Biochemical Aspects of Male & Female Subfertility/ Infertility

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

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

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

Infertility Etiology Female Factors: 35% Unexplained: 28% Other: 13% Some sources list female factors as high as 50% Female Factors Breakdown: Ovarian Dysfunction: 21% Tubal Factors: 14% 5

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

Spirnolactone antihyperstensive Cimetidine : antiacid

Galactorrhoea (inappropriate breast milk production; i. e Galactorrhoea (inappropriate breast milk production; i.e. in the absence of pregnancy most commonly caused be hyperprolactinaemia) Hirsutism (an increase in body hair with male pattern distrubutuon

LABORATORY Diagnostic Approaches of Male Infertility Seminal Fluid Analysis Hormonal Assay

Laboratory Seminal Fluid Analysis Normal Constituents of Seminal Fluid Seminal Vesicle Secretion Fructose: source of energy for sperms Needed for sperms motility Prostaglandins: Controlling sperm movement & sperm penetration of cervical mucus 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 Testicular Secretion % Ejaculate Source of Secretion 5 % Testis 40 – 80 % Seminal vesicles 13 – 33 % Prostate 2 - 5 % Bulbo-urethral & urethral glands

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

Main Causes of Male Infertility 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

Diagnostic Approach to Infertility in Males Other Anomalies Abnormal Forms Sperm Agglutin. Antobodies Pus cells RBCs Seminal Fluid Analysis Normal Sperm Analysis Low Sperm Count NORMAL Hormonal Profile No endocrine tests are required Testosterone FSH & LH Prolactin Prostate Abnormal Profile Seminal Vesicle & Ejacul. Duct Vas Deference Obstruction Vasectomy Trauma Congenital Absence * Lecture Notes on Clinical Biochemistry In both men & women infertility a serum [FSH] > 25U/L indicates primary gonadal failure Prostatic Invest. Acid Phosphatase PSA FSH & LH  Testosterone Testosterone  FSH & LH Testost.  Prolactin Secondary hypogonadism Primary hypogonadism (e.g. testicular) Hyperprolactinemia Low Semen Amount Low or no Semen Coagulation Low Semen pH Low Sperm Motility & Viability Low Semen Fructose Hypothalamic or Pituitary Disease Causes ?? Orchitis, Radiation, Trauma

Primary Hypogonadism (Primary Testicular Failure) Damage of BOTH the interstitial cells & semniferous tubules  Testosterone Gonadotrophins (LH & FSH) Damage of Only semniferous tubules  in FSH (but LH normal) 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. Varicocele is an abnormal enlargement of the pampinform plexus of veins in the scrotum. 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. 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

Common Causes Female Infertility Ovulation Disorders Causes: Aging Diminished ovarian reserve Premature ovarian failure Endocrine disorders (as PCOS) Tubal Causes: Pelvic inflammatory disease Tubal Surgery Previous ectopic pregnancy Salpingectomy Uterine/Cervical Causes: Congenital uterine anomaly Fibroids Endometriosis Poor cervical mucus quantity/quality Infection

Diagnostic Approach to Infertility in Females Detailed History & Physical Examination Normal menses Amenorrhea, Oligomenorrhoea No Further Tests Investigations for Ovulation Progesterone n day 21 (mid luteal) Pregnancy Test + ve -ve >30 nmol/L <10 nmol/L *Lecture Notes on Clinical Biochemistry Investigations depend on the phase of the menstrual cycle Elevated serum [progesterone] at day 21 of the menstrual cycle indicates that ovulation has occurred LH, FSH & Prolactin Ovulation No Ovulation High Prolactin Low FSH & LH High FSH & LH High LH Low FSH All Normal Further Investig. Pituitary or hypothalam. 1ry Ovarian Failure Investigation for a cause of hyperprolactinemia PCOS

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

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 Hyperprolactinaemia Hormone secreted by the anterior pituitary It acts directly on the mammary glands to control lactation Hyperprolactinaemia Elevated blood prolactin A common cause of infertility in both sexes due to gonadal function impairment Early indication of hyperprolactinemia: amenorrhea & galctorrhoea

Hyperprolactinemia Increased prolactin hormone secretion by the anterior pituitary gland. Common causes of hyperprolactinemia Stress Medications e.g. estrogens intake Primary hypothyroidism :prolactin is stimulated by  TRH Pituitary disease Prolactinoma: microadenoma of the pituitary cells secreting prolactin Idiopathic 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 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: Prolactinoma 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 (POCS) 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 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)

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

Polycystic Ovarian Syndrome (POCS) ↑ LH (with N. or ↓ FSH) Stimulation of theca cells of the ovary by LH to produce androstendione Which is converted to testosterone in granulosa cells Anovulation Hirsutism Treatment of PCOS: try to break the cycle ↑ Estradiol in granulosa cells ↑ Free testosterone Start here ↓ SHBG Biochemical, Endocrinal & Clinical Changes in PCOS Obesity Insulin resistance

Polycystic Ovary Syndrome (POCS)

Polycystic Ovarian Syndrome (POCS) 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: - Hypersecretion of LH (in 60% of cases) - Androgen (testosterone) excess - Normal (or low) concentration of FSH It is important to exclude disorders with similar presenting features as androgen secreting tumors & CAH )

Polycystic Ovarian Syndrome (POCS) Laboratory Investigations of POCS ↓ 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 Ovary Syndrome (POCS) Ultrasonographic (Sonar) Diagnosis of POCS

Polycystic Ovary Syndrome (POCS) Biochemical Aspects of Treatment of POCS 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)