evaluation of the subfertile man. infertility affects 15 % of couples, and 50 % of male infertility...

Evaluation of the Evaluation of the Subfertile Man Subfertile Man

Infertility affects Infertility affects 15 % of couples15 % of couples, ,

and and 50 % of male 50 % of male

infertilityinfertility is potentially is potentially correctable. correctable.

Evaluation of the Evaluation of the subfertile man requires: subfertile man requires:

1.1. A complete medical A complete medical historyhistory, ,

2.2. Physical examinationPhysical examination, , and and

3.3. LaboratoryLaboratory studies. studies.

The main purpose of The main purpose of the male evaluation is the male evaluation is to to

identify and identify and treat correctable treat correctable

causescauses of of subfertility. subfertility.

In addition, In addition, many men seek an many men seek an explanationexplanation

for their for their condition, which can be condition, which can be discovered during their discovered during their

evaluation. evaluation.

The male fertility The male fertility evaluation can evaluation can

uncover significant uncover significant medical and genetic medical and genetic

pathologypathology that could that could affect the patient's health affect the patient's health

or that of his or that of his offspring. offspring.

Although pregnancies can Although pregnancies can be achieved without be achieved without any evaluation other than a any evaluation other than a semen analysissemen analysis, ,

This test This test alone is insufficientalone is insufficient to adequately evaluate to adequately evaluate the male patient. the male patient.

Treatment of correctable Treatment of correctable male-factor pathology is : male-factor pathology is :

1.1. Cost effectiveCost effective, , 2.2. Does not increase the risk of Does not increase the risk of

multiple birthsmultiple births, and , and 3.3. Can spare the woman Can spare the woman

invasive procedures and invasive procedures and potential complicationspotential complications associated with associated with assisted reproductive assisted reproductive technologies. technologies.

Appropriate evaluation Appropriate evaluation and treatmentand treatment of the subfertile of the subfertile man are critical man are critical in delivering suitable in delivering suitable

care to care to the infertile couple.the infertile couple.

IInfertility,nfertility, defined as the inability defined as the inability to conceive after to conceive after

one year of one year of unprotected intercourseunprotected intercourse, , affects affects

15 % of 15 % of couplescouples. .

Male subfertility Male subfertility is one of the is one of the

most rapidly most rapidly growing fields in medicinegrowing fields in medicine, ,

with with dramatic advances in dramatic advances in diagnosis and treatment. diagnosis and treatment.

Although infertility Although infertility (or subfertility) (or subfertility)

is often is often attributed attributed to female causes, to female causes, fertility is a two-fertility is a two-

person phenomenonperson phenomenon. .

Successful conception depends Successful conception depends on many complicated events, on many complicated events,

including including : :1.1. SSatisfactory sexual and atisfactory sexual and

ejaculatory function, ejaculatory function, 2.2. AAppropriate timing, and a ppropriate timing, and a 3.3. CComplex set of interactions omplex set of interactions

between the male and the female between the male and the female reproductive tracts. reproductive tracts.

Male and female factorsMale and female factors coexist in about coexist in about one thirdone third of of cases, while cases, while one thirdone third of cases of cases are secondary to are secondary to male factors male factors onlyonly. .

Therefore, evaluation of Therefore, evaluation of both partners is criticalboth partners is critical, , and the woman's gynecologic and the woman's gynecologic evaluation should proceed evaluation should proceed simultaneously with the man's. simultaneously with the man's.

Causes of Male SubfertilityCauses of Male Subfertility

The most common identifiable The most common identifiable cause of male subfertility is acause of male subfertility is a

varicocelevaricocele, , a condition of a condition of

palpably distended palpably distended veins of the pampiniform plexus veins of the pampiniform plexus

of the spermatic cordof the spermatic cord..

varicocelevaricocele

Doppler of testis(valsalva)Doppler of testis(valsalva)

varicocelevaricocele

The term The term "subclinical "subclinical

varicocele"varicocele" refers to a refers to a lesion too small lesion too small

to be detected by to be detected by physical examination.physical examination.

Causes of Male Causes of Male SubfertilitySubfertility

The concept of a The concept of a subclinical varicocelesubclinical varicocele arose arose from the observation in early from the observation in early reports that the detrimental effect reports that the detrimental effect of small varicoceles equaled of small varicoceles equaled that of larger varicoceles. that of larger varicoceles.

However, However, more recent studiesmore recent studies suggest that larger varicoceles suggest that larger varicoceles have a have a greater impactgreater impact on fertility. on fertility.


As a result, As a result, most subspecialistsmost subspecialists

who deal with who deal with male subfertility male subfertility do not regard do not regard

subclinical varicocelessubclinical varicoceles as clinically as clinically

significant. significant.

Another common Another common correctable cause of correctable cause of

male subfertility is male subfertility is obstructionobstruction, , which may occur which may occur

after a vasectomyafter a vasectomy..


Less common correctable Less common correctable causes include :causes include :

1.1.EEjaculatory dysfunctionjaculatory dysfunction, ,

2.2.IInfectionnfection, ,

3.3.MMedicationsedications, and , and

4.4.HHormonal deficiencyormonal deficiency


When the sum of these When the sum of these correctable causes correctable causes is calculated, is calculated, it becomes apparent that it becomes apparent that more than one half more than one half

of cases of male of cases of male subfertility are subfertility are potentially correctablepotentially correctable. .


The specific corrective The specific corrective treatments such as treatments such as vasectomy reversal and vasectomy reversal and

varicocele ligationvaricocele ligation are more cost effective are more cost effective

than empiric treatment with than empiric treatment with assisted reproductive assisted reproductive

technologies.technologies.


Furthermore, correction of Furthermore, correction of underlying male factors canunderlying male factors can::

1.1. Allow for Allow for natural conceptionnatural conception, ,

2.2. Does not carry an increased risk Does not carry an increased risk of of multiple birthsmultiple births, and , and

3.3. Spares the woman Spares the woman invasive invasive proceduresprocedures and the potential and the potential complicationscomplications of these therapies. of these therapies.


Recent advances, particularly Recent advances, particularly in in molecular geneticsmolecular genetics, have , have improved our understanding of improved our understanding of some forms of male subfertility. some forms of male subfertility.

A significant proportion of A significant proportion of male subfertility currently is male subfertility currently is unexplainedunexplained. .


About About 13 %13 % of men with of men with nonobstructive azoospermianonobstructive azoospermia

(i.e., no sperm in the (i.e., no sperm in the semen because of low or absent semen because of low or absent

sperm production)sperm production) have been shown to have have been shown to have

Y-Y-chromosome microdeletionschromosome microdeletions, ,


About About 70 %70 % of men with of men with congenitalcongenital bilateral bilateral absence of the vas absence of the vas

deferensdeferens are carriers of are carriers of cystic fibrosis cystic fibrosis

mutations.mutations.


((ICSIICSI))The most significant advance in the The most significant advance in the

treatment of severe male infertility is treatment of severe male infertility is in vitro in vitro fertilization with intracytoplasmic fertilization with intracytoplasmic sperm injection (ICSI). sperm injection (ICSI).

With this technique, a With this technique, a single spermsingle sperm is injected directly into the oocyte. is injected directly into the oocyte.

Only one viable sperm per eggOnly one viable sperm per egg is required for ICSI, and a is required for ICSI, and a precise diagnosis is not required to precise diagnosis is not required to achieve conception. achieve conception.

((ICSIICSI))When using sperm from men When using sperm from men

with known or presumed with known or presumed genetic infertilitygenetic infertility, it must be , it must be assumed that assumed that any male offspring any male offspring also will be infertilealso will be infertile. .

Y-chromosome microdeletionsY-chromosome microdeletions from the father are inherited from the father are inherited by the sons when ICSI is by the sons when ICSI is used. used.

There There does not appeardoes not appear to be an to be an increased increased

risk risk of of major major malformationsmalformations in in children born from ICSI children born from ICSI

compared with compared with the general population. the general population.

Counseling Counseling about these potential about these potential genetic issuesgenetic issues is a critical part is a critical part of the male fertility of the male fertility

evaluation. evaluation.

EvaluationEvaluation

The main goals of evaluating The main goals of evaluating the subfertile man are to the subfertile man are to identify correctable identify correctable

causes of infertilitycauses of infertility and to help him and to help him and his partner to conceive and his partner to conceive

by the by the most most natural, least invasivenatural, least invasive means means

possible. possible.

In addition, In addition, the evaluation the evaluation

may uncover may uncover significant underlying significant underlying

medical or medical or genetic pathologygenetic pathology. .


Subfertility may be Subfertility may be related to an underlying related to an underlying malignancymalignancy, ,

such as a such as a testicular or pituitary testicular or pituitary

tumortumor. .


If the only evaluation If the only evaluation is a is a semen analysissemen analysis, , underlying pathology underlying pathology

can be can be missedmissed. .


History and Physical History and Physical ExaminationExamination

A careful A careful historyhistory can : can :

1.1. Offer clues to the Offer clues to the underlying causeunderlying cause of of infertility and infertility and

2.2. Provide an Provide an assessment ofassessment of the man's the man's fertility potentialfertility potential. .

These data should be documented:These data should be documented: 1.1. TThe duration of the infertility, he duration of the infertility,

2.2. PPrevious evaluation and treatment, revious evaluation and treatment,

3.3. PPrevious pregnancies revious pregnancies (for either partner), (for either partner), and and

4.4. AAny difficulty establishing these ny difficulty establishing these pregnanciespregnancies


1.1. IInadequate frequency or nadequate frequency or timing of intercourse, timing of intercourse,

2.2. SSexual dysfunction, and exual dysfunction, and

3.3. LLubricant use ubricant use

can impede pregnancy.can impede pregnancy.


Evidence level BEvidence level B

The optimal frequency The optimal frequency of intercourse is of intercourse is every day or every other every day or every other dayday around the expected around the expected time of ovulation.time of ovulation.


Evidence level BEvidence level B

Because nearly Because nearly all commercially all commercially

available lubricantsavailable lubricants are are spermatotoxicspermatotoxic, ,

their use is their use is discouraged.discouraged.


Most menMost men of reproductive age of reproductive age do not have a significant medical do not have a significant medical historyhistory, but some specific , but some specific risk factors may be identified. risk factors may be identified.

For example, For example, diabetes mellitusdiabetes mellitus can cause can cause erectile and ejaculatory erectile and ejaculatory dysfunction.dysfunction.


Previous disorders of the testes, Previous disorders of the testes, such as : such as :

1.1. Cryptorchidism or Cryptorchidism or

2.2. Spermatic cord torsion, or Spermatic cord torsion, or

3.3. A history of inguinal, scrotal, or A history of inguinal, scrotal, or retroperitoneal surgery,retroperitoneal surgery,

are associated with subfertility. are associated with subfertility.


Use of: Use of: 1.1. PrescriptionPrescription or or2.2. DrugsDrugs and and 3.3. Exposure to Exposure to environmental environmental

toxinstoxins also can impair fertility also can impair fertility


AnosmiaAnosmia may suggest an underlying may suggest an underlying

hypothalamic hypothalamic etiologyetiology (such as (such as

Kallmann's syndrome) or a Kallmann's syndrome) or a pituitary etiology, pituitary etiology,


Frequent respiratory infectionsFrequent respiratory infections are a feature of : are a feature of :

1.1. Young's syndrome:Young's syndrome: (e.g., chronic sinusitis, bronchiectasis, (e.g., chronic sinusitis, bronchiectasis, obstructive azoospermia) and obstructive azoospermia) and

2.2. Kartagener's syndrome:Kartagener's syndrome: (e.g., primary ciliary (e.g., primary ciliary dyskinesia/immotile cilia, chronic dyskinesia/immotile cilia, chronic sinusitis, bronchiectasis, situs sinusitis, bronchiectasis, situs inversus). inversus).


1.1. HHeadaches, eadaches,

2.2. VVisual field disturbances, or isual field disturbances, or

3.3. GGalactorrhea alactorrhea

should prompt an should prompt an investigation for a tumor of investigation for a tumor of the central nervous systemthe central nervous system..


Clues to the Diagnosis of Male Clues to the Diagnosis of Male InfertilityInfertility

Clinical clue Possible Clinical clue Possible diagnosisdiagnosis

A A thorough examinationthorough examination can identify underlying can identify underlying causes of subfertility. causes of subfertility.

Abnormal distribution of hair Abnormal distribution of hair and fat and fat can suggest an can suggest an underlying endocrinopathy, underlying endocrinopathy, such as such as hypogonadotropic hypogonadotropic hypogonadism. hypogonadism.


The The position and size position and size of the urethral meatus of the urethral meatus should be noted because should be noted because

severe hypospadiassevere hypospadias can impair can impair sperm deposition sperm deposition

near the cervix. near the cervix.


Normal testes are Normal testes are 20 cm320 cm3 or or more or at least more or at least 4 cm4 cm in in greatest dimension. greatest dimension.

Those smaller than Those smaller than 20 cm320 cm3 are are suggestive of decreased sperm suggestive of decreased sperm production and may occur in production and may occur in hypogonadal menhypogonadal men as well. as well.


The presence of the The presence of the vasa deferentiavasa deferentia and and epididymidesepididymides

as well as as well as any any induration induration or or engorgementengorgement

suggestive of suggestive of obstructionobstruction should be noted. should be noted.


VaricocelesVaricoceles are found most are found most commonly on the commonly on the left sideleft side, , but up to but up to 20 %20 % may be may be bilateralbilateral. .

Diagnosis should be made Diagnosis should be made in a in a warm roomwarm room by palpation by palpation of the spermatic cord with of the spermatic cord with the patient in the the patient in the standing standing positionposition. .


VaricocelesVaricoceles are graded: are graded: 1+1+ : : (palpable with Valsalva's maneuver only),(palpable with Valsalva's maneuver only), 2+2+ : : (palpable), and(palpable), and 3+3+ : : (visible through the (visible through the scrotal skin). scrotal skin).


1.1. An isolated An isolated right-sided varicoceleright-sided varicocele or or

2.2. A lesion on either side that A lesion on either side that does not disappear when the does not disappear when the patient assumes the supine patient assumes the supine positionposition: :

Should prompt imaging of the Should prompt imaging of the retroperitoneum to evaluate forretroperitoneum to evaluate for

inferior vena caval or inferior vena caval or renal vein obstructionrenal vein obstruction..


Digital rectal examinationDigital rectal examination is performed to examine: is performed to examine:

1.1. The The prostateprostate gland, gland,

2.2. Seminal vesiclesSeminal vesicles, and , and

3.3. Possible cystsPossible cysts that can cause that can cause ejaculatory duct obstruction. ejaculatory duct obstruction.


Laboratory EvaluationLaboratory Evaluation

The The semen analysissemen analysis is the is the foundation of the laboratory foundation of the laboratory evaluation. evaluation.

At least At least two samplestwo samples, , preferably taken at preferably taken at least two or three weeksleast two or three weeks apartapart, , should be analyzed should be analyzed after after two to three two to three days of sexual abstinencedays of sexual abstinence. .

The sample should be collected The sample should be collected by by masturbationmasturbation in a clean in a clean container and analyzed container and analyzed within within one hourone hour of collection. of collection.

The sample can be The sample can be collected at collected at homehome if it is kept at body if it is kept at body temperature and brought to the temperature and brought to the laboratory in sufficient time. laboratory in sufficient time.


In addition to the In addition to the numbernumber of sperm per mL of sperm per mL (concentration), (concentration), other parameters, such as other parameters, such as motilitymotility, are important in , are important in assessing a man's fertility assessing a man's fertility potential. potential.


Reference Values of Semen Reference Values of Semen VariablesVariables

LeukocytospermiaLeukocytospermia, which is , which is defined as defined as more than 1 million more than 1 million white blood cells per mL of white blood cells per mL of semensemen, requires specific testing. , requires specific testing.

It is It is not possiblenot possible to definitively to definitively identify these cells by identify these cells by microscopic appearance alone. microscopic appearance alone.


In the presence of significant In the presence of significant leukocytospermialeukocytospermia, empiric antibiotic , empiric antibiotic therapy is reasonable. therapy is reasonable.

DoxycyclineDoxycycline (Vibramycin), in a (Vibramycin), in a dosage of 100 mg twice a day for two dosage of 100 mg twice a day for two weeks, is an effective regimen. weeks, is an effective regimen.

A A repeat semen analysisrepeat semen analysis should be should be performed at the completion of performed at the completion of therapy. therapy.


The semen analysis The semen analysis does not test fertilitydoes not test fertility, , but rather but rather fertility potentialfertility potential. .

The chance of initiating a The chance of initiating a pregnancy correlates with pregnancy correlates with the total number of the total number of moving spermmoving sperm. .


Pregnancies can be established with Pregnancies can be established with subnormal subnormal parametersparameters, illustrating the , illustrating the

importance of the importance of the female partner's fertility female partner's fertility

potentialpotential and the fact that an and the fact that an abnormal semen analysis cannot abnormal semen analysis cannot be equated with subfertility be equated with subfertility. .


The The morphology morphology is a is a measurement of the measurement of the percentage percentage of the normal-shaped sperm. of the normal-shaped sperm.

The The Kruger or strict morphology Kruger or strict morphology scorescore has been correlated with has been correlated with decreased success with in vitro decreased success with in vitro fertilization. fertilization.


The The significancesignificance of of morphologymorphology in estimating the chance for in estimating the chance for natural conceptionnatural conception is less clear. is less clear.

As with any other single semen As with any other single semen parameter, parameter, it cannot be usedit cannot be used in an absolute way to in an absolute way to predict fertility. predict fertility.


A semen analysis does not A semen analysis does not assess assess sperm functionsperm function. .

Specialized testing is available Specialized testing is available to evaluate this factor. to evaluate this factor.

Most tests attempt to examine Most tests attempt to examine some component of some component of sperm-sperm-oocyte interaction or fertilization.oocyte interaction or fertilization.


Hormone testingHormone testing for for all all subfertile men is subfertile men is not necessarynot necessary. .

When sperm concentration is When sperm concentration is less than 10 million per mLless than 10 million per mL, , measurement of the measurement of the serum testosterone and serum testosterone and follicle-stimulating hormonefollicle-stimulating hormone (FSH) levels is indicated. (FSH) levels is indicated.


The levels of The levels of serum testosterone serum testosterone

and FSHand FSH are adequate to are adequate to assess the assess the pituitary-pituitary-

testicular axistesticular axis in the majority of cases. in the majority of cases.


If the If the total testosterone level is normaltotal testosterone level is normal, , no further no further endocrine testing is needed. endocrine testing is needed.

If the If the total testosterone level is lowtotal testosterone level is low, , the the serum serum luteinizing hormone and luteinizing hormone and prolactinprolactin levels can levels can be checked to evaluate for be checked to evaluate for a a pituitary causepituitary cause..


When When testosterone is merely testosterone is merely borderline or only slightly lowborderline or only slightly low, ,

supplementation should be supplementation should be avoidedavoided unless the man is unless the man is significantly symptomaticsignificantly symptomatic (i.e., erectile dysfunction, (i.e., erectile dysfunction,

markedly decreased energy markedly decreased energy level, lack of libido).level, lack of libido).


Testosterone Testosterone supplementation will supplementation will actually actually lower lower the sperm concentrationthe sperm concentration in in such men because it can such men because it can cause cause pituitary suppression pituitary suppression of gonadotropins of gonadotropins. .


If the If the FSH level is elevatedFSH level is elevated, , it suggest end-organ it suggest end-organ

(testicular) failure(testicular) failure. . A A low levellow level may indicate an may indicate an underlying FSH deficiency, underlying FSH deficiency,

such as occurs with such as occurs with hypogonadotropic hypogonadotropic hypogonadismhypogonadism..


Evaluation of the Subfertile Evaluation of the Subfertile ManMan

More specialized testingMore specialized testing may be required based may be required based on the outcome of this initial on the outcome of this initial evaluation evaluation . .

These tests require These tests require referralreferral to a center with to a center with clinical and laboratory clinical and laboratory expertiseexpertise in the field of in the field of reproductive medicine. reproductive medicine.


For example, men with For example, men with low ejaculate volumelow ejaculate volume

(less than 1 mL) (less than 1 mL) should have a should have a post-post-

ejaculatory urine sampleejaculatory urine sample analysis to rule out analysis to rule out

retrograde ejaculationretrograde ejaculation..


Azoospermic men can undergo Azoospermic men can undergo testicular biopsytesticular biopsy to evaluate to evaluate the the

level of sperm productionlevel of sperm production and differentiate and differentiate between between

testicular failure and obstructiontesticular failure and obstruction (i.e., normal sperm (i.e., normal sperm

production) production)

AzoospermiaAzoospermia

AzoospermiaAzoospermia In patients with azoospermia: In patients with azoospermia: 1.1. Low semen volume Low semen volume

(less than 1 mL), and (less than 1 mL), and 2.2. A normal FSH level,A normal FSH level, Transrectal ultrasonographyTransrectal ultrasonography

is indicated to evaluate is indicated to evaluate for possible for possible ejaculatory duct obstructionejaculatory duct obstruction..

Genetic testing and counselingGenetic testing and counseling are indicated in specific instances. are indicated in specific instances.

In patients with In patients with azoospermia or severe azoospermia or severe

oligospermiaoligospermia, the , the karyotype karyotype should be determined because of should be determined because of

the the increased incidence of increased incidence of karyotypic abnormalitieskaryotypic abnormalities

in this population. in this population.


Men with Men with congenital absence congenital absence of the vas deferens, of the vas deferens, either unilateral either unilateral

or bilateralor bilateral, , may be may be carriers of cystic fibrosiscarriers of cystic fibrosis. .

These men should have These men should have abdominal ultrasonographyabdominal ultrasonography to check for to check for

renal agenesis.renal agenesis.


The outcome of the initial evaluation The outcome of the initial evaluation can help guide treatment. can help guide treatment.

If If correctable causes are foundcorrectable causes are found, , specific corrective treatment is offered. specific corrective treatment is offered.

If If no correctable problem existsno correctable problem exists, , the couple may wish to pursue the couple may wish to pursue treatment with treatment with assisted reproductive assisted reproductive technologies (ART)technologies (ART) such as intrauterine such as intrauterine insemination and (ICSI) . insemination and (ICSI) .


An An alternative alternative to to (ART)(ART)

is empiric treatment is empiric treatment with with clomiphene citrateclomiphene citrate , , although although few convincing datafew convincing data

show benefit. show benefit.


Some reproductive Some reproductive subspecialists advocate subspecialists advocate

abandoning abandoning the male evaluation the male evaluation, ,

with the with the exception of the exception of the semen semen

analysisanalysis. .

Whether this is an efficient approach Whether this is an efficient approach to conception, to conception,

is debatableis debatable, , But denying the man an evaluation, But denying the man an evaluation, including an opportunity including an opportunity to learn the cause of his problemto learn the cause of his problem

and the and the chance for specific corrective chance for specific corrective

therapy,therapy, seems inappropriateseems inappropriate

evaluation of the subfertile man. infertility affects 15 % of couples, and 50 % of male infertility...

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