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8/17/2019 curs1_tradus_engleza

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Male Infertility

Asist. Univ. Dr. Raluca Tulin

Endocrinology/ Embryology Specialist

Profle: Anatomy

Embryology Department U!" #arol Davila$

%ptional #ourse &ear '() *eneral!edicine#linical Embriology + Assisted ,uman

Reproduction

Course 1


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Male Infertility – Bad News!!!

1. Couple Infertility-aects 15% of couples in thereproductie ae

-"#% of cases

$ale factor-"#% of cases fe$ale factor-#% of cases &oth

. Men and wo$en are e'uallyaected(. Infertility aects all ethnicities

and races


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Male Infertility – )ood news!!!

1. *ndroloy+s addressa&ility isrisin.

. *ssisted hu$an reproductiontechni'ues hae su&stantially

eoled ,oerin solutionseen to the $ost seere casesof $ale infertility.

(. *l$ost all patients with $aleinfertility ,#% &eco$e a&leto conceie their own childthrouh assisted hu$anreproduction techni'ues.


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Causes of Male Infertility

/ne0plained Infertility- Idiopathic ,$odied

sper$ora$

- /ne0plained ,nor$al

sper$ora$


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Causes of Male Infertility –Medication!!!

Medication

*nti&iotics 2rythro$ycin3 )enta$icin3Neo$ycin3 Nitrofurantoin34etracycline

*ntihyperten

sie rus

*lfa 6 Beta &loc7ers3 Calciu$

&loc7ers3 8pironolactone34hia9ide iuretics

Che$otherapy rus

Busulfan3 Cisplatin3:in&lastine3 etc ...

;or$ones *na&olic steroids3*ntiandroen3 2stroen3thers *lopurinol3 Ci$etidine3

Ciclosporin3 Colchicine


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Male Infertility – *na$nesis @

The most important factors in obtaining pregnancy

?re'uencyAuality of se0ual act

- *


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Male Infertility – =a& 4ests

-8)*M -) days o0

abstinence1

-;alosper$ 4est

-8per$oculture @ /rine 4est

-2ndocrynoloical 4ests -"S, 2

testosteron1

-)ene 4ests -cariotip microdeletion

cromo3om & 4A5" abc and gene #"TR

mutation1

-4esticularA *&do$inal ultrasound

-ductus de0erens epididymis/ renal

agenesis1.


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4a7e ho$e $essae !!!!!!!

Male infertility can &e the rst sin towards

dianosin other seere illnesses , &rain neoplasia3

&one $arrow neoplasia3 endocrinopathies3

enitourinary infections3 conenital $alfor$ations.

4esticular cancer is 5#0 $ore fre'uent in infertile

$en.


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Primordial *erminal #ells

• Primordial *erminal #ells 4 6aveectodermal origins -S71. !igrateto8ards t6e vitelline yol9 sac -S1

and t6en intraembryonic at gonadalvein level anteromedial o0mesonep6ros -7 9idney1 S;)S


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=>7= 4 it 6as been demonstrated t6at men and8omen 6ave di?erent 9aryotypes -;


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SR& *ene

Sex-determining Region

• C!aster gene 4 in testicular0ormation. "ormed o0 somatic cells o0gonads gro8t6.

• Discovered in =>> Sinclair

• 8D3 4? ,testis deter$ininfactor protein3 initiates $ale se0deter$ination. Mutations of thisene are responsi&le for onadal

dysenesis ,ED wo$en or 8wyersyndro$e

• 4ranslocation of short ar$ of Dchro$oso$e containin 8D eneon chro$oso$e E deter$ines$ale EE syndro$e.


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S8yer syndrome

"emale @&

• Sant6i Soundaraan=>F=

• (ndian At6lete48inner

o0 == internationalmedals

• 7


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%t6er genes involved in seH

di?erentiation

• S%@ > gene -c6romosome =I1) regulates genetranscription o0 A!, 6ormone

• *ene t6at codes A!, 6ormone -c6romosome =>1

• *ena 0or "g0> -fbroblast gro8t6 0actor1 4semini0erous tubules

• JT = gene -c6romosome ==1

• S" = gene -c6romosome >1

•DA@ = gene -c6romosome @1) antagonises SR&action 4 its mutation: 6ypoplasia andrenal9ongenital and 6ypogonadotropic 6ypogonadism


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SeHual Di?erentiation in!ales

• *enetic seH 4at 0ecundation

• *onadal seH -testicles or ovary1 4 S< - untilt6en t6e embryo is in non)di?erentiation stage

o0 gonadal seHualisation 4 bipotential gonads• *enital seH -genital ducts %*E1 4 under t6e

inKuence o0 testosterone secreted startingSI/s -absence o0 testosterone: bipotential

gonads

ovary1 until SF 4 seHual non)di?erentiation o0 genital ducts stage

• S=7) genital seH distinguis6ed at ultra)sound


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(ntrauterine SeHualisation


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Spermatogenesis

• Starts at puberty -testicular cords becomesemini0erous tubules1 4 it never ends

• At #ontorted semini0erous tubules level

• = mil sp3/day -(L #%!PAR(S%L J(T, =

%'%#(T/mont61• ,ormone controlled -*nR, , "S, Testosterone

(n6ibina1 and t6roug6 temperature control -)7M# 0orman and )FM# at mouse1

• Testicule volume ) =Fcm -N7N1 O g ).F o0body 8eig6t

– At Qlue J6ale 4 test volume )g


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J6y 6ave a car i0 you donGt 6ave

roads

F)=


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Spermatogene3a

Mitosis of thespermatogonia

16 days Up to the primaryspermatocytes

First meiosis 24 days For the division of theprimary spermatocytes

to formsecondaryspermatocytes

Second meiosis A few hours For engendering

the spermatids

Spermiogenesis 24 days Up to thecompeted sperm cells

Total ~64 days


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A c6impGs testicle is =H biggert6an a 6umanGs


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SpermatogenesisAdustment


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!ale #ontraception• #ondom

• 'asectomy 4 t6e male vas de0erens are severed and t6entied/sealed$ reversible but a small portion can still 6ave c6ildren

• E@P) Analogue nontoHic Adudin -substance t6at disrupts spermmaturity1 can be use0ul in bloc9ing spermatogenesis

• E@P )CLo 6ormones pill 86ic6 is capable to induce a Cdry orgasm. T6e man can still orgasm -erection is not a?ected1 but t6e substance

prevents sperm production. T6is is administered ;)< 6ours be0oreseHual intercourse and 0ertility e?ect is reversible a0ter =7)7; 6ours.

• E@P ),ormonal 4in study combination

• Progesterone -doses/mont614 reduces spermatogenesis 2

• Testosterone -implant 4c6anged every ; mont6s14 maintains

potency – ,ormonal treatments 6ave side e?ects: nausea

6eadac6es icterus.

– ong term prostate issues may appear.

– (n addition disadvantage o0 long latency period until itcan ta9e e?ect - mont6s1.


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#oming soonO

7=I

• 'asalgel 4 inection o0 a nontoHic polymer int6e de0erent duct -local anaest6etic1. = yearsprotection. #ancelling t6e e?ect is madet6roug6 t6e inection o0 a polymer dissolvent..


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#6emical castration 4 brings

in0ertility• #linical use:

– ,ormone)dependant cancer: prostate breastcancer

– Prison -pedop6iles seHual abusers1

Used met6ods:

=. Antiandrogens -cyproterone acetate1

7. Depo)Provera -inection every mont6s1 4frst in =>


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Testosterone Substitution

L%T (L (L"ERT((T&

• (nactive oral$ Preparations (! -esteri1


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• engt6 di?erence bet8een indeH fnger and ring fngerdepends on testosterone level t6e 0etus 6as be eHposed to

• (0 ring fnger is longer t6an indeH fnger t6en t6is s6o8s a6ig6er testosterone concentration and i0 s6orter t6en t6is

s6o8s a lo8er testosterone concentration 86ic6 meanst6at even ot6er 0eatures may be more 0eminine -source:ive Science1


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#linical use:

(!P%TEL#E 's (L"ERT((T&

IN?24I=I4D IM42NC2,5% "#-F# years

Reduced capacity o0 conceiving ac6ild

(ncapacity o0 6aving completeseHual intercourse

#ystic fbrosis !edication

!umps in postpuberty Leurological illness

Drug abuse smo9ing Trauma

*enetically illness -almannline0elter1 ,ig6 c6olesterol

ToHines Arterial 6ypertension

(n0ections Testicular Trauma Diabetes

Drugs $ Endocrine Disruptors

-non)biodegradable1


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Evaluation o0 (n0ertility

• Medical history -c6ild6ood illnesses cryptorc6idism c6ronictreatment 0amily medical 6istory illicit drugs smo9er previousin0ections 8or9ing in toHic environment1

• Clinical tests -rectal eHam inguinal scars %*E test4 varicocele-le0trig6t1 epididymis vas de0erent1

• ;or$onal dosae -"S, , PR Testosterone0reeTestosterone PR Estradiol A!,1

• 8pecic 4ests -testicular ultra sound transrectal abdominalspermogram !AR test ,alosperm1

• /rine test 4determining o0 sperm cell retrograde eaculation

• *ccessory landes $ar7ersa. 3inc citrate or c6olesterol 0or prostate

b. 0ructose prostaglandin bicarbonate 0or seminal vesicles

c. alp6a)glucosidase glycerylp6osp6orylc6oline )carnitine 0orepididymis


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A!, in !ales

• (ndicator o0 presence/0unctionality o0 Sertoli cells

• (ndications:• SeHual ambiguity$

• Pseudo6ermap6roditism

• ,ermap6roditism

• #ryptorc6idism

• "emale testicle

• A3oospermia -adult1

o8 4 a3oospermia L%L)%QSTRU#T('E

!ARER o0 A5%%SPER!(E( L%L)%QSTRU#T('E -testiculartissue a?ected1


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Prolactin in (n0ertility• (ndications : In Men:

– ginecomastia in0ertility a3oospermia eHposure to pituitary glandtumours -microadenome and macroadenome1 si breast tumours

• Real ,yperprolactinemia -increase o0 prolactin monomers1

• "alse ,yperprolactinemia -presence o0 prolactin dimers andpolimers -macroprolactinemia1 4 86ic6 are biologicalinactive or 8it6 a reduced activity -it is t6e case o0 lab,yperprolactinemia 8it6out image s6o8ing1

• Results: – Real ,iperPR 4Recovery #oeVcient


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Seminoma / epididymitis

8)*M


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8)*M


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• ,uman spermato3oon 6as a small si3e. T6ere0ore en3ymes suc6 as t6eacrosin are important 0or 6uman sperm penetration into t6e oocyte


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Spermogram ResultsValues following test Normal values

Volume: mlColour: opalescent pH:Liquefying: completeTime to liquefy: 15minViscosity: normal

Concentration: mil/mlTotal no. of sp in sample: mil!otility a"#: $!otility a"#"c: $

% 1&5ml'palescent(&)*+&,Complete: -istinguise- -rops), min Normal

≥ 15 x 106

/ml or% 0 2 1,3 in sample≥32%

%4,$

Values following test Normal values Normal forms: $#normal forms: $

Leucocyte: 1$

6 4$ normal forms7accor-ing to 8H' ),1,9 1$ leucocyte

!or0ology


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Spermogram

• Results:• L%R!%SPER!(A 4 normal values

• >lio9oosper$ia lo8 concentration o0 sperm

• ;yposper$ia sperm volume W = !l

•*sper$ia absence o0 sperm• *9oosper$ia absence o0 sperm cells

• lio*steno9oosper$ia mobile sperm cells W = mil./mand motility W ;

• >lio*steno4erato9oosper$ia ,>*4


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!AR Test-!iHed Antiglobulin Reaction1

irect M* test is done to detect antisperm antibodies o0 t6e (gA class in 6uman semen.

T6e presence o0 antisperm antibodies can inter0ere 8it6 sperm 0unction and 3ona binding

and t6e acrosome reaction.

*ntisper$ anti&odies. T6e presence o0 antisperm antibodies 86ic6 react 8it6 antigenes

present on sperm cells is considered typical and specifc to8ards immunological in0ertility.

T6ese antibodies can be 0ound in approH. F o0 in0ertile men.

=i$itations. Direct !AR testing can only be done on mobile sperm cells. Samples 8it6 lo8

concentration or lo8 mobility can deliver a 0alse negative result.

Interpretation – reference alues.

J6en antispermatic antibodies are present t6e mobile sperm cells 8ill tie t6e lateH

particles 0orming agglutinate in a proportion -percentage1 86ic6 is correlated directly 8it6

t6e severity o0 t6e immunological reaction.

Re0erence values:

•G 1#% - neati$

•1# – (% - inter$ediary -suspicion o0 in0ertility o0 immunological cause1$

•H "#% - positie -very 6ig6 probability o0 in0ertility o0 immunological cause1.


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,alosperm is a dianosis test based on t6etec6niXue o0 c6romatin dispersal o0 t6e sperm cell nucleus

?ra$entation of sper$ cell N* ,8? – "actors t6at can inKuence bro9en sperm cell DLA: some medication toHins

0ever smo9ing drugs in0ections age long abstinence.

Method consists in gentle brea9ing t6e DLA 86ile 0orming a 6aloaround t6e sperm 6ead.

Indications of the ;alosper$ test • (n0ertile men 8it6 varicocele 6ave a 6ig6 percentage o0 sperm 8it6bro9en DLA. T6e test indicates t6e degree o0 t6is a?ection.

• (n (n0ections -particularly 8it6 #6lamydia Trac6omatis and!ycoplasma1 t6e test allo8s t6e validation o0 t6e antibioticeVciency and c6oosing t6e best samples 0or assisted 6uman

reproduction.(nterpretations – reference alues.

• 8?G(#% normal$

• 8?H(#% severe DLA brea9ing


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A5%%SPER!(A

>B84/C4I:2 N>N->B84/C4I:2

%bstr. Epididymis -post)in0ectiuouspost) surgery1

(diopat6ic

%bstruction de0erent vas #ryptorc6idism

%bstruction eaculatory duct -prostaticcysts post)in0ectiuous post)surgery1

!umps drugs

(rradiate -a0 cel sertoli1

Sclerosis semini0eroustubules


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*enetic #auses

• #6romosome anomalies: present in )= o0 men 8it6oligo3oospermia and =)= o0 t6ose 8it6 a3oospermia$ t6e best9no8n anomaly is line0elter syndrome -;I @@&1$ ) 0or A5%% non)obstructive

• !icrodeletions o0 & c6romosome: present in =)=F patients 8it6severe oligo)or a3oospermia$ *? ,*9oosper$ia ?actor culocalisation &X==.7 ) 0or A5%% non)obstructive

• !uatations o0 cystic fbrosis gene -#"TR1: transmits autosomal)recessive$ several mutations can determine: bilateral congenitalabsence o0 t6e vas de0erens -#QA'D1 unilateral absence o0 it8it6out pulmonary or pancreatic mani0estations -#UA'D1 orobstruction o0 t6e vas de0erens$ 0or A5%% obstructive


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Absence o0 bilateral vas de0erens

• !issing palpation dilated epididymis

• Determining al0a)glucosidase sperm

• )carnitine sperm

• *licerol0os0oclorid sperm

• #ystic fbrosis gene mutation -#"TR1blood


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*? ,*9oosper$ia ?actor localisedin &X==.7

CTransmitted to male

A5" i d l i l # &


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A5" 4 microdeletions long arm #r & -A5"a A5"b A5"c1

)vein blood collection))

• Deletion o0 t6e entire A5"a region leads to S#% Sertoli)#ell)%nly)Syndrome and to t6e impossibility to collect mature sperm cells 0romt6e testicular tissue

• #omplete deletion A5"b and A5"bc 4 stopping t6e maturity processo0 spermatogonia leads to a3oospermia. T6e same as in t6e case o0

complete deletion A5"a (#S( assisted reproduction tec6niXue is notrecommended. T6ey can be counseled by t6e specialist doctorrecommending alternatives -0or eHample sperm donors1.

• Deletion o0 A5"c region -b7/b;1 is associated 8it6 clinical and6istological p6enotypes and in general 8ill be compatible 8it6

residual spermatogenesis. Deletion A5"c can be encountered in men8it6 a3oospermia or severe oligoa3oopermia and in rare cases t6eycan be transmitted to male descendants. Also patients 8it6 *?cdeletions can &enec fro$ IC8I$ t6eir male c6ildren 8ill presentA5"c deletions.


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#ryptorc6idism

• *ects (% of new &orns and (#% of

pre$ature new &orns• F unilateral ) 7 bilateral

• F inguinal canal 4 7 abdominal

• Etiology) un9no8n• Testicule 46ypotrop6y

• ,(*, R(S 4 in0ertility and testicular cancer


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'aricocele

• (ncidental )=)7

• Dilation pampini0orm pleHus veins

• (n0ertility and stopping testicular gro8t6

– A?ected Spermatogenesis$

– %Hidative stress apoptosis

– Acro3omial Ka8s


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• %ld aging is associated 8it6 t6e rise o0 , "S,and S,Q* and lo8ering o0 testosteroneconcentration

• 'olume motility and morp6ology 8ill modi0y intime) t6ere are no relevant studies 8it6 regardsto concentration

Jorld+s oldest $anK*ntonio 4odde ,1LL –

##3 11ani;is recipe for loneityKust loe your &rother and drin7a oodlass of wine eery day!O

, l ' l d T t t


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,ormonal 'alues and Treatment

• ,yperPR on in0ertile man Qromocriptineisuride -7.)


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"ertility a0ter neoplasm treatment

A0ter radiot6erapy 4 = year-normospermia1

4 =


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#linical Use

• #6oosing t6e rig6t assistedreproduction met6od

• A3oospermia ))) donor

• %ligoAstenoTerato3oospermia ))) ('" cu(#S(• Lormospermia )))(nsemination -(U(1

• !AR positive -over ;1)))(#S(

• ,alosperm positive -SD" over 1)))(#S( or

('"

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