Biochemical Aspects of Male & Female Subfertility/ Infertility

Biochemical Aspects Biochemical Aspects of Male & Female of Male & Female

Subfertility/ Subfertility/ InfertilityInfertility

Objectives of the LectureObjectives of the Lecture

Recall factors required for conception conception Recall the definition of infertilityinfertility. Understand the correlation of biochemical and clinical aspects of the

common endocrinal causes infertility endocrinal causes infertility in males and females. Recognizing the biochemical aspects of overall laboratory laboratory

investigations of infertilityinvestigations of infertility in males and females.

Requirements for Requirements for Conception Conception

• Production of healthy Production of healthy ovaova & & spermsperm• Unblocked tubesUnblocked tubes that allow sperm to reach the ova that allow sperm to reach the ova• The The sperms ability to penetrate sperms ability to penetrate & fertilize the ova& fertilize the ova• Implantation of the embryo into the Implantation of the embryo into the uterusuterus• Finally a Finally a healthy pregnancyhealthy pregnancy

Infertility/ SubfertilityInfertility/ Subfertility

The inability to conceive The inability to conceive following unprotected sexual intercourse following unprotected sexual intercourse

for 1 year (age < 35) for 1 year (age < 35) or 6 months (age >35)or 6 months (age >35)

Infertility EtiologyInfertility Etiology

Evaluation of the Infertile coupleEvaluation of the Infertile couple

• HistoryHistory • Physical Physical examinationexamination• SemenSemen analysis (to exclude male causes) analysis (to exclude male causes) • Determination of Determination of ovulationovulation

– Basal body temperature record– Serum progesterone– Ovarian reserve testing

• EndocrineEndocrine investigations investigations• HysterosalpingogramHysterosalpingogram (for uterus & tubes) (for uterus & tubes)

LABORATORYLABORATORY Diagnostic Approaches of Diagnostic Approaches of Male Infertility Male Infertility

Seminal Fluid AnalysisSeminal Fluid AnalysisHormonal AssayHormonal Assay

Seminal Vesicle SecretionSeminal Vesicle SecretionFructoseFructose:

source of energy for sperms Needed for sperms motility

ProstaglandinsProstaglandins: Controlling sperm movement

& sperm penetration of cervical mucusFibrinogen-like substance Fibrinogen-like substance :

Cause of viscosity of semen (coagulation)

Prostatic SecretionProstatic SecretionpH 6.5pH 6.5 (weak acidic) (weak acidic) Reduces acidity of vag.sec Reduces acidity of vag.sec

ContainsContains::vesiculasevesiculaseReduces semen viscosityReduces semen viscosity

Acid phosphataseAcid phosphataseSpermine: bacteriostaticSpermine: bacteriostatic

Laboratory Seminal Fluid Analysis Laboratory Seminal Fluid Analysis

Source of SecretionSource of Secretion % %EjaculateEjaculate

TestisTestis 55% %

Seminal vesiclesSeminal vesicles 4040 – – 8080% %

ProstateProstate 1313 – – 3333% %

Bulbo-urethral & urethral Bulbo-urethral & urethral glandsglands 22 - - 55% %

Testicular Testicular SecretionSecretion

NormalNormalConstituents Constituents

of of Seminal FluidSeminal Fluid

Laboratory Seminal Fluid Laboratory Seminal Fluid AnalysisAnalysis

Physical Analysis Volume Liquefaction time (after coagulation) pH

Microscopic Analysis Sperm countcount Sperm morphologymorphology Sperm motility motility Sperm viability viability Sperm agglutinationagglutination

Biochemical AnalysisBiochemical Analysis Fructose test Acid phosphatase

OthersOthers Antisperm antibody

Testicular CausesTesticular Causes: : Radiation (as X-ray, etc)Radiation (as X-ray, etc)Trauma of testisTrauma of testisVaricoceleVaricoceleOrchitis (inflammation of the testis)Orchitis (inflammation of the testis)Systemic disorder causing low testosterone or spermatogenesisSystemic disorder causing low testosterone or spermatogenesisAbnormal sperm morphologyAbnormal sperm morphology

Secondary Hypogonadism: Secondary Hypogonadism: (Low GnHR, FSH , LH)(Low GnHR, FSH , LH)Hypothalamic causesHypothalamic causesPituitary causesPituitary causes

HyperprolactinemiaHyperprolactinemia

Altered Sperm Transport:Altered Sperm Transport: Obstruction of vas deferenceObstruction of vas deference Congenital absence vas deferensCongenital absence vas deferens Vasectomy (sperm count reaches zero after 3-6 months)Vasectomy (sperm count reaches zero after 3-6 months) Congenital absence or obstruction epidedimesCongenital absence or obstruction epidedimes Erectile dysfunction (ED)Erectile dysfunction (ED) Retrograde ejaculationRetrograde ejaculationOther less common causesOther less common causesAs antiandrogens medications intakeAs antiandrogens medications intake

Main Causes of Male Main Causes of Male InfertilityInfertility

Low Sperm CountLow Sperm CountNormal Sperm AnalysisNormal Sperm Analysis

No endocrine tests are No endocrine tests are requiredrequired

Testosterone Testosterone FSH & LH FSH & LH ProlactinProlactin

FSH & LHFSH & LH TestosteroneTestosterone

TestosteroneTestosterone FSH & LHFSH & LH

Testost.Testost. ProlactinProlactin

Diagnostic Approach to Infertility in Diagnostic Approach to Infertility in MalesMales

Seminal Fluid AnalysisSeminal Fluid Analysis

Primary Primary hypogonadismhypogonadism(e.g. testicular)(e.g. testicular)

Secondary Secondary hypogonadism hypogonadism


NORMALNORMALHormonal Hormonal

ProfileProfile

Vas Vas DeferenceDeference

ObstructionObstructionVasectomyVasectomy

Trauma Trauma Congenital Congenital AbsenceAbsence

SeminalSeminalVesicle Vesicle

& & Ejacul. Duct Ejacul. Duct

ProstateProstateAbnormal ProfileAbnormal Profile

Low Semen AmountLow Semen AmountLow or no Semen CoagulationLow or no Semen Coagulation

Low Semen pHLow Semen pHLow Sperm Motility & ViabilityLow Sperm Motility & Viability

Low Semen FructoseLow Semen Fructose

Prostatic Prostatic Invest. Invest.

Acid Acid PhosphatasePhosphatase

PSAPSA

Orchitis, Radiation, TraumaOrchitis, Radiation, Trauma

Hypothalamic Hypothalamic or Pituitary or Pituitary

DiseaseDisease

Causes ??Causes ??

Other AnomaliesOther AnomaliesAbnormal FormsAbnormal FormsSperm Agglutin.Sperm Agglutin.AntobodiesAntobodiesPus cellsPus cellsRBCsRBCs

Primary HypogonadismPrimary Hypogonadism

((Primary Testicular Failure)Primary Testicular Failure)

• Damage of Damage of BOTHBOTH the interstitial cells & semniferous tubules the interstitial cells & semniferous tubules Testosterone Testosterone Gonadotrophins (LH & FSH)Gonadotrophins (LH & FSH)

• Damage of Damage of OnlyOnly semniferous tubules semniferous tubules in FSH (but LH normal)in FSH (but LH normal) Testosterone normal (as interstitial cells intact)Testosterone normal (as interstitial cells intact)

VaricoceleVaricoceleA Cause of Male InfertilityA Cause of Male Infertility

Common, disease affecting 15% of men overall & Common, disease affecting 15% of men overall & 40% of men with known 40% of men with known infertilityinfertility..

Varicocele is an abnormal enlargement of the pampinform plexus of veins in the scrotumthe pampinform plexus of veins in the scrotum. Pampinform plexus of veins Pampinform plexus of veins drains the testicles.

Varicocele may raise the temperature the testicles or cause blood to back up in the veins supplying the testicles.

Varicocele seem to help damage or kill the sperm.Varicocele seem to help damage or kill the sperm.

The detrimental effect of varicocele on sperm production is progressive and due to reduction in supply of oxygenated blood & nutrient material to the sperm production sites, which persistently reduces the quality & the quantity of the quality & the quantity of the sperms, leading to reduction in their fertility capacity with timesperms, leading to reduction in their fertility capacity with time

Assessment of Sperm MorphologyAssessment of Sperm Morphology

Normally the sperm count contains fewer Normally the sperm count contains fewer than 20 % abnormal forms e.g. bitailed, short than 20 % abnormal forms e.g. bitailed, short tailed , 2 heads …..etc.tailed , 2 heads …..etc.A Cause of Male InfertilityA Cause of Male Infertility

LABORATORYLABORATORY Diagnostic Approaches of Diagnostic Approaches of Female Infertility Female Infertility

Hormonal AssayHormonal Assay

Common Causes Female Common Causes Female InfertilityInfertility

Ovulation Disorders CausesOvulation Disorders Causes::AgingAgingDiminished ovarian reserveDiminished ovarian reservePremature ovarian failurePremature ovarian failureEndocrine disorders (as PCOS)Endocrine disorders (as PCOS)

Tubal CausesTubal Causes:: Pelvic inflammatory disease Pelvic inflammatory disease Tubal SurgeryTubal Surgery Previous ectopic pregnancy Previous ectopic pregnancy SalpingectomySalpingectomy

Uterine/Cervical Causes:Uterine/Cervical Causes:Congenital uterine anomalyCongenital uterine anomalyFibroidsFibroidsEndometriosisEndometriosisPoor cervical mucus quantity/qualityPoor cervical mucus quantity/qualityInfectionInfection

Detailed History & Physical ExaminationDetailed History & Physical Examination

Amenorrhea, OligomenorrhoeaAmenorrhea, OligomenorrhoeaNormal mensesNormal menses

Investigations for Investigations for OvulationOvulationProgesterone n day 21 (mid luteal)Progesterone n day 21 (mid luteal)

Pregnancy TestPregnancy Test

FurtherFurther Investig.Investig.

+ ve+ ve

LH, FSH & ProlactinLH, FSH & Prolactin

High FSH High FSH & LH& LH

>30 nmol/L>30 nmol/L <10 nmol/L<10 nmol/L

1ry 1ry Ovarian FailureOvarian Failure

OvulationOvulation NoNo Ovulation Ovulation

No No Further Further

TestsTests

-ve-ve

High LHHigh LHLow FSHLow FSH

PCOSPCOS

High High ProlactinProlactin

Investigation for a cause of Investigation for a cause of hyperprolactinemiahyperprolactinemia

All NormalAll Normal

Diagnostic Approach to Infertility in Diagnostic Approach to Infertility in FemalesFemales

Low FSH Low FSH & LH& LH

Pituitary or Pituitary or hypothalam.hypothalam.

Endocrine investigation is of diagnostic value for women who Endocrine investigation is of diagnostic value for women who have:have:• Irregular or no menstruationmenstruation• No ovulationovulation

Endocrine causes of infertility in Endocrine causes of infertility in FemalesFemales

Endocrine causes of infertility in Endocrine causes of infertility in womenwomen

Primary ovarian failure:Primary ovarian failure: oestradiol & ↑ gonadotrophins (FSH & LH) oestradiol & ↑ gonadotrophins (FSH & LH) Hyperprolactinemia (↑ blood prolactin)Hyperprolactinemia (↑ blood prolactin) Polycystic ovary syndrome (PCOS)…Polycystic ovary syndrome (PCOS)… Cushing’s syndrome (↑Cushing’s syndrome (↑ steroid hormones) steroid hormones) Hypogonadotrophic hypogonadism (Hypogonadotrophic hypogonadism (↓ ↓ pituitary hormones FSH & LH): pituitary hormones FSH & LH): rarerare

Cushing SyndromeCushing Syndrome

• Overproduction of cortisol by the adrenal cortex mainly caused by adrenal cortical adenoma

• Due to increased production of adrenal cortical androgens (androstendione)


ProlactinProlactin Hormone secreted by the anterior pituitaryIt acts directly on the mammary glands to control lactation

HyperprolactinaemiaHyperprolactinaemia Elevated blood prolactin A common cause of infertility in both sexes due to gonadal function

impairment Early indication of hyperprolactinemia: amenorrhea & galctorrhoea

Increased prolactin hormone secretion by the anterior pituitary gland.Increased prolactin hormone secretion by the anterior pituitary gland.

Common causes of hyperprolactinemiaCommon causes of hyperprolactinemia

•StressStress•MedicationsMedications e.g. estrogens intake•PrimaryPrimary hypothyroidism hypothyroidism :prolactin is stimulated by TRH•Pituitary disease Pituitary disease •ProlactinomaProlactinoma: microadenoma of the pituitary cells secreting prolactin•IdiopathicIdiopathic hypersecretionhypersecretion: e.g. due to impaired secretion of dopamine that usually inhibits prolactin release


Diagnosis of the cause of hyperprolactinemiaDiagnosis of the cause of hyperprolactinemia::•FFIRST, the followings causes should be EXCLUDEDFFIRST, the followings causes should be EXCLUDED:

Stress Medications intake Primary hypothyroidism (low T3 & T4, High TSH) Pituitary diseases (assay of other pituitary hormones) If all above are excludedIf all above are excluded

•Differential diagnosis between:Differential diagnosis between:• Prolactinoma Prolactinoma • Idiopathic hypersecretion: Idiopathic hypersecretion:

– Detailed pituitary MRI (to exclude prolactinoma)– Dynamic tests of prolactin secretion: 1- Administration of TRH. 2- Then, blood prolactin (PRL) is measured:

• if PRL : Idiopathic hyperprolactinemia (caused by low dopamine)• If no in PRL: Pituitary tumor


Polycystic ovary syndrome is a problem in which a woman’s hormone are out of balance.

It can cause irregular menstruation & may lead to infertility (due to anovulation).

Polycystic ovary syndrome (or PCOS) is common, affecting as many as 1 out of 15 women.

Often the symptoms begin in the teen years.

For reasons that are not well understoodnot well understood, in PCOS the hormones get out of balance.

One hormone change triggers another, which changes another.

For example, the sex hormones get out of balance. Normally, the ovaries make a tiny

amount of male sex hormones (androgens). In PCOS, ovaries produce more androgens. &

thus this may cause anovulation, menstrual disturbances, infertility, acne & grow extra facial

& body hair (hirsutism)

Polycystic Ovary Syndrome Polycystic Ovary Syndrome (POCS)(POCS)

Theca cellTheca cell Granulosa cell of ovaryGranulosa cell of ovary

LHLH

LH receptor

cholesterolcholesterol

AndrostendioneAndrostendione AndrostendioneAndrostendione TestosteroneTestosterone

FSHFSH

aromatasearomatase

EstradiolEstradiol

Review of Review of Synthesis of Steroid HormonesSynthesis of Steroid Hormones

(testosterone & estradiol) in the Ovary(testosterone & estradiol) in the Ovary

FSH receptors

↑ ↑ LHLH(with N. or ↓ FSH)(with N. or ↓ FSH)

Stimulation Stimulation of theca cells of the ovary of theca cells of the ovary

by by LHLHto produce androstendioneandrostendione

Which is converted to testosterone Which is converted to testosterone in granulosa cellsin granulosa cells

↑ Free testosteroneFree testosterone↑ ↑ EstradiolEstradiol in granulosa cellsin granulosa cells

↓ ↓ SHBGSHBG

Insulin resistanceInsulin resistanceObesityObesity

HirsutismHirsutism

AnovulationAnovulation

Polycystic Ovarian Syndrome Polycystic Ovarian Syndrome (POCS)(POCS)

Biochemical, Biochemical, Endocrinal & Endocrinal &

Clinical Clinical Changes in PCOSChanges in PCOS

Start hereStart here

Polycystic Ovary Syndrome (POCS)Polycystic Ovary Syndrome (POCS)


• The common The common clinical features clinical features of PCOS are:of PCOS are: - Menstrual irregularities - Signs of androgen excess (as hirsutism) - Subfertility/Infertility (due to anovulation) - Insulin resistance (due to obesity)

• The classical The classical hormonal profile hormonal profile of PCOS is:of PCOS is: - Hypersecretion of LHLH (in 60% of cases) - Androgen (testosteronetestosterone) excess - Normal (or low) concentration of FSHFSH

• It is important to It is important to excludeexclude disorders with similar presenting features as disorders with similar presenting features as androgen secreting tumors & CAHandrogen secreting tumors & CAH

↓↓ SHBGSHBG (sex hormone binding globulin) (sex hormone binding globulin) ↑↑ Free Testosterone (Free Testosterone (&& ↓ Total testosterone ) ↓ Total testosterone ) ↑↑ AndrogensAndrogens (androstendione) (androstendione)↑↑ LHLH: in 60% of cases: in 60% of cases Normal (or low) Normal (or low) FSH FSH ↑ ↑ LH/FSH ratio : in > 90% of patientsLH/FSH ratio : in > 90% of patients


Laboratory Investigations of POCSLaboratory Investigations of POCS


Ultrasonographic (Sonar) Diagnosis of POCSUltrasonographic (Sonar) Diagnosis of POCS

Biochemical Aspects of Treatment of POCSBiochemical Aspects of Treatment of POCS

Is directed towards interrupting the cycle interrupting the cycle by Lowering LH Lowering LH levels with oral contraceptive pillslevels with oral contraceptive pillsIncreasing FSH Increasing FSH production by clomiphenproduction by clomiphenWeight reduction Weight reduction in obese patients (to reduce insulin resistance)in obese patients (to reduce insulin resistance)


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Biochemical Aspects of Male & Female Subfertility/ Infertility