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“Adisease affecting the physical, mental and psychological well -being of the individual”. Recent statistics from WHOquotethat affects 15 % of couplesworldwide, while male factorinfertility has been acknowledged widelyto contribute to 40 – 50% ofthe infertile couples . Clinicalevaluation of

Evaluation ofthe male partner should begin at the same time as in the female partner,generally when pregnancyfails to occurafter 1 yearof reasonablyregular unprotected intercourse . Earlierevaluation is indicated for menwith any obvious infertility risk factor, those whose partner is age 35 or older Dr. Manisha Choudhary Prof.& Head Dept. of & Surgery

AIMOFEVALUATION OFTHE INFERTILE MALE PREREQUISITES FOR HISTORY TAKING Thisprimarily targets the assessment of spermatogenic and endocrine function . � Consultation room should offer total privacy, calm atmosphere and • Toidentify the probable cause and treat it for achieving spontaneous pregnancy, comfortable setting for the couple. ifpossible . � The female partner is encouraged to be present along with the male • Torefer patients with irremediable causes for higher reproductive technologies . partner during history taking is preferable, unless not desired. • Todiagnose and offer concurrent genetic counseling in specific circumstances . � It is the clinician's duty to convey adequate allotment of time to the • To diagnose testicularmalignancies and pituitary lesionswhich may be couple for discussion. Questions are encouraged from both the partners for associatedwith infertility as the leading complaint . This later may become a cause free discussion and guidance. forsexual dysfunction

HISTORY Age of the Male Partner Though the age of the female influences the outcome of treatment to a greater Symptoms of androgen deficiency may include extent, the age of male partner especially after 40 years, has a significant impact � decreasedlibido, too. The systematic review by johnson et al. included 90 studies on the association � withor without between age and male infertility and concluded that all except � reducedstrength, energy, or stamina concentrationwere consistently associated with small age – dependent declines � irritabilityand perceptions of a lowerquality of life ( ie parameters decrease as age increases ). � sleepdisturbance, � depressedmood, and lethargy � Increases paternal age has been associated with increase in numerical and � changesin cognitive function . structural chromosomal abnormalities , with increased DNA fragmentation and higher frequency of point mutations . Symptoms may be accompanied by physical changes, including � Advanced paternal age has been asociated with an increased incidence in new � osteopenia or osteoporosis, autosomal dominanat mutations ( achondroplasia and alpert , waardenburg , � decreased muscle mass, crouzon, pfeiffer and marfans syndromes. ) � increased visceral adipose tissue, � In older fathers mutations in X linked diseases also may be more common . Ex: � testicular atrophy, hemophilia A, duchenne muscular dystrophy . � gynecomastia. � There is also potential impact on the off spring . Data indicates that advanced age increases denovo intra and inter genetic germline mutations , sperm aneuplodiesand genetically – mediated conditions ( chondrodysplasia , schizophrenia , autism ) in the off springs. � advanced paternal age may be associated with a small increase in the risk of spontaneous abortion

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Risk factor Methodologyconclusion age Older men has slightly lower Occupational and Environmental History fertility � Specifically, occupations involving direct handling of chemicals, pesticides and Obesity Obese menhas moderately radiation would certainly impact semen parameters and lead to infertility. reduced fertility � Similarly, any history of exposure to high heat, disturbed sleep and nutrition, increased stress would also influence semen quality. Life style � Exposure to volatile compounds including anesthetic agents can result in diet Poor diet results in reduced temporary suppression of gonadotropin secretion and increase in prolactin fertility levels. They have a major impact on sperm production. caffeine Not a riskfactor � In theory, environmental sources of heat, including tight-fitting underclothing, hot baths and spas, and occupations that require long hours of sitting (long- Anabolic steroids use Anabolic steroid useis distance driving) might decrease fertility, but none has ever been associated with reduced substantiated in clinical studies. fertility Cell phones Not a riskfactor stress Associated with reduced sperm progressive motility , Di 2 ethyl hexyl phthalate Associated with lower sperm (DEHP) Quality ( sperm concentration, sperm motility , sperm DNA damage )

Risk factor Methodology conclusion Pesticides Association betweenexposure Substance Abuse— a Truly Reversible Cause to certain pesticides ( � This history is often not considered or ignored by both the patients and physicians. pyrethroids, Cigarette smoking, either active/passive, is a well-known cause for deranged seminal organophosphates and parameters— a truly reversible cause for male infertility. abamectin) and poor semen � Similarly, excessive alcohol intake is known to impair sexual function. parameters. � Hard drugs like cannabis/marijuana and cocaine hamper the sexual desire and decrease the performance lead Lead levels are higher in infertile men thanfertile men Direct affect by interfering Alcohol Drinkers have slightly lower with the ability of semen volume and slightly spermatozoanto undergo poorer sperm morphology, acrosomalreaction but drinking does not Zinc Zinc levels are lower in adversely affect sperm infertile men than in fertile concentration or sperm men motilit Cadmium Cadmiumlevels are higher in smoking Slightly reduced fertility infertile men than in fertile men

SexualHistory — theBasic Step in Reproduction

� Though it is a very sensitive subject, a detailed sexual history � (erectile dysfunction) and infertility can also be due to (frequency/week,erection, intravaginal penetration and )is hyperprolactinemia. This again is another medically treatable cause for male mandatoryto ensureproper coital practice which isthe basic step of infertility. reproduction. � Retrograde ejaculation should be suspected, if there is no history of antegrade � Thiscan also reveal correctable cause of infertility like the use of lubricants ejaculate or history of passing cloudy urine postcoitally . duringthe act . Spermatozoa areknown to surviveonly in the natural vaginalsecretions and notin any other artificial solutions/liquid . These � Some medical drugs administered for other diseases can also impair sexual lubricants are either spermiostatic orspermicidal . Pregnancies have dysfunction . happenedby simply stopping the use of lubricants . � A detailed history and guidance by the andrologist would go a long way in alleviating � Non-consummation of marriage, infrequent sexual intercourse and this problem. impropertechniques are potentially treatable causes for male infertility .

� Manya times,couples report to us for only infertility, masking their sexual dysfunction.

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Drug history : FertilityHistory finasteride, which has been associated with decreased semen volume and appears to � Durationof marriage, be dose dependent. Systemic dermatologic medications: finasteride 5 mg/day is associated with reduced semen volume, but 1 mg/day data are inconclusive. � pastconception ; ifany, either with thepresent partner or previous Gastroesophagealreflux disease (GERD) or acid peptic disease, which is a common partner condition often treated by the H2 receptor antagonists. These drugs are known to impair sexual function and sperm production. � anyprevious treatment for infertility are allcrucial to ascertain the currentfertility potential of the male partner .

: Medical drugs impairing sperm parameters.16

: Medical drugs impairing sexual dysfunction.16 Effect of treatment Drugs or group of drugs Effect of treatment Drugs or group of drugs Suppression of spermatogenesis: • Antibiotics: Gentamicin, Loss of libido and erectile H2 receptor antagonists— Reversible neomycin, penicillin G, dysfunction due to cimetidine, ranitidine. cephalothin, ampicillin, spiramycin increased prolactin • Antibacterials: Nitrofurantoin, concentration sulfasalazine, cotrimoxazole Loss of libido and erectile drugs: • Testosterone and its esters: dysfunction (due to Phenothiazine Injected testosterone increased prolactin Arrest of spermatogenesis and Antimitotics/Antimetabolites : concentration), ejaculatory : Irreversible Cyclophosphamide, colchicine dysfunction (retrograde ejaculation) Erectile dysfunction Antihypertensives: Impairment of sperm motility: • Antibiotics: Tetracyclines , Clonidine, , Reversible neomycin, erythromycin, hydralazine, methyl- dopa , lincomycin, tylosin , dicloxacillin prazosin, beta blockers • Antibacterials: Sulphasalazine , Erectile dysfunction, Anticonvulsants: cotrimoxazole, quinolones ejaculatory dysfunction Spironolactone, finasteride , • Antiepileptics: Phenytoin (retrograde ejaculation) ketoconazole • Antimalarial: Quinine Fertilization failure Calcium channel blockers and antihypertensive: Nifedipine

chemoradiations. � Anothercommon history is treatment for malignancies with chemoradiations . � The recovery of sperm in the ejaculate may take months to years when the radiation dose exceeds 1 Gy ; � Therecovery of sperm productionfollowing radiotherapy and/or chemotherapy depends � a dose exceeding 10 Gy will often result in permanent azoospermia . onthe survival of spermatogonial stem cellsin the testis . � A radiation dose exceeding 7.5 Gy has been associated with a significantly reduce probability of fertility in a large cohort study � Radiotherapyand/or chemotherapy treatments that affect differentiating spermatogenic cells(e .g ., spermatocytes,spermatids) but that do not kill stem cellsin the testis will Fractionated radiation (given over the course of weeks) may have a more cause a temporarydecline in sperm production followed by a gradualrecovery of detrimental effect on spermatogenesis than a single radiation dose. spermatogenesisafter cessation of therapy . Clinicians should inform patients undergoing chemotherapy and/or radiation � However,some radiation and/or chemotherapy regimens can damage spermatogonial therapy to avoid pregnancy for a period of at least 12 months ( preferably 24 stem cells,resulting in delayed orincomplete recoveryof spermatogenesis or even months ) after completion of treatment. permanentazoospermia . Clinicians should encourage men to bank sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility in men.

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HIGH RISK INTERMEDIATE LOWRISK UNKNOWN RISK Medicalhistory : RISK AlkylatingAgents Platinum analogues Plant derivatives Biologicalagents Cisplatin Etoposide Monoclonal antibodies � Infertilemen also have a higherrate of medical comorbidities (e .g ., , Cyclophosphamide Carboplatin Vincaalkaloids Tyrosine kinase hyperlipidemia,obesity, ) that can contribute to impaired fecundability Ifosfamide Oxaliplatin inhibitors Busulfan Immunomodulating � Klinefeltersyndrome isassociated withtestosterone deficiency,abnormal muscle Chlorambucil agents mass and pubertal development, decreased facial/body hair, gynecomastia, Procarbazine Anthracyclines Antibioticagents Mtorinhibitors autoimmunedisorders, osteoporosis, and impaired spermatogenesis . Mechlorethamine Doxorubicin ActinomycinD Histones deacetylase Mitoxantrone inhibitors � Cystic Fibrosis (CF) is also associated with male infertility (i.e. , obstructive Taxanes bleomycin Monoclonal antibodies azoospermia) aswell as pulmonary problems, pancreatic deficiency, and dental Paclitaxel carries. It is associated with CBAVD Docetaxel Cabazitaxel � Cryptorchidism isassociated with infertility as well as a higherrisk of testis cancer and Combination Combination Antimetabolites canoccur with other genitourinary abnormalities such as hypospadias therapy therapy Methotrexate MOPP ABVD Mercaptopurine CHOP BEP 5FU FUDR

Surgical History • Past childhood history of inguinal surgeries like orchidopexy , inguinal hernia Kartagenersyndrome ( primaryciliary dyskinesia ) : isa geneticdisease that adversly affects repair, correction of hypospadiasis and epispadiasis are to be enquired. ciliastructure and function and generallypresents as recurrent sinus and pulmonary Hernia repair surgery can lead to inadvertent damage to . infectionsbronchiectasis , situsinversus and male infertility due to oligoasthenospermia Vas is extremely vulnerable in childhood operations such as herniotomy .

Youngsyndrome : itis another genetic disease in which inspissated secretions in vas and • Adult history of vasectomy, varicocelectomy , hydrocelectomy , torsion correction, epididymisresult in obstructive azoospermia . bladder neck surgeries or corrections is to be enquired.

Chronicillness : suchas chronic renal insufficiency , chirrosisor malnutrition , canresult in • Any history of surgery in para -aortic region including retroperitoneal node primarygonadal failure . dissection and lumbar sympathectomy may lead to sexual dysfunction.

Infertilityis common in sickle cell disease , probablydue to testicular ischemia . Clinicians should inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of . RPLND is a cornerstone in the management of some patients with testis cancer. It can be performed either before the delivery of chemotherapy (pre-chemo RPLND) or after chemotherapy (post-chemo RPLND). Given the distribution of the nodes involved in drainage of the testes, the lumbar sympathetic fibers responsible for ejaculation (T10-L2) are in close proximity to the node dissection templates. In the hands of an experienced testis cancer surgeon, nerve sparing RPLND should only rarely result in permanent nerve damage and long-term failure to ejaculate (RE or FOE .However, in the post-chemo RPLND patient the likelihood of this is higher.

As with any neural trauma, maximum recovery can take 12 to 24 months and thus, patients who have had nerve sparing RPLND should be told that return of antegrade FamilyHistory ejaculation may take a protracted period of time. If aspermia remains 24 months after Itis crucial to ascertain any history of infertility in the family members especially male siblings. Conditionslike CBAVD, cryptorchidism, and metabolic/endocrine disorders RPLND, then the patient should be informed that this is likely to be permanent. canrun in families .

Developmental/Childhood History � The timing and extent of secondary sexual development may alert one to the possibility of an endocrinopathy � History of mumps, rubella, viral illness, tuberculosis which may cause epididymal obstruction, leprosy, and human immunodeficiency virus (HIV). � testicular injury, and torsion,any disturbances during puberty, sexual infantilism and testicular maldescent are to be enquired. � Local trauma causes testicular edema and varying degree of ischemia.

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PART II: CLINICAL EVALUATION OF INFERTILE MALE EVIDENCEOF ANDROGENIZATION NUTRITIONALSTATUS AND BODY MASS INDEX • Theglobal pandemic obesity also has its toll on the fertility of the male as well . � Thisdirectly reflects the role of testosterone and in turn the endocrine axis . • Obesityin men causes decreased sperm concentration . • Associated medicalillness like diabetes mellitus,hypertension can also � A hypoandrogenizedmale exhibits signs of reduced or absence of facial and body hair, confoundthe problem causing sexual dysfunction . femalehabitus and gynecomastia . Theseindicate reduction in testosterone production or malfunctioning of Leydig cells. He needs evaluation for hypogonadotropic hypogonadism. This, if identified, is a potentiallycurable cause of male infertility with successfulmedical management .

� Eunuchoidalmale with gynecomastia and soft small testis may prove to be a caseof Klinefelter'ssyndrome .

CARDIOVASCULARSYSTEM ANDLUNGS THYROIDDISORDER Ratheruncommon in themale unlike women butit can beassociated with � Blood pressure and routine heartmonitoring can be done to identify any hyperprolactinemiawhich, results in erectile dysfunction syndromeand in turn associatedabnormal findings . infertility.

� Chestauscultation will pick up pulmonary problems (especially bronchiectasis and tuberculosis)which are associated with azoospermia ;

� Chestauscultation willalso pick up dextrocardia orsitus inversus which is BREASTEXAMINATION associatedwith bronchiectasis (immotile cilia syndrome) . Besidesgynecomastia (as a partof hypogonadism — i.e. Klinefelter'ssyndrome), rarelyone can demonstrate galactorrhea as an evidence of increased prolactin andany palpable tumors of the male breast can be revealed in the routine examination. Thiswill lead to early diagnosis and treatment of any pathology detected.

ABDOMINAL EXAMINATION UrologicEvaluation : � Liver enlargement will indicate the chronic hepatitis, cirrhosis or tumors. Ifnot performed earlier,grossly abnormal semen parametersare indication fora � Any visible scar in the lower abdomen/inguinal region will be a tell-tale thoroughphysical examination by a urologistor other specialist in male reproduction ; evidence of previous varicocelectomy , hernia surgery or correction of somemen also may require further urologic evaluation undescended testes. Thisis best done both in the supine and standing position .

� Examination of any scars from prior surgical procedures that may involve the pelvis or impact the urogenital system Phallus: � Meatallocation ashypospadias/ epispadias may make semen deposition in the vaginachallenging � Penileplaque as Peyronie’s disease may make vaginal intercourse difficult � Penilelesions/ulcers/discharge may be a signof sexually transmitted infection . � Penilepathologies like displaced urinary meatus, meatal strictures, and are indicativeof faulty or no semen deposition into the female genital system . � Simplecorrection will ameliorate the sexual dysfunction and infertility .

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Scrotum/Testes. Examination

� Forprior scars suggesting prior scrotal surgery/trauma Volume of Testis • Normal volumes (8 cc to 15 cc) - indicates the presence of significant amount � Locationas scrotal position of the testes is important for normal function of the seminiferous tubules. • Low volume (less than 8 cc)— soft, shrunken testis, suggestive of � Size/consistency/contoursas a majorityof the testis is devoted to spermatogenesis . hypogonadotropichypogonadism or seminiferous tubular failure • High volume (more than 20 cc)— Hydrocele, (Tenderness +), � Theexam may also reveal masses consistent with a testicularcancer tumors, filariasis .

� In normalmen , thetestes are firm andmeasures 15 -25 ml in volume . Testicular Sensation � Softtestes suggests testicular failure • Mildly painful sensation to touch— normal male • Exquisite tenderness— torsion, infection � Well-distended scrotum withrugae is indicative of descended testes into the normal • Absent sensation— seminoma testes, leprosy. positionin the scrotal sac .

� Sizeof the testis is assessed by Prader orchidometer . This can also be assessed by ultrasound,bedside examination or with a VernierCaliper .

Verniercaliper. Praderorchidometer

Bedside assessment of testicular volume.

Epididymis : Spermatic cord / Varicocele assessment � It is felt on the posterolateral aspects of testes— distended and obviously enlarged in � examined in erect and supine , with and with out valsalva . case of the obstructive azoospermia � Best felt in the erect standing position like a bag of worm feeling at the neck of � EpididymidesShape/consistency as normal development should be identified to scrotum. determine atresia that could be identified by the presence of a CFTR mutation. � Palpation of spermatic cord may some times reveal a varicocele , which can be � Induration/dilation could suggest obstruction. graded according to severity ( grade 1-3 ) . Venous bruit and reversal flow in � Epididymalcysts or spermatoceles may also lead to obstruction. pampiniformplexus during valsalva maneuver is detected with Doppler . ultrasound. � Cough impulse elicits an inguinal hernia, which may be missed in the lying position Vas Deferens � It is felt as a cord like structure in the spermatic cord at the root of the scrotum, between thumb and index finger. It snaps when rolled between the fingers. Absent in congenital bilateral absence of vas deferens (CBAVD). � Vas Deferens Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a CFTR mutation or aberrant Wolffian duct embryogenesis � The presence/location of any vasectomy defect or granuloma should also be assessed

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INVESTIGATIONS FOR MALE INFERTILITY RECTAL EXAMINATION � defines the size and symmetry of the and may reveal the presence of T midline cysts , absence of seminal vesicle the initial evaluation for male factor infertility should include at least one properly � by rectal examination adds to the suspicion of vasal aplasia. performed semen analysis. If abnormal, another semen analysis should be obtained after � Rarely, ejaculatory ductal obstruction can be noted. at least 4 weeks.

� It is the only test available for assessing man's fertility, despite its limitations and fluctuations. � The andrologist correlates the previous and present analyses in conjunction with the clinical and endocrine evaluation and can come to a diagnosis and decide on further management options. � Semen analysis is performed as per WHO 2010 criteria in current day practice. � However, in most men, the exact cause of the semen abnormalities and infertility remains unknown and could be genetic.

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