Biochemical Investigations of Infertility

1. Biochemical Investigations of Infertility

2. OBJECTIVES • Recall the definition of infertility. • Understand the biochemical and clinical aspects and correlations of female and male infertility. • Recognizing the biochemical aspects of overall laboratory investigations of infertility. • Understanding the biochemical and clinical aspects of hyperprolactinemia as a cause of female infertility. • Explain the biochemical aspects of laboratory diagnosis polycystic ovary syndrome as a cause of female infertility. • Recognize the biochemical and clinical concepts of semen analysis in investigations of male infertility.

3. 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

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

5. Infertility Etiology

6. Female Factors

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

8. Female Infertility Ovulation Disorders: • Aging • Diminished ovarian reserve • Endocrine disorder • Polycystic ovary syndrome (PCOS) • Premature ovarian failure Tubal Factors: To Investigate Tubal Obstruction: • History of pelvic inflammatory disease (PID) • Tubal Surgery • Previous ectopic pregnancy • Salpingectomy Uterine/Cervical Factors: • Congenital uterine anomaly • Fibroids • Poor cervical mucus quantity/quality • Infection

9. Diagnostic approach to infertility in the woman History & Examination Normal menses Amenorrhoea, Oligomenorrhoea No further tests required + ve ? Ovulating Measure [Progesterone] in day 21 (mid-luteal) 3xs Perform pregnancy test -ve >30 nmol/L <10 nmol/L Measure [LH], [FSH], & [Prolactin] Ovulating Not ovulating High Prolactin High LH Low /N FSH, β-estradiol↓ High FSH. (+ LH) , β-estradiol↓ All Normal Further investigate hyperprolactinaemia Further tests indicated Ovarian failure PCOS

11. Endocrine causes of infertility Infertility may be caused by endocrine problems: • Common in the females • Rare in the males Endocrine investigation is of diagnostic value for women who have: • Irregular or no menstruation • No ovulation

12. 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

13. Cushing Syndrome • Overproduction of cortisol by the adrenal cortex • Prolonged exposure of body tissues to cortisol or other glucocorticoids • Prolonged exposure of body tissues to cortisol causes infertility in women

14. Hyperprolactinemia Prolactin 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: In women: amenorrhea & galctorrhoea In men: none

15. Hyperprolactinemia Causes of hyperprolactinemia • Stress • Drugs e.g. estrogens • Seizures • Primaryhypothyroidism :prolactin is stimulated by  TRH • Other pituitary diseases • Prolactinoma: commonly microadenoma of the pituitary • Idiopathic hypersecretion: e.g. due to impaired secretion of dopamine that usually inhibits prolactin release

16. Hyperprolactinaemia Diagnosis of the cause of hyperprolactinemia: • First, exclude: • Stress • Drugs • Other disease • Differential diagnosis between: • prolactinoma • idiopathic hypersecretion: • Detailed pituitary imaging • Dynamic tests of prolactin secretion: Administration of thyrotropin releasing hormone (TRH), then measure blood prolactin: • if : idiopathic hyperprolactinemia • If no: pituitary tumor

17. Polycystic Ovarian Syndrome (POCS) • The common clinical features of PCOS are: Menstrual irregularities Signs of androgen excess (Virilism, Anovulation & Infertility) Obesity • The classical hormonal profile of PCOS is: - Hypersecretion of LH (60%) - Androgen (testosterone) excess - Normal (or low) concentration of FSH • It is important to exclude disorders with similar presenting features as androgen secreting tumors & CAH

18. Polycystic Ovary Syndrome (POCS) Commonly associated with: • Obesity: 40% of cases • Insulin resistance: in 50% of patients • Excessive androgen production (very common) • Hirsutism • Chronic anovulation (& infertility) • Menstrual disorders • Hypersecretion of luteinizing hormone (LH) & androgens Obesity causes insulin resistance which leads to: • Glucose intolerance • Hyperlipidemia • Hypertension

19. Biochemical, metabolic & endocrine changes in PCOS LH ↑ FSH ↓ ↑ plasma [oestrone] Stimulation of ovarian stroma & theca by LH Anovulation Hirsutism Aromatisation in adipose tissue ↑ Androgens & free androgens ↓SHBG Obesity Insulin resistance

20. Polycystic Ovarian Syndrome (POCS) ↑ LH (with N. or ↓ FSH) Stimulation of theca cells of the ovary by LH Anovulation Hirsutism ↑ Estrogen ↑Free testosterone Start here ↓ SHBG Biochemical, Endocrinal & Clinical Changes in PCOS Obesity Insulin resistance

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

22. Polycystic Ovarian Syndrome (POCS) Laboratory Investigations of POCS: • ↓ sex hormone-binding globulin (SHBG) • ↓ total testosterone & ↑ free testosterone • ↑ Androgens (androstendione) • ↑ Luteinizing hormone (LH): in 60% of cases • Normal (or low) follicle stimulating hormone (FSH): often • ↑ LH/FSH ratio : in > 90% of patients

23. Polycystic Ovary Syndrome (POCS) 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)

24. Male Infertility Primary Hypogonadism: • Radiation • Testicular trauma • Varicocele • Orchitis • Systemic disorder Altered Sperm Transport: • Absent vas deferens or obstruction • Epididymal absence or obstruction • Erectile dysfunction (ED) • Retrograde ejaculation Secondary Hypogonadism: • Infiltrative disorder (Sarcoid, TB) • Pituitary adenoma • Trauma Other medications: • Antiandrogens

26. Diagnostic approach to subfertility in the man History & examination Normal Sperm Analysis Abnormal sperm count No endocrine tests are required Measure testosterone, gonadotrophins & prolactin Testosterone Gonadotrophins Testosterone  Gonadotrophins • Testosterone •  Prolactin Hypogonadotrophic hypogonadism: due to hypothalamic-pituitary disease Hyperprolactinaemia: rare Primary testicular failure

27. Primary Testicular Failure • Damage to both the interstitial cells & tubules  Testosterone Gonadotrophins (LH & FSH) If the sperm count is low on two occasions, measurements of serum LH , FSH and testosterone should be made to determine is it primaty hypogonadism or due to hypothalamic-pituitary region. Both forms lead to infertility • Azospermia with raised FSH suggests severe seminiferous tubular impairment • Azospermia with normal FSH and normal testicular volume indicates bilateral genital tract obstruction.