Male infertility too often ignored & forgotten

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1 Male infertility too often ignored & forgotten The journey 1. of the men A review of the guidelines Joo Teoh FRANZCOG MRCP(Ire) MRCOG MBBCh MSc(Lon) MD(Glasgow) SubspecialtyRepromed(UK) Consultant Obstetrician & Gynaecologist We got sperms, full stop. Sperm + Egg = Embryo Sperm + Egg = Embryo Sperm + Egg = Embryo The Numbers Game Surely it is enough? _,000,000 I only need 1 1

2 Tests: KISS Keep it sophisticated and subspecialised DNA integrity Chromatin assays for DNA fragmentation evaluation Sperm chromatin structure assay (SCSA) TdT-mediated-dUTP nick end labeling (TUNEL) Sperm chromatin dispersion (SCD) Acridine orange straining technique (AOT) Chromatin assays for DNA fragmentation evaluation Chohan et al; J Androl; 27:53-59 pregnancy loss 25. However there is insufficient evidence to warrant routine testing in these couples until further evidence accumulates. A variety of treatments have been suggested for patients with poor sperm DNA integrity, however there is no evidence demonstrating that treatment DNA results integrity improved sperm DNA integrity and improved pregnancy/delivery rates. Recommendation: Currently there is insufficient evidence in the literature to support the routine use of DNA integrity testing in the evaluation and management of the male partner of an infertile couple. Presently, there are no proven therapies to correct an abnormal DNA integrity test result. Reactive oxygen species (ROS) Reactive oxygen species are generated by both seminal leukocytes and sperm cells, and can interfere with sperm function by peroxidation of sperm lipid membranes and creation of toxic fatty acid peroxides. ROS also have a normal physiological role in the regulation of capacitation and the acrosome reaction. Elevated ROS have been implicated as a cause of male infertility. 2

3 Chromatin assays for DNA fragmentation evaluation Tests: Chromatin assays for DNA fragmentation evaluation Tests: - To know you I have to kill you - Difficulty in finding threshold value - To know you I have to kill you - Difficulty in finding threshold value Sperm selection techniques HA sperm selection HA sperm selection MACS IMSI Hyaluronic acid Bind to HA in vitro Completed plasma membrane remodelling, cytoplasmic extrusion and nuclear maturation Low chromosomal aneuploidies & DNA fragmentation, good nuclear morphology Only mature spermatozoa which have extruded their specific receptors to bind to & digest HA can reach the oocyte & fertilize it HA sperm selection IMSI Parmegiani et al. J Assist Reprod Genet (2010) 27:13-16 HA-ICSI sigificantly improves embryo quality & implantation Awaiting multi-center randomized studies (UK) Morphologically selected sperm injection What is the best criteria for selection? 3

4 IMSI IMSI Conflicting results: No difference in fertilisation rate, early embryo cleavage rate or cleavage rate. Similar proportion of top quality embryos. (Mauri et al. Eur J Obstet Gynecol Reprod Biol May; 150(1):42-6) Based on motile sperm organellar morphology exam (MSOME), individuals with best morphologically normal nucleus has significantly higher pregnancy & delivery rates. Also significantly lower miscarriage rates. (Bertovitz et al. Reprod Biomed Online May; 12(5):634-8 Conflicting results: IMSI group significantly lower number of cycles with no embryo transfer. Trend of higher no. of blastocysts, higher pregnancy rates, less miscarriage rates. Score of spermatozoa = (2 x head) + (3 x vacuole) + (base). Knez at al. Reproductive Biology & Endocrinology :123 MACS MACS (meta- analysis) Magnetic-activated cell sorting Colloidal superparamagnetic microbeads conjugated with annexin V Gil et al. J Assist Reprod Genet (2013) 30: MACS (meta- analysis) Sperm selection techniques HA sperm selection MACS IMSI TOO EARLY FOR INTERNATIONAL GUIDELINES Gil et al. J Assist Reprod Genet (2013) 30:

5 Tests: KISS Keep it sophisticated and subspecialised Tests: KISS Keep it simple & sweet Sperm + Egg = Embryo Have you got the latest WHO manual? In 2010 the World Health Organization (WHO) updated its reference values for the Se This update was long overdue as the last version was published in There is a significant difference on how the old and new reference ranges were derive data from random populations of men were analyzed and the results were plotted on a distribution curve. The 5th percentile was considered to be the lower limit of normal ( another word, 95% of men tested would have sperm parameters higher than the refere Sperm + Egg = Embryo In WHO 2010, the new normal values are based on data from men with proven fertilit known to help their partners conceive in the previous 12 months. Following a large an parameters from over 4000 men in 14 countries, a new set of 5th percentile parameter recommended. Below are the comparisons of the old and new reference values: Parameter WHO 1999 WHO 2010 Volume 2 ml 1.5 ml Concentration 20 million/ml 15 million/ml Progressive motility 50% 32% Normal forms 14% 4% Based on our experience, concentration and progressive motility are the most importa in predicting the likelihood of pregnancy via coitus or intrauterine insemination. For e sperm concentration is < 10 million/ml and/or progressive motility < 20%, the chance the conventional methods is very low. In vitro fertilization would provide the best cha Somewhat more difficult to interpret is sperm morphology, or the proportion of sperm under light microscopy. Morphology is the most subjective parameter in a semen anal centers using different criteria to evaluate morphology. Moreover, technicians within t In 2010 the World Health Organization (WHO) updated its reference values for the Se This update was long overdue as the last version was published in There is a significant difference on how the old and new reference ranges were derive data from random populations of men were analyzed and the results were plotted on a distribution curve. The 5th percentile was considered to be the lower limit of normal ( another word, 95% of men tested would have sperm parameters higher than the refere Sperm + Egg = Embryo In WHO 2010, the new normal values are based on data from men with proven fertilit known to help their partners conceive in the previous 12 months. Following a large an parameters from over 4000 men in 14 countries, a new set of 5th percentile parameter recommended. Below are the comparisons of the old and new reference values: Parameter WHO 1999 WHO 2010 Volume 2 ml 1.5 ml Concentration 20 million/ml 15 million/ml Progressive motility 50% 32% Normal forms 14% 4% In 2010 the World Health Organization (WHO) updated its reference values for the Semen Analysis.[1] This update was long overdue as the last version was published in There is a significant difference on how the old and new reference ranges were derived. In the past, semen data from random populations of men were analyzed and the results were plotted on a statistical distribution curve. The 5th percentile was considered to be the lower limit of normal (or reference), in another word, 95% of men tested would have sperm parameters higher than the reference ranges. In WHO 2010, the new normal values are based on data from men with proven fertility, men who were known to help their partners conceive in the previous 12 months. Following a large analysis of semen parameters from over 4000 men in 14 countries, a new set of 5th percentile parameters was recommended. Below are the comparisons of the old and new reference values: Parameter WHO 1999 WHO 2010 Based on our experience, concentration and progressive motility are the most importa in predicting the likelihood of pregnancy via coitus or intrauterine insemination. For e sperm Why concentration the is < 10 difference? million/ml and/or progressive motility < 20%, the chance the conventional methods is very low. In vitro fertilization would provide the best cha Somewhat more difficult to interpret is sperm morphology, or the proportion of sperm under light microscopy. Morphology is the most subjective parameter in a semen anal centers using different criteria to evaluate morphology. Moreover, technicians within t 5

6 One step back- history and examination!! One step back- history and examination!! One step back- history and examination!! One step back- history and examination!! 6

7 The journey 1. of the men 2. Further investigations Further investigations What is needed and when to test? patient s clinical endocrine status. The relationship of testosterone, LH, FSH and prolactin helps to identify the clinical condition (see Table 2). A normal serum FSH level does not guarantee the Further investigations presence of intact spermatogenesis, however, an elevated FSH level even in the upper range of normal Endocrine is indicative evaluation of an abnormality in spermatogenesis. Recommendation: An initial endocrine evaluation should include at least a serum testosterone and FSH. It should be performed if there is: (1) an abnormally low sperm concentration, especially if less than 10 million/ml; (2) impaired sexual function; or (3) other clinical findings suggestive of a specific endocrinopathy. Endocrine evaluation Copyright 2010 American Urological Association Education and Research, Inc. 11 structural defects, including chromosome rearrangements (translocations), duplications, f only 11%. However, for those patients who have CBAVD and CFTR mutations the deletions, and inversions. Chromosome abnormalities account for about 6% of all male Further investigations infertility, and the prevalence increases with increased spermatogenic impairment (severe oligospermia and nonobstructive azoospermia). Paternal transmission of chromosome defec Genetic studies can result in pregnancy loss, birth defects, male infertility, and other genomic syndromes. Recommendation: Karyotyping and genetic counseling should be offered to all patients with nonobstructive azoospermia and severe oligospermia (<5 million sperm/ml). Y-chromosome microdeletions Approximately 13 % of men with nonobstructive azoospermia or severe oligospermia have underlying Y-chromosome microdeletion. 57 Y chromosome microdeletions responsible for infertility regions AZF a, b, or c are detected using sequence tagged sites (STS) and polymerase chain reaction (PCR) analysis. There is no consensus on the number of STS req revalence of renal anomalies is extremely rare. 47 Therefore, imaging of the kidneys with either Further investigations ltrasound or CT scan is more likely to detect abnormalities in men with unilateral vasal agenesis r men with CBAVD who do not have mutations in CFTR. Genetic studies Recommendations: Men with congenital bilateral absence of the vasa deferentia should be offered genetic counseling and testing for cystic fibrosis transmembrane conductance regulator mutations. The female partner should also be offered cystic fibrosis transmembrane conductance regulator mutations testing before proceeding with treatments that utilize the sperm of a man with congenital bilateral absence of the vasa deferentia. Imaging for renal abnormalities should be offered to men with unilateral vasal agenesis or congenital bilateral absence of the vasa deferentia and no evidence of cystic fibrosis transmembrane conductance regulator abnormalities. Cystic fibrosis transmembrane conductance regulator testing outine screening for mutations of CFTR is currently performed by testing for a panel of 7

8 Further investigations Genetic studies Y-microdeletion testing Is there anything I can do to improve my sperms? The journey 1. of the men 2. Further investigations 3. Strategy to improve sperm parameters Medical Surgical Medical Surgical The insult can be permanent 8

9 Medical Medical Medical Medical NO MENTION OF MALE SUPPLEMENT! Medical Medical 9

10 Surgical Urology Obstruction Medical Surgical Urology Varicocoele repair Surgical Urology Varicocoele Surgical Urology Varicocoele Surgical Urology Varicocoele 10

11 Surgical Urology Varicocoele The journey 1. of the men 2. Further investigations 3. Strategy to improve sperm parameters 4. Surgical sperm retrieval The insult can be permanent Table 2 - Advantages and Disadvantages of Sperm Retrieval Techniques for Assisted Reproduction. PESA Advantages Disadvantages Fast and low cost Minimal morbidity, repeatable No microsurgical expertise required Surgical sperm retrieval Few instruments and materials Few sperm retrieved Cryopreservation limited Fibrosis and obstruction at aspiration site No surgical exploration Risk of hematoma/spermatocele Surgical sperm retrieval MESA TESA TESE Large number of sperm retrieved Excellent chance of sperm cryopreservation Reduced risk of hematoma Reconstruction possible 1 Fast and low cost Repeatable No microsurgical expertise required Few instruments and materials No surgical exploration Minimal/mild postoperative discomfort No microsurgical expertise required Fast and repeatable Surgical exploration required Increased cost and timedemanding Microsurgical instruments and expertise required Postoperative discomfort Relatively low success rate in NOA Few sperm retrieved in NOA Cryopreservation limited Risk of hematoma/testicular atrophy Relatively low success rate in NOA Relatively few sperm retrieved in NOA Risk of testicular atrophy (with multiple biopsies) Postoperative discomfort Micro-TESE Higher success rates in NOA 2 Larger number of sperm retrieved 2 Relatively higher chance of sperm cryopreservation 2 Low risk of complications Surgical exploration required Increased cost and timedemanding Microsurgical instruments and expertise required Postoperative discomfort Esteves et al, International Braz J Urol, 2011 PESA: percutaneous epididymal sperm aspiration; MESA: microsurgical epididymal sperm Aspiration; TESA: percutaneous testicular sperm aspiration; TESE: conventional testicular sperm extraction; micro-tese: microsurgical testicular sperm extraction. The journey 1. of the men 2. Further investigations 3. Strategy to improve sperm parameters 4. Surgical sperm retrieval 5. Counselling Summary Semen analysis History & examination Referral for further evaluation & treatment If <10 million/ml FSH, LH, prolactin, testosterone, TFT Karyotyping Y- chromosome deletion Cystic fibrosis if absent vas deferens Surgical sperm retrieval for azoospermia, or severe oligospermia when appropriate 11

12 Quiz Quiz How about eggs How many is enough in a fresh cycle? How about eggs How many is enough in a fresh cycle? Sunkara et al., Hum Reprod Thank you 12