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UPDATES IN MALE INFERTILITY

TET YAP/CONSULTANT URO-ANDROLOGIST ST GEORGES /CROYDON /ROYAL MARSDEN THE LISTER & PRINCESS GRACE HOSPITAL

Infertility is defined as the failure to conceive after regular, unprotected intercourse for at least 12 months Infertility affects up to 15% of couples. A male factor is solely responsible in about 20% of infertile couples and contributory in 30% to 40% of cases

Out of 100 couples trying to conceive naturally: 20% will conceive within one month 70 % will conceive within six months 85 % will conceive within one year 90 % will conceive within 18 months 95 % will conceive within two years

INFERTILITY: DEFINITION

In the United Kingdom (UK); 1 in 7 couples (14%) will experience difficulty in conceiving This is approximately 3.5 million people in the UK. Comparable societies report rates between 8% and 20% . The annual incidence of infertility is estimated at 1.2 couples per 1000 total general population For an average general practice with 6000 patients, this equates to 7 couples presenting with a fertility problem each year Male infertility is identified as a cause in 19-57% of all infertile couples

BASIC FACTS

Of the 35% with male factor infertility 25% - oligozoospermic 10% - azoospermic In azoospermia: 53% - non-obstructive azoospermia 30% - obstructive azoospermia 17% - presumed rete block

PREVALENCE OF MALE FACTOR INFERTILITY

Idiopathic Cryptorchidism Varicoceles Drugs and gonadotoxins Chemotherapy Radiotherapy

Genito-urinary infection Endocrinopathy Partial ejaculatory duct obstruction Unilateral vasal obstruction Reduced Spermatogenesis (hypospermatogenesis) Genetic

AETIOLOGY

WHO LABORATORY MANUAL FOR THE EXAMINATION AND PROCESSING OF HUMAN SEMEN (5TH EDN., 2010 )

Semen centrifugation at 3000 g for 15 minutes and a thorough microscopic examination by phase contrast optics at x200 magnification of the pellet

In WHO 2010 ”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 set of 5th percentile parameters was set as the lower limit of “normal” So 95% of men tested would have sperm parameters higher than the reference ranges

EAU GUIDELINES 2016

• Primary/ Secondary • Age of wife* • PMH (UDT/ Surgery/

Mumps/ Testis Ca / Endocrine disorder / Diabetes)

• Family history • Drugs (chemotherapy,

oestrogens, anabolic steroids, illicit drugs)

• Social (smoking, ETOH excess, excess heat)

HISTORY TAKING

BREAKING NEWS - EAU 2016: THE EFFECT OF ALCOHOL, SMOKING AND MALE AGE ON SEMEN PARAMETERS AND IVF/ICSI OUTCOMES : IS THERE A CORRELATION?

1257 couples. Mean male age of 36.4. Mean Female age was 34. 13%of males were smokers. 77% of males had a history of alcohol consumption. 35.8% of couples underwent IVF treatment, 57% underwent ICSI and 7.2% had failure of embryo development. Increasing male age was significantly associated with a reduction in semen volume, sperm count, motility and morphology (p< 0.05). Fertilization rate, pregnancy and live birth rate were unaffected (p=0.603, p=0.895 and p=0.088 respectively). Smoking in all groups showed a reduction in sperm count but didnot affect other parameters. Fertilisation, pregnancy and live birth rates in couples that underwent ICSI showed no significant difference between smokers and non-smokers. Alcohol consumption had a significant effect on sperm motility and morphology (p < 0.0001) but not volume or count (p=0.544 and p=0.232 respectively) For those undergoing ICSI, fertilization rates were reduced (p<0.013) whereas pregnancy and live births were not (p<0.132 and p<0.099 respectively) Yap T et al

EXAMINATION

SEMENALYSIS HORMONES MSU GENETICS SCROTAL USS TRUS ? VASOGRAPHY ? TESTICULAR BIOPSY

TESTS

FSH, LH, Testosterone, Prolactin Broadly distinguish obstructive from non obstructive

HORMONE EVALUATION

HYPOGONADISM

76 of 795 (9.6%) men were found to have impalpable indeterminate lesions on USS: 3 of these 76 (4%) were seminomas Hypoechoic & vascular indeterminate lesions were significantly associated with pathologically significant testicular tumours (ITGCN, seminoma, Leydig cell tumours) (p = 0.01) but not testicular size, lesion size, presence of TML, sperm concentration or FSH/LH levels

BREAKING NEWS – AUA15 : ULTRASOUND SCANNING IN THE SCREENING OF MEN WITH SUBFERTILITY FOR TESTICULAR MALIGNANCY

Karyotype X linked genetic defect Kallman’s, Androgen insensitivity Sex chromosome defect Klinefelter’s XXY Autosomal defects ICSI Y gene deletion Hypospermatogenesis CFTR gene Vasal aplasia

ESSENTIAL GENETIC INVESTIGATIONS

INCIDENCE OF CHROMOSOMAL ANOMALIES

azoospermia oligozoospermia

Obstructive Non-obstructive <5x106/ml 5-10 >10-20 total

N° of subjects 144 648 648 628 583 % Anomalies 3 0.5 16.7

2651

9.7 4.3 7.7

% in the General population 0.4-0.6

Vincent et al. J. of Andrology, 2002

THE HUMAN AZOOSPERMIA FACTOR

AZF = DAZ gene deleted in azoospermia Y chromosome 11q position Deletions => Azoospermia

12 patients with micro-deletions in 3 non overlapping regions of AZF (Vogt, 1996) Micro-deletion AZFa*- Sertoli only Micro-deletion AZFb- maturation arrest Micro-deletion AZFc- severe oligzoospemia (no histological pattern) * uncommon

Azoospermia (8-12%) Oligospermia (3-7%) >5 million spermatozoa / ml (0.7%) AZFc deletions most common (65-70%) AZFb, AZFb+c,AZFa+b+c regions (25-30%) AZFa region deletions (5%)

YQ DELETIONS

A threshold of <1 M sperm/ml was as sensitive but much more specific for detecting Y microdeletions than 5 M/ml (EAU guidelines). Karyotype anomalies are nearly all detected with a cut off of <10 M/ml.

BREAKING NEWS: AUA 2015 - CYTOGENETIC ABNORMALITIES IN MEN WITH SUBFERTILITY YAP T.L., ET AL

Prevalence 1 in 2500 Autosomal-Recessive disorder Short arm of chromosome 7 CBAVD - Mild clinical symptoms of CF 25% chance of having CF if female carrier 50% chance of CF if male homozygous. If negative for known mutations, the risk of being a carrier of unknown mutations is about 0.4%.

CYSTIC FIBROSIS

Strong association between unilateral vasal agenesis and ipsilateral renal anomalies Weaker association of renal anomalies and CBAVD with a prevalence of only 11% However, for those patients who have CBAVD and CFTR mutations the prevalence of renal anomalies is extremely rare Imaging of the kidneys is more likely to detect abnormalities in:

• men with unilateral vasal agenesis • men with CBAVD who do not have mutations in CFTR

RENAL ANOMALIES

• this test evaluates the percentage of spermatozoa with chromosomal abnormalities in a sperm sample

• This analysis allows the estimation of the transmission risk of chromosomal abnormalities to the offspring. This test analyzes the chromosomes mostly implicated in spontaneous miscarriages and affected offspring with chromosomal abnormalities (chromosomes 13, 18, 21, X and Y).

• Over a third of patients who failed ICSI have a raised sperm aneuploidy rate) suggesting that determining sperm AR has a role in patients who have failed ICSI

• Male age and sperm concentration appear to be predictive of patients with raised AR and are of prognostic value in counselling patients prior to ICSI treatment.

BREAKING NEWS : AUA 2015 – THE CLINICAL VALUE OF ASSESSING SPERM CHROMOSOMAL ANEUPLOIDY IN COUPLES UNDERGOING FAILED INTRACYTOPLASMIC SPERM INJECTION (ICSI) AND ITS CORRELATION WITH SEMEN PARAMETERS S

OTHERS: SPERM DFI DNA Fragmentation Index (%DFI; % sperm cells containing damaged DNA - <15% DFI = excellent fertility potential)

EAU GUIDELINES: MALE FERTILITY 2016

Dilated & tortuous veins of pampiniform plexus 15% men, 40% infertile men

• grade I palpable only with Valsalva

• grade II are palpable

with the patient in the standing position

• grade III are visible

through the scrotal skin and are palpable when the patient is supine

DO VARICOCELES CAUSE INFERTILITY ?

Hyperthermia Raised Venous pressure- reduced arterial

flow Hormonal Imbalance- reduced Testosterone-

reduced Leydig cell function Reflux of toxic substances- Catecholamines Reactive Oxygen Species

PATHOPHYSIOLOGY OF VARICOCELE INDUCED CHANGES IN THE TESTIS

The idea supporting varicocele relationship with infertility depends upon three aspects: (1) The increased incidence of varicocele among infertile men (2) The association between varicocele and reduced semen parameters (3) The improvement of semen parameters and pregnancy rates following surgical correction of clinical varicocele

VARICOCELES AND INFERTILITY

Is there increased incidence of varicoceles amongst infertile men?

QUESTION 1

Normal semen quality 11.7% Abnormal semen quality 25.4%

INCIDENCE OF VARICOCELE IN 9034 INFERTILE COUPLES

WHO, Fertil Steril 1992; 57:1289

Couples were recruited in 34 World Health Organization collaborating centers in 24 countries Varicocele was found in 25.4% of men with abnormal semen, compared with 11.7% of men with normal semen. It was accompanied by decreased testicular volume, impaired sperm quality, and decline of Leydig cell secretion (Testosterone) Spontaneous pregnancies were as frequent in couples in whom the men did or did not have varicocele. Frequency of varicocele in infertile couples among different geographical regions varied from 6% to 47%

DETAILS OF WHO STUDY

Is there an association between varicoceles and reduced semen parameters?

QUESTION 2

VARICOCELE GRADE AND SEMEN QUALITY

Varicocele Grade n Total sperm count ( mil) Not present 5841 115 Grade 1 434 86 Grade 2 548 67 Grade 3 271 60

WHO, Fertil Steril 1992; 57:1289

0

5

10

15

20

25

30

35

Varicocele Control

Increased % sperm DNA damage (DFI) in patients with a clinical varicocele. (Varicocele n= 55, Control 25) Smith, Human Reproduction. 21(4):986-93, 2006

Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis

Ying-Jun Wang, Rong-Qiu Zhang, Yan-Jun Lin, Rong-Gui Zhang and Wei-Li Zhang

Reproductive BioMedicine Online Volume 25, Issue 3, Pages 307-314 (September 2012)

DOI: 10.1016/j.rbmo.2012.05.002

This meta-analysis concludes that there is an increase in sperm DNA damage in patients diagnosed with varicoceles. A surgical varicocelectomy may be a possible treatment for decreasing the damage. In the future, studies should be conducted with appropriate controls to determine the usefulness of varicocelectomies.

Is there an improvement in semen parameters and pregnancy rates following surgical correction of clinical varicoceles?

QUESTION 3

Improvement in sperm concentration : 12.32 million sperm per milliliter (p<0.0001, 22 trials) (UP TO 51% improvement in sperm concentration)* Improvement in sperm total : 10.86% (p<0.0001, 17 trials)* and Improvement in progressive motility : 9.69% (p=0.003, 5 trials) (UP TO 70% increased motility)* Up to 44% improvement in morphology (EAU) Semen characteristics usually improve between 3 months to 1 year after surgery *(Baazeem A et al, Eur Urol 2011)

META-ANALYSIS OF SEMENALYSIS POST VARICOCELECTOMY

Maybe secondary to oxidative stress (higher semen ROS vs fertile men without varicocele) (Agarwal A, Reprod Med Online 2006) Damage can be reversed with varicocelectomy: •Decrease oxidative stress (Chen SS, J Urol 2008) •Decrease DNA damage •Lower DNA fragmentation index (Zini A, Int J Androl 2011) •Improved morphology (Reichart M, Andrologia 2000)

VARICOCELES ARE ASSOCIATED WITH INCREASED SPERM DNA DAMAGE

Parameter Pre-op Post- op Count M/ml 4.8 14.3 Motility % 16.7 26.6 DNA Frag % 35.2 30.2

49 men with at least a 1-year history of infertility, a palpable varicocele and oligospermia.

World Health Organization semen analysis and sperm DNA damage expressed as the DNA fragmentation index using the sperm chromatin structure assay were assessed preoperatively and postoperatively.

Pregnancy (spontaneous and after assisted reproductive technique) was recorded 2 years after surgery.

J Urol. 2013 Jan;189 (1 Suppl):S146-50. Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate

• Natural pregnancy and from ART-37.7% and 24%.

• The mean postoperative DNA fragmentation index was significantly higher in couples who did not conceive spontaneously or with assisted reproductive technique (p = 0.033).

PURPOSE: We evaluated the impact of varicocelectomy on intracytoplasmic sperm injection outcomes in infertile men with clinical varicocele. MATERIALS AND METHODS: We studied 242 infertile men with a history of clinical varicocele who underwent intracytoplasmic sperm injection. Of the men 80 underwent prior subinguinal

microsurgical varicocelectomy (treated group 1) and 162 had any grade of clinical varicocele (untreated group 2) at sperm injection. We compared semen analysis results before and after varicocelectomy, and the sperm injection procedure outcomes. Mean time from surgery to sperm injection was 6.2 months. Logistic regression was done to verify whether varicocelectomy influenced the odds of clinical pregnancy, live birth and miscarriage.

RESULTS: We noted an improved total number of motile sperm (6.7 × 10(6) vs 15.4 × 10(6), p <0.01) and a decreased sperm defect score (2.2 vs 1.9, p = 0.01) after vs

before varicocele repair. The clinical pregnancy (60.0% vs 45.0%, p = 0.04) and live birth (46.2% vs 31.4%, p = 0.03) rates after the sperm injection procedure were higher in the treated than in the untreated group. The chance of achieving clinical pregnancy (OR 1.82; 95% CI 1.06-3.15) and live birth (OR 1.87, 95% CI 1.08-3.25) by the sperm injection procedure were significantly increased while the chance of miscarriage was decreased (OR 0.433, 95% CI 0.22-0.84) after varicocele was treated.

CONCLUSIONS: Results suggest that varicocelectomy improves clinical pregnancy and live birth rates

by intracytoplasmic sperm injection in infertile couples in which the male partner has clinical varicocele. The chance of miscarriage may be decreased if varicocele is treated before assisted reproduction

. Clinical outcome of intracytoplasmic sperm injection in infertile men

with treated and untreated clinical varicocele . J Urol. 2010 Oct;184(4):1442-6. Epub 2010 Aug 19

An increase in testosterone was seen in 65 of the 78 men (83%) The mean follow-up was 7 months. The mean serum testosterone level increased from 308.4 to 417.5 ng/dL Overall a mean increase of 109.1 ± 12.8 ng/dL (n = 78) The improvements in the serum testosterone levels were seen regardless of the clinical grade.

A retrospective review of 59 men with a total serum testosterone level <400 ng/dL who had undergone microsurgical subinguinal varicocelectomy for infertility and/or hypogonadism. All men had clinically palpable left varicoceles and preoperative and postoperative total serum testosterone levels available. The changes in the testosterone levels were evaluated.

. Varicocelectomy Is Associated With Increases in Serum Testosterone Independent of Clinical Grade (Urology, 2013 Apr: S0090-4295(13)00214-8)

Evers & Collins, Lancet. 361(9372):1849-52, 2003 7 RCTs: Nilsson 1979, Breznick 1993, Madgar 1995, Yamamoto 1996, Nieschlag 1998, Grasso 2000, Unal 2001

META-ANALYSIS OF EFFICACY OF VARICOCELE REPAIR FOR MALE SUBFERTILITY

Pregnancies 61/281 treated vs 50/259 controls Relative benefit 1.01 NS Varicocele repair does not seem to be an effective treatment for male or unexplained subfertility. But! Several heterogenous studies (inclusion criteria, patient characteristics) The Nilsson study includes patients with normal semen analysis The studies by Breznick et al. and Yamamoto et al. include both patients with normal semen analysis and subclinical varicocele The studies by Grasso et al. and Unal et al. include patients with subclinical varicocele 3 RCTS - Normal semenalysis - no clear benefit vs observation 3 RCTS - Repair of subclinical varicocele ineffective

When remaining 3 RCTs analysed as treated: significant increase in pregnancy rate (36.4%) compared with the control group (20%) (p = 0.009) (Ficarra, Eur Urol 2005)

Baazeem Meta-analysis (2011) 4 RCTs of varicocelectomy reporting on pregnancy outcomes • Infertile with Clinical

Varicocele & Oligospermia • ITT Odds ratio was 2.23

(95% confidence interval [CI], 0.86-5.78; p=0.091), indicating that varicocelectomy is moderately superior to observation, but the effect is not statistically significant

• May be due to the

heterogeneity of data (same problem as Cochrane)

Intention-to-treat analysis: Forest plot depicting odds ratio and 95% confidence interval for pregnancy outcome in the four randomized controlled trials on varicocele repair or observation in men with abnormal semen parameters and clinical varicocele [18], [19], [20], and [21]. The random effect model was used (heterogeneity χ2 = 14.60 [df = 3]; p = 0.024).OR = odds ratio; CI = confidence interval.

Abdulaziz Baazeem et al. Eur Urol 2011;4:796-808 1/1

“As-treated” analysis: Forest plot depicting odds ratio and 95% confidence interval for pregnancy outcome in the four randomized controlled trials on varicocele repair or observation in men with abnormal semen parameters and clinical varicocele [18], [19], [20], and [21]. The random effect model was used (heterogeneity χ2 = 7.41 [df = 3]; p = 0.060).OR = odds ratio; CI = confidence interval.

Abdulaziz Baazeem et al. Eur Urol 2011;4:796-808 2/5

Latest RCT

894 men, 10 studies Preg rate 17.3% (control) vs 23.5% (varic) The odds ratio (OR) of the 10 studies for the outcome of pregnancy was 1.47 (p = 0.03,), favouring the intervention (NNT = 17) Omission of normal semen analysis and subclinical varicocele trials -> subgroup analysis. The outcome of the subgroup analysis (five studies) also favoured treatment, with a combined OR 2.39 (p = 0.03). NNT = 7 “The evidence was suggestive rather than conclusive, as the main analysis was subject to fairly high statistical heterogeneity (I(2) = 67%)”

COCHRANE 2012 META-ANALYSIS (KROESE ET AL)

NICE GUIDELINES, LAST UPDATED 2013

2016 EAU guidelines

AUA Guidelines, last updated 2001

VARICOCELECTOMY: WHICH TECHNIQUE?

COMPARISON OF THE RESULTS AND COMPLICATIONS OF RETROPERITONEAL, MICROSURGICAL SUBINGUINAL AND HIGH INGUINAL APPROACH IN THE TREATMENT OF VARICOCELE (SHIRAISHI, JOURNAL OF ANDROLOGY 2012)

•Significant postoperative improvements in sperm concentration and motility were observed after all approaches, but such improvements were observed sooner and showed higher sperm concentration and motility after the use of the microsurgical approaches. •Both microsurgical sub-inguinal and high inguinal approaches yielded comparable success rates, but the operative time and pain control were superior with the high inguinal approach. •Due to its favourable safety profile, the microsurgical high inguinal approach should be of value to both experienced micro-surgeons and trainees.

Varicoceles found in 5% of men with NOA Even after improvement of spermatogenesis in a subset of NOA men following varicocele repair, most individuals will remain azoospermic after varicocelectomy Inci et al. reported a 2.6-fold increase in the chances of retrieving testicular sperm for ICSI using micro-TESE in NOA men with treated as compared to untreated varicocele (J Urol 2009)

VARICOCELES AND AZOOSPERMIA

200 men with clinical varicocele and NOA Mean follow up of 13 months Motile sperm was found in 39% of subjects Pregnancy was achieved in approximately 26% of men with sperm in

the ejaculate, 60% unassisted, and 40% with IVF Postoperative mean sperm density and motility were 1.6 million and

20%, respectively Histopathology was the only predictor of success (p< 0.004)

Biopsy-proven hypospermatogenesis (HS) and maturation arrest (MA)

were significantly more likely to correlate with finding sperm in the ejaculate than Sertoli-cel only (SCO) (odds ratio 9.4; CI 95% 3.2–27.3)

. VARICOCELE REPAIR IN PATIENTS WITH NON-OBSTRUCTIVE AZOOSPERMIA: A META-ANALYSIS. WEEDIN 2010 JUN;183(6):2309-15.

Obstruction (OA)- reconstruction + sperm retrieval Non Obstructive (NOA) - sperm retrieval

TREATMENT OF AZOOSPERMIA

Site of obstruction n %

Intra-testicular 47 16

Epididymal 163 51

Bilateral vasal aplasia 58 18

Unilateral vasal aplasia 39 12

Ejaculatory duct 3 1

CAUSES OF OBSTRUCTIVE AZOOSPERMIA

Causes

1.Absent vas (CF, CBAVD)

2.Obstructed vas (inc post vasectomy)

3.Epididymal obstruction

4.Ejaculatory duct obstruction

MANAGEMENT OF OA Treatment

1.PESA/ MESA, IVF, adoption (test partner for CF)

2.Epidimovasostomy, vasovasostomy

3.Epidimovasostomy

4.TURED

Sperm retrieval 100% in obstructive azoospermia (no abnormal spermatogenesis)

OBST. PATENCY PREG. 2 yrs 96% 77% 4 92 57 6 87 54 8 85 52 10 76 43 12 85 28 14 79 55 >15 yrs 71 30

Belker '91

OUTCOMES VV

Authors Year Patency Pregnancy

Fogdestam et al 1986 85% 37%

Silber 1989 77% 49%

Schlegel et al 1993 70% 31%

Thomas 1993 76% 42%

Matsuda et al 1994 81% 42%

Jarow et al 1995 67% 27%

Takihara 1998 71% 29%

Kim et al 1998 81% 37%

OUTCOMES VE

INDICATIONS Ejaculatory failure Non obstructive azoospermia Obstructive azoospermia Vasa aplasia Ejaculatory duct obstruction Vasal obstruction Epididymal obstruction Intratesticular obstruction

SURGICAL SPERM RETRIEVAL

Seminal Vesical obstruction : Ejaculatory duct aspiration

Vasostomy : vas

PESA : epididymis

MESA : epididymis

TESA : testis

TESE : testis

SPERM RETRIEVAL TECHNIQUES

Indications

Testicular Failure/Non Obstructive Azoospermia

Technique

GA

Midline scrotal incision

Transverse equatorial incision on Tunica

Operating microscope- X25 magification

Dilated and opaque tubule removed

Tunical incision closure- 4-5/0 vicryl

MICRODISSECTION TESE

MICROTESE

COMPARISON OF TESE : SRR

A systematic review by Bernie et al. (2015) showed that mTESE was 1.5 times more likely (95% CI 1.4–1.6) to result in successful sperm retrieval compared with TESE in men with non-obstructive azoospermia.

COMPARISON OF COMPLICATIONS

BREAKING NEWS - EAU 2016: ASSESSMENT OF ICSI OUTCOME UTILIZING FRESH/FROZEN EPIDIDYMAL AND TESTICULAR SPERM IN OBSTRUCTIVE AND NON-OBSTRUCTIVE AZOOSPERMIA

ICSI outcomes (live birth and pregnancy rates) depend primarily on female age and number of eggs fertilized. After successful sperm retrieval, male infertility factors such as age, aetiology, source of sperm and whether it was frozen/fresh was not significantly associated with ICSI outcomes.

BREAKING NEWS – EAU 2016: PREVALENCE OF BIOCHEMICAL HYPOGONADISM IN MEN WITH NON-OBSTRUCTIVE AZOOSPERMIA (NOA) BEFORE AND AFTER TESTICULAR SPERM EXTRACTION (M-TESE)

Conclusion The lack of statistical difference in SRR between men with low and normal testosterone levels suggests that hormonal stimulation prior to m-TESE may not influence sperm retrieval rates. Post-operatively m-TESE was associated with significant increases in FSH and LH levels but Testosterone levels are not significantly affected confirming the safety of this procedure **EAU GUIDELINES 2016-7**

BREAKING NEWS: EAU 2016 - LIVE BIRTH RATES IN MEN UNDERGOING MICRODISSECTION TESE IN NON-OBSTRUCTIVE AZOOSPERMIA (NOA) Results

A total of 230 patients were included.

The mean age of male and female patients was 42.8 (range 27-74) and 33.4 (range 19-43) respectively. Sperm was retrieved in 105 of 230 (45.7%) of men. 83 patients had ICSI cycles.

The mean number of embryos implanted was 1.8 and pregnancy rate was 43.8%, with a live birth rate of 17.3. 43 second ICSI cycles were done with a cumulative live birth rate of 23.3%.

Pregnancy rates and number of successful embryo implants were associated with successful live birth

Conclusion

Sperm can be retrieved in 46% of all men with NOA, although overall only 23 % are able to achieve paternity, which is independent of the histological diagnosis.

SURGICAL SPERM RETRIEVAL COMMISSIONING

SURGICAL SPERM RETRIEVAL COMMISSIONING

SURGICAL SPERM RETRIEVAL COMMISSIONING

The male infertility service design impacts on: Improved patient experience – care closer to home Access to one-stop male fertility clinic for the South West London region Access to specialist andrology provision Improved patient flows as part of an integrated seamless pathway of care Effective and efficient internal and external partnership working Oncotestis/ Testicular Trauma/Fertility emergencies

No male infertility services in South West London region Patients are either being referred out of area or accessing private services NICE guidelines: Surgical sperm may be performed using several different techniques depending on the pathology and wishes of the man. In all cases facilities for cryopreservation of spermatozoa should be available (2004)

MALE FERTILITY SUPRAREGIONAL SERVICE

ONCOFERTILITY Fertility in men with cancer can be compromised by both the disease and its treatment (including surgery) Oligospermia in 60% Hodgkins, 50% Testicular CA

BREAKING NEWS – EAU 2016: THE EARLY AND LATE EFFECTS OF CANCER ON SEMEN PARAMETERS IN MEN

Conclusion •Sperm banking before surgical or medical intervention for cancer is mandatory and an important aspect of survivorship management and planning, with up to 0.9% of men potentially requiring surgical sperm retrieval for azoospermia •Further research in this area will allow us to understand and target future fertility therapies in this cohort of relatively young men who often require multimodality treatment for their malignancy

ONCOFERTILITY Sperm should not be banked while a patient is receiving chemotherapy (5 x rate chromosomal damage) Contraceptive intercourse is advised during chemotherapy treatment Fertility should not be considered until at least 6 months after chemotherapy finishes NB However, children conceived naturally & with IVF-ICSI using testicular sperm from men who had received chemotherapy did not show higher rates of birth defects than that expected with natural conception.

STRATEGIES Pretreatment: SPERM CRYOPRESERVATION or BANKING GONADAL SHIELDING ELECTROEJACULATION SPERM RETRIEVAL TECHNIQUES TESTIS-SPARING SURGERY FOR CANCER Posttreatment: BLADDER HARVEST ELECTROEJACULATION SPERM RETRIEVAL TECHNIQUES

BREAKING NEWS: EAU 2016 - MICRODISSECTION ONCO-TESE IN MEN WITH AZOOSPERMIA AND CANCER Results 27 testes units were operated on. The mean age for the testis group was 34 (range 24-44) years and the non-testicular group 24 (range 23-26)

The overall sperm retrieval rate in men with testicular and non-testicular tumours was 37.5% and 33.3% respectively. Of the patients with testicular tumours, 7 units out of 22 (31.82%) had sperm found at surgery with 2 (9.09%) found on the tumour side. There was no difference in sperm retrieval relative to tumour sub-type, age or FSH

Conclusion

We conclude that all men with cancer presenting with azoospermia prior to cytotoxic or ablative gonadal treatments should be offered a microdissection onco-TESE

ONCOFERTILITY: THE FUTURE PROTECTING SPERM PRODUCTION – hormonal manipulation to slow spermatogenesis GERM CELL TRANSPLANTATION - harvesting testis tissue containing testis stem cells to be transplanted back into testis after rx TESTIS GRAFTING – returning stem cells under skin ARTIFICIAL TESTICLE - embryonic stem cells (hESCs) or induced pluripotency stem cells (iPCs), this technology attempts to “grow” sperm in culture from testis, skin or other stem cells to the point of mature sperm development

THANK YOU

TETYAP@NHS.NET

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Maternal Medicine Overview

Miss K Joash BSc MSc MBBS MRCOG Consultant in Obstetrics and Gynaecology

Why maternal medicine?

Confidential enquiries into maternal deaths show

an increased number of women with indirect causes.

With rapid advances in medicine and progression in fertility interventions our obstetric population is increasingly older and surviving with diseases to a reproductive age.

Medical problems may exist prior to pregnancy but they may also develop de novo in pregnancy.

Maternal Medicine

Started to meet the need for more specialised care of high risk patients

To improve links between obstetrics and medical specialities

How will it affect me doctor?

It is important for us to realise the impact of the disease on the pregnancy and the impact of pregnancy on disease to best care for these women.

Maternal or obstetric medicine is a subspecialty which aims to improve the care to these patients by bridging the gap between physicians and obstetricians.

General practitioners have a vital role in timely referral

in early pregnancy and referral for pre-pregnancy counselling.

Haematology

Immune thrombocytopenia Thrombotic disorders e.g. protein S

deficiency Haemostatic disorders e.g. von Willebrands Antiphospholipid syndrome Red cell disorders e.g. sickle cell disease,

hereditary spherocytosis VTE disease

Haematology management

GP 1. Prepregnancy counselling 2. Optimise Hb level 3. Baseline blood tests 4. Start aspirin/clexane in VTE/APS/sickle 5. Genetic counselling

Hospital: Dedicated multidisciplinary approach. Start prophylaxis as soon as pregnant

Cardiac

Cardiology Congenital heart disease Ischaemic heart disease Arrhythmias Cardiomyopathy Chronic Hypertension

Cardiac Management Gp Majority cardiac conditions have hospital

involvement prepregnancy Chronic Hypertension – ensure fully

investigated: renal US scan, ECG, Baseline bloods

Start Aspirin 75mg (CLASP trial) and calcium (Cochrane review) in hypertensive disorder or history of disorder.

In Ischaemic heart disease continue usual medications and refer urgently.

Neurology

Epilepsy Benign intracranial hypertension Severe Migraine CVA Multiple Sclerosis Myasthenia Gravis Epilepsy

Epilepsy management GP Refer for prepregnancy counselling – aim for monotherapy Advise not to stop drugs – fits & hypoxic effects on the fetus High dose folic acid 5mg Prepregnancy therapeutic drug levels Contraceptive advice

Hospital 25-30% increased seizure frequency Highest risk peripartum 1-2% during labour/first 24hours Pregnancy associated with sudden unexplained death in pregnancy

(SUDEP) New advances: Keppra excellent AED

Migraine management

Severe migraine Stop contraindicated drugs eg. Sumatriptan and ergotamine Consider prophylaxis if attacks longlasting or frequent with aspirin

75mg Migraine may present for the first time Aura alone Most tend to improve in pregnancy 1st line aspirin 2nd line amitryptiline 3rd line calcium antagonists Others Pzotifen (serotonin antagonist) and propranolol (B blocker)

Respiratory Recent TB Severe asthma Bronchiectasis

Asthma: All drugs can be given as per non-

pregnant patient. Assocn GORD/hayfever Hayfever: Piriton, Beconase nasal spray, eyedrops.

In severe cases a short course of steroids Remember flu vaccination

Gastroenterology

Gastroenterology Severe Hyperemesis Severe Obstetric Cholestasis Crohns disease Ulcerative Colitis Gastric Banding Hepatitis Ulcer disease

Gastroenterology management

GP Prepregnancy counselling Adequate nutrition Optimise deficiencies e.g. vitamin b12, vitamin D, ferritin Baseline blood tests

Hospital: combined approach. Regular review. Optimise

therapy prepregnancy IBD. Start azathioprine. Sulphasalazine safe. Steroids

used for flares. High dose folic Acid. Hyperemesis: Outpatient approach

Rheumatology

Rheumatoid arthritis Systemic Lupus erythematous Connective tissue disorders

GP refer for pre-pregnancy counselling Optimise drug therapy Beware of postnatal inflammatory arthritis SLE: increased flare rate. Adverse outcomes related to

organ involvement and disease activity. Anti-Ro and La antibodies are checked.

Thyroid disorders Diabetes

GP - ensure pre pregnancy stability. Postnatal thyroid 6/52 check

important GTT 6/52 and annual checks.

Lifestyle measures.

Endocrinology

Dermatology

Eczema Psoriasis Melanoma

Topical emoillents and steroids as necessary Don't withhold as infected eczema can be difficult to treat.

Obstetric Emergencies

Sepsis – Low threshold for treatment. Especially in URTI Breathlessness – PE, cardiac, asthma Chest pain – PE, cardiac (ischaemic, dissection), GORD Headache – meningo-encephalitis, SAH, CVA, Cerebral sinus

thrombosis

Psychiatry

Affects 15-20% of women Hx Severe postnatal depression or puerperal psychosis Anxiety disorder Depression on medication Psychosis Eating disorders Self-harm

Burden of illness

Spectrum of disorders MILD • Depression • Anxiety • Baby Blues

MODERATE • Depression • Anxiety • Tokophobia • PTSD • OCD • Sub Misuse • Personality Disorder

SEVERE & ENDURING • Bipolar Affective

Disorder • Schizophrenia • Schizoaffective

Disorder • Severe depression

+/- psychosis • Postpartum

Psychosis

Psychiatry management Gp Optimise medication prepregnancy Use of CBT /other therapies If known to CMH services advise them of pregnancy Postnatal support is key Mood questions at each visit Hospital MDT approach spec midwife/dedicated consultant/

psychological services

Prescribing principles

AVOID ABRUPT CESSATION OF MEDICATION Lowest dose Avoid multiple drugs Timing of exposure during pregnancy Presence in breast milk

Avoid sodium valproate!

Antidepressant Choice Continuity of treatment where needed Risks of swapping/stopping Most tolerated/lower risk: Sertraline Alternatives: Tricyclic antidepressants Cautions: Venlafaxine (High BP), Paroxetine

(malformations) Newer medications- less knowledge Seek advice if unsure

Mood questions

During the past month, have you often been bothered

by feeling down, depressed or hopeless? During the past month, have you often been bothered

by having little interest or pleasure in doing things?

Also consider asking about anxiety using the 2-item Generalized Anxiety Disorder scale (GAD-2):

During the past month, have you been feeling nervous, anxious or on edge?[7]

During the past month have you not been able to stop or control worrying?[7][new 2014]

Anxiety questions

Also consider asking about anxiety using the 2-item Generalized Anxiety Disorder scale (GAD-2):

During the past month, have you been feeling nervous, anxious or on edge?

During the past month have you not been able to stop or control worrying?[new 2014]

Adverse outcomes

Suicide Fetal & infant death

Obstetric complications

Attachment & bonding problems

Emotional & behavioural

problems

Developmental /cognitive delay

Accidents, neglect, abuse

Findings

Identification – 50% undetected Equal attention to physical & mental health 6 week check a security net Disclosure ‘red flag’ Interventions – IAPT, community support, as well as medication

Thank you for listening