caused by a luteal phase deficiency, despite standard luteal phase supplementation with progesterone and estradiol Reduction of Hyperstimulation Syndrome Stimulation with a daily dose of 150 300 IU FSH on day 2 or 3 of the cycle with recombinant FSH or hmg Co-treatment with a GnRH antagonist (0.25 mg, ) initiated at a follicle size of 13mm. As soon as 3 follicles had reached a size of 17 mm, a bolus of GnRHa (Triptorelin 0.2 mg) is administered. Oocyte pick-up (OPU) is performed 35 h later. Embryos are transferred on Day 2 or 3 post-opu. The luteal phase is supported with a bolus of 1500 IU hcg following 1-3 after OPU depending on P levels An additional bolus of 1500 IU hcg on day OPU+ 4 or 5. Combining GnRHa triggering with cryopreservation of all oocytes or embryos lead total avoidance of OHSS providing a good chance of pregnancy for the patient in later frozen-thawed embryo transfers 39 Kol et al. Hum Reprod. 2011;26:2874-7.) 40 What did we learn 90 % of Infertile couples can have their genetic child. LBR /aspiration increased significantly, due to better methods and culture media LBR / initiated cycles increased significantly, However large variation worldwide due to age distribution and protocols used and embryos transferred still exist 41 What did we learn? Multiple deliveries decreased significantly. Hyperstimulation rates decreased significantly. We now have safe products with batch to batch consistency We now have tools such as US (AFC )and AMH to predict dose and treatment protocols. 42 7
What did we learn? The availability of cryopreservation of sperm, embryos, ovarian tissue and oocytes permitted fertility preservation in male or female cancer patients or in women who desire to postpone child bearing for socio economic or other reasons What did we learn? The development of in-vitro maturation (IVM): is helping patients with cancer to avoid the risk of cancer cell stimulation, and patients with thrombophilia to avoid the risk of thrombosis following ovarian stimulation and has also been proposed for avoiding hyperstimulation in high risk patients Supplementation with low concentrations of melatonin (1 nm)improves nuclear maturation 43 44 What did we learn? What are our expectations for the future of reproductive medicine Preimplantation genetic diagnosis (PGD) gained an important role in the prevention of genetic diseases. More indications have recently been applied such as aneuploidy screening, HLA typing and mitochondrial disease We now need to discover objective biomarkers of ovarian response including a combination of genetic, hormonal and functional markers that will help us define the right individual treatment for the right patient to reduce cancellations due to OHSS and poor response, while maximizing the chances of achieving each time the birth of a single healthy child, not only in ART patients but also in unovulatory patients of Groups WHO I and WHO II 45 46 What are our expectations for the future of reproductive medicine (ii) Evaluation of gametes viability, evaluation of embryos implantation potential and uterine receptivity potential are today still subjectively defined. To improve the efficiency of the system we need to discover ways of move away from empirical subjective systems and move to objective repeatable and validated biomarkers of ovarian response, of gametes health and viability, of embryo implantation potential and of uterine receptivity! What are our expectations for the future of reproductive medicine (v) We need to discover: ways of protecting the primordial follicles during their latent time in the ovary to avoid ageing ways to control the number of follicles to grow in each cycle by turning on/off dormant follicles. 47 48 8
Thoughts for the future Health Education Should we not spend some time and money to prevent the conditions which make IVF necessary? Prevention of STD through proper sex education will reduce tubal factors making IVF necessary Educating women to seek treatment before the age of 35 will give more the 90 % of women the change to deliver a healthy genetic offspring Let us promote health education, fight the global epidemic of obesity, promote a healthy life style with proper nutrition and physical exercise and help to reduce stress- this might be a very good investment and may decrease hypothalamic- pituitary and metabolic conditions related to male and female sub fertility or infertility. We are privileged to be among those who can bring the joy of parenthood to the childless couples, we must continue to strive to obtain our goal a singleton pregnancies with healthy children to every couple 49 50 Thank You for Your Attention! 51 52 9