Biochemical Aspects of Male & Female Subfertility/ Infertility

Objectives of the Lecture conception  Recall factors required for conception infertility  Recall the definition of infertility. endocrinal causes infertility  Understand the correlation of biochemical and clinical aspects of the common endocrinal causes infertility in males and females. laboratory investigations of infertility  Recognizing the biochemical aspects of overall laboratory investigations of infertility in males and females.

Requirements for Conception Production of healthy ova & spermProduction of healthy ova & sperm Unblocked tubes that allow sperm to reach the ovaUnblocked tubes that allow sperm to reach the ova The sperms ability to penetrate & fertilize the ovaThe sperms ability to penetrate & fertilize the ova Implantation of the embryo into the uterusImplantation of the embryo into the uterus Finally a healthy pregnancyFinally a healthy pregnancy

Infertility/ Subfertility The inability to conceive following unprotected sexual intercourse for 1 year (age < 35) or 6 months (age >35)

Evaluation of the Infertile couple HistoryHistory Physical examinationPhysical examination Semen analysis (to exclude male causes)Semen analysis (to exclude male causes) Determination of ovulationDetermination of ovulation –Basal body temperature record –Serum progesterone –Ovarian reserve testing Endocrine investigationsEndocrine investigations Hysterosalpingogram (for uterus & tubes)Hysterosalpingogram (for uterus & tubes)

LABORATORY Diagnostic Approaches of Male Infertility Seminal Fluid Analysis Hormonal Assay LABORATORY Diagnostic Approaches of Male Infertility Seminal Fluid Analysis Hormonal Assay

Seminal Vesicle Secretion Fructose Fructose: source of energy for sperms Needed for sperms motility Prostaglandins Prostaglandins: Controlling sperm movement & sperm penetration of cervical mucus Fibrinogen-like substance Fibrinogen-like substance : Cause of viscosity of semen (coagulation) Prostatic Secretion pH 6.5 (weak acidic) Reduces acidity of vag.sec Contains: vesiculase Reduces semen viscosity Acid phosphatase Spermine: bacteriostatic Laboratory Seminal Fluid Analysis % Ejaculate Source of Secretion 5 % 5 %Testis 40 – 80 % Seminal vesicles 13 – 33 % Prostate % Bulbo-urethral & urethral glands TesticularSecretion Normal Constituents of Seminal Fluid

Laboratory Seminal Fluid Analysis Physical Analysis  Volume  Liquefaction time (after coagulation)  pH Microscopic Analysis count  Sperm count morphology  Sperm morphology motility  Sperm motility viability  Sperm viability agglutination  Sperm agglutination Biochemical Analysis  Fructose test  Acid phosphataseOthers  Antisperm antibody Physical Analysis  Volume  Liquefaction time (after coagulation)  pH Microscopic Analysis count  Sperm count morphology  Sperm morphology motility  Sperm motility viability  Sperm viability agglutination  Sperm agglutination Biochemical Analysis  Fructose test  Acid phosphataseOthers  Antisperm antibody

Testicular Causes :  Radiation (as X-ray, etc)  Trauma of testis  Varicocele  Orchitis (inflammation of the testis)  Systemic disorder causing low testosterone or spermatogenesis  Abnormal sperm morphology Secondary Hypogonadism: (Low GnHR, FSH, LH)  Hypothalamic causes  Pituitary causes Hyperprolactinemia Altered Sperm Transport:  Obstruction of vas deference  Congenital absence vas deferens  Vasectomy (sperm count reaches zero after 3-6 months)  Congenital absence or obstruction epidedimes  Erectile dysfunction (ED)  Retrograde ejaculation Other less common causes  As antiandrogens medications intake Main Causes of Male Infertility

Low Sperm Count Normal Sperm Analysis No endocrine tests are required Testosterone FSH & LH Prolactin  FSH & LH  Testosterone  FSH & LH  Testost.  Prolactin Diagnostic Approach to Infertility in Males Seminal Fluid Analysis Primaryhypogonadism (e.g. testicular) Secondaryhypogonadism Hyperprolactinemia NORMALHormonalProfile VasDeferenceObstructionVasectomyTrauma Congenital Absence SeminalVesicle& Ejacul. Duct Prostate Abnormal Profile Low Semen Amount Low or no Semen Coagulation Low Semen pH Low Sperm Motility & Viability Low Semen Fructose Prostatic Invest. Acid Phosphatase PSA Orchitis, Radiation, Trauma Hypothalamic or Pituitary Disease Causes ?? Other Anomalies Abnormal Forms Sperm Agglutin. Antobodies Pus cells RBCs

Primary Hypogonadism ( Primary Testicular Failure) Damage of BOTH the interstitial cells & semniferous tubulesDamage of BOTH the interstitial cells & semniferous tubules   Testosterone  Gonadotrophins (LH & FSH)  Gonadotrophins (LH & FSH) Damage of Only semniferous tubulesDamage of Only semniferous tubules   in FSH (but LH normal) Testosterone normal (as interstitial cells intact) Testosterone normal (as interstitial cells intact)

Varicocele A Cause of Male Infertility Common, disease affecting 15% of men overall & 40% of men with known infertility. the pampinform plexus of veins in the scrotum Varicocele is an abnormal enlargement of the 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. quality & the quantity of the sperms, leading to reduction in their fertility capacity with time 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 sperms, leading to reduction in their fertility capacity with time

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

LABORATORY Diagnostic Approaches of Female Infertility Hormonal Assay LABORATORY Diagnostic Approaches of Female Infertility Hormonal Assay

Detailed History & Physical Examination Amenorrhea, Oligomenorrhoea Normal menses Investigations for Ovulation Progesterone n day 21 (mid luteal) Pregnancy Test Further Investig. Investig. + ve LH, FSH & Prolactin High FSH & LH >30 nmol/L <10 nmol/L 1ry Ovarian Failure Ovulation No Ovulation No Further Tests -ve High LH Low FSH PCOS High Prolactin Investigation for a cause of hyperprolactinemia All Normal Diagnostic Approach to Infertility in Females Low FSH & LH Pituitary or hypothalam.

Endocrine investigation is of diagnostic value for women who have: menstruationIrregular or no menstruation ovulationNo ovulation Endocrine causes of infertility in Females

Endocrine causes of infertility in women  Primary ovarian failure:  oestradiol & ↑ gonadotrophins (FSH & LH)  Hyperprolactinemia (↑ blood prolactin)  Polycystic ovary syndrome (PCOS)…  Cushing’s syndrome (↑ steroid hormones)  Hypogonadotrophic hypogonadism ( ↓ pituitary hormones FSH & LH): rare

Cushing Syndrome Overproduction of cortisol by the adrenal cortex mainly caused by adrenal cortical adenoma Due to increased production of adrenal cortical androgens (androstendione)

Hyperprolactinemia Prolactin Hormone secreted by the anterior pituitary It acts directly on the mammary glands to control lactationHyperprolactinaemia  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. Common causes of hyperprolactinemia StressStress MedicationsMedications e.g. estrogens intake Primary hypothyroidism Primary hypothyroidism :prolactin is stimulated by  TRH Pituitary diseasePituitary disease ProlactinomaProlactinoma: microadenoma of the pituitary cells secreting prolactin IdiopathichypersecretionIdiopathic hypersecretion: e.g. due to impaired secretion of dopamine that usually inhibits prolactin release Hyperprolactinemia

Diagnosis 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 excluded Differential diagnosis between:Differential diagnosis between: ProlactinomaProlactinoma 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 Hyperprolactinemia

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. not well understood For reasons that are not 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 (POCS)

Theca cell Granulosa cell of ovary LH LH receptor cholesterol cholesterol Androstendione AndrostendioneTestosterone Androstendione TestosteroneFSHaromatase Estradiol Review of Synthesis of Steroid Hormones (testosterone & estradiol) in the Ovary FSH receptors

Polycystic Ovary Syndrome (POCS)

Polycystic Ovarian Syndrome (POCS) The common clinical features of PCOS are:The common clinical features of PCOS are: - Menstrual irregularities - Signs of androgen excess (as hirsutism) - Subfertility/Infertility (due to anovulation) - Insulin resistance (due to obesity) The classical hormonal profile of PCOS is:The classical hormonal profile of PCOS is: LH - Hypersecretion of LH (in 60% of cases) testosterone - Androgen (testosterone) excess FSH - Normal (or low) concentration of FSH It is important to exclude disorders with similar presenting features as androgen secreting tumors & CAHIt is important to exclude disorders with similar presenting features as androgen secreting tumors & CAH

 ↓ SHBG (sex hormone binding globulin)  ↑ Free Testosterone (& ↓ Total testosterone )  ↑ Androgens (androstendione)  ↑ LH: in 60% of cases  Normal (or low) FSH  ↑ LH/FSH ratio : in > 90% of patients Polycystic Ovarian Syndrome (POCS) Laboratory Investigations of POCS

Biochemical Aspects of Treatment of POCS interrupting the cycle Is directed towards interrupting the cycle by  Lowering LH levels with oral contraceptive pills  Increasing FSH production by clomiphen  Weight reduction in obese patients (to reduce insulin resistance) Polycystic Ovary Syndrome (POCS)