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INTRODUCTION

DISORDERS CAUSING INFERTILITY IN COUPLES By Syed Tanveer Abbas Gilani MBBS, FCPS, Classified Chemical Pathologist CMH Bahawalnagar.

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INTRODUCTION

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  1. DISORDERS CAUSING INFERTILITY IN COUPLESBySyedTanveerAbbas Gilani MBBS, FCPS, Classified Chemical PathologistCMH Bahawalnagar

  2. SEQUENCE OF PRESENTATIONIntroduction of infertilityCauses, evaluation & diagnostic criteria of male infertilityCauses, evaluation & diagnostic criteria of female infertilityClinical cases (10 to 20)

  3. INTRODUCTION What was once an act of private “Love” is now a public act, a commercial transaction and a professionally managed procedure Sarah Franklin

  4. INFERTILITY

  5. INFERTILITY • Hormonal dysfunction of hypothalamic- • pituitary-gonadal axis

  6. PREVALENCE OF INFERTILITY Ref. Sharlip I, Jarow J, Belker A, Lipshultz L, Sigman M, Thomas A, et al. Best practice policies for male infertility. Fertil Steril 2002;77: 873– 82., Turek PJ. Practical approaches to the diagnosis and management of male infertility. Nat Clin Pract Urol 2005;2:226–38. 3. Mackay HT. Gynecology. In: Tierney LM, McPhee SJ.Papadakis MA. Current medical diagnosis and treatment. 42nd ed. New York: Mc Graw-Hill; 2003.p. 699–733.

  7. CAUSES OF MALE INFERTILITY Figure-1 Different types of disorders causing infertility in 91 (46 %) male patients out of total 200 cases who reported to CMH Bahawalnagar, as in 109 (54%) patients no demonstrable cause found (n=91).

  8. Primary testicular failure

  9. Ref. Burtis CA, et al. Tietz fundamentals of clinical chemistry, 6th ed. Saunders, 2008. Tritos NA. Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism Workup. Medscape. Updated: Jun 4, 2014.

  10. FEMALE INFERTILITY Female infertility factors are 1.OVARIAN OR HORMONAL FACTORS a. METABOLIC DISEASE • Polycystic ovarian syndrome • Thyroid • Liver • Obesity • Androgen excess

  11. FEMALE INFERTILITY FACTORS b. HYPERGONADOTROPIC HYPOGONADISM • Premature ovarian failure (autoimmune, cytotoxic chemotherapy, tumor) • Menopause • Luteal phase deficiency • Gonadal dysgenesis • Resistant ovary syndrome c. HYPOGONADOTROPIC HYPOGONADISM • Hyperprolactinemia (tumor, drugs) • Hypothalamic insufficiency (Kallmann syndrome) • Pituitary insufficiency (tumor, necrosis, stress, anorexia)

  12. FEMALE INFERTILITY FACTORS d. OVULATORY DYSFUNCTION • Ovulatory dysfunction manifests itself in presence or absence of normal menses • Metabolic diseases affect ovulatory function • PCOS is the most common cause of anovulation • CAH should be considered (21-hydroxylase deficiency or 3ß-hydroxysteroid deficiency may be present in 26% cases)

  13. FEMALE INFERTILITY FACTORS 2. TUBAL FACTORS • Occlusion or scarring • Infectious salpingitis • Isthmica nodosa 3. CERVICAL FACTORS • Stenosis • Inflammation or infection • Abnormal mucus viscosity 4. UTERINE FACTORS • Leiomyomata • Congenital malformations, adhesions • Endometritis or abnormal endometrium

  14. FEMALE INFERTILITY FACTORS 5. PSYCHOSOCIAL FACTORS • Decreased libido • Anorgasmia 6. IATROGENIC 7. IMMUNOLOGICAL • Anti sperm antibodies

  15. Causes of Female Infertility Figure-2 Different types of disorders causing infertility in 120 (60 %) female patients out of total 200 cases who reported to CMH Bahawalnagar, as in 80 (40 %) patients no demonstrable cause found (n=120).

  16. EVALUATION OF FEMALE INFERTILITY Detailed history Physical examination PAP smear Search for tubal patency, endometriosis or adhesions Assessment of ovulation & adequate luteal function Endocrine parameters (serum FSH, LH, estradiol, progesterone, prolactin, TSH, free T4, testosterone, DHEAS and 17-OH -progesterone) Immunological parameters (anti sperm antibody) Genetic screening Karyotyping

  17. EVALUATION OF FEMALE INFERTILITY STEPS OF EVALUATION 1 DETAILED HISTORY • Irregular periods or no menstrual periods • Very painful periods • Endometriosis • Pelvic inflammatory disease • More than one miscarriage

  18. 1 DETAILED HISTORY (CONT) Many things can affect a woman's ability to have a baby. These include: • Age • Stress • Poor diet • Athletic training • Overweight or underweight • Smoking • Alcohol • STDs

  19. 2.PHYSICAL EXAMINATION • Body mass index (BMI): kg/m2 • Weight change >10% within past year • Blood pressure • Body shape and stature • Abdominal scars • Abnormalities in body systems • Assessment of hirsutism • Assess secondary sex characteristics • Record Tanner stage for women not mature • Examine nipple discharge microscopically • Examine external genitalia for inflammation • Clitoral enlargement • Intact hymen • Pubic hair distribution

  20. 3. PAP SMEAR • A papanicolaou cervical and vaginal smear (tumor of squamocoloumnar junction) • Along with appropriate cervical and endocervical cultures (infections) 4. USG / HYSTEROSALPANGIOGRAM / LAPROSCOPY • If ovulation is normal, these tests are needed to search for tubal patency, endometriosis or adhesions • Performed between the 7th and 11th day of the cycle (hysterosalpangiogram)

  21. 5. ASSESMENT OF MENSTRUAL STATUS No amenorrhea or amenorrhea If no amenorrhea EVALUATION OF OVULATION • Serum progesterone levels Measurement of midluteal (21 day of menses) serum progesterone • If< 15nmol/l anovulation or leuteal defect • If >30nmol/l indicates normal ovulation • Basal body temperature (rapid rise in body temperature by 0.5ºF, persists through luteal phase) • Evaluation of LH surge (LH appears in urine just after serum LH surge & 24 to 36 hrs before ovulation)

  22. 5. ASSESMENT OF MENSTRUAL STATUS (cont) If amenorrhea • Rule out pregnancy by β - HCG For primary amenorrhea • Asses karyotyping For secondary amenorrhea • Perform estrogen / progesterone challenge test • Abnormal result shows uterine disease

  23. 6. ENDOCRINE PARAMETERS • Female fertility profile (serum) • FSH • LH • Estradiol (2nd day of menses) • Progesterone (21 day of menses) • Prolactin • GnRH stimulation test • Other endocrine tests are • TSH, f T4 • Testosterone & DHEAS (hirsutism) • 17-OH-progesterone (CAH) • Misc (plasma glucose )

  24. 6. ENDOCRINE PARAMETERS (Cont) • Serum prolactin (elevated) • Suppression of ovulation Reference: Kronenberg, Melmed, Polonsky, Larsen Williams textbook of endocrinology 11th edition 2008.

  25. 6. ENDOCRINE PARAMETERS (Cont) • If Serum estradiol is low (2nd day of menses) a.HYPERGONADOTROPIC HYPOGONADISM • Premature ovarian failure • FSH > 20 mIU/ml, estradiol < 73 pmol/L • Relative ovarian age • Serum FSH (rise) • As FSH increases rate of successful pregnancies decreases b. HYPOGONADOTROPIC HYPOGONADISM • Serum FSH < 2 mIU/mL, LH < 2 mIU/mL, estradiol < 110 pmol/L (hypothalamic or pituitary insufficiency) • Serum prolectin elevated • TSH increase, f T4 decrease (hypothyroidism)

  26. 6. ENDOCRINE PARAMETERS (Cont) • If estradiol / progesterone challenge test is normal than measure • Serum FSH and LH if normal/low perform GnRH or clomiphene tests • Normal response suggests nutritional, psychogenic or excess exercise as a cause of infertility with amenorrhea • Abnormal response is due to pituitary failure or delayed in hypothalamic insufficiency • If serum FSH and LH are elevated LH<FSH (ovarian failure or resistance) LH>FSH (2.5) (polycystic ovary syndrome)

  27. 7. ENDOCRINE PARAMETERS (Cont) GnRH stimulation test • Indication: • To diagnose hypothalamic pituitary disease in precocious and delayed puberty in both sexes in children with low basal gonadotrophins • Procedure: • 0 min: Take 3ml blood for LH and FSH • Inj GnRH 100 ug IV (child 2.5 ug/kg body weight to max 100ug) • After 30 & 60 min : Take 3ml blood for LH and FSH

  28. 7. ENDOCRINE PARAMETERS (Cont) • Interpretation: • In follicular phase; LH increases 2 fold over baseline or a net change of at least 10 mIU/ml and FSH 1.5 fold over baseline or a change of at least 2 mIU/ml • In luteal phase; LH increases 8 fold over baseline or a net change of 20 mIU/ml and FSH 1.5 fold over baseline or a net change of 2 mIU/ml Reference: (Lufkin et al,1983)

  29. 7. ENDOCRINE PARAMETERS (Cont) Clomiphene stimulation test • Clomiphene acts by interrupting the negative feedback loop and thereby stimulating release of gonadotropin from pituitary Indication • To diagnose hypothalamic pituitary disease in precocious and delayed puberty in both sexes in children with low basal gonadotrophins Procedure • 100 mg of clomiphene citrate is given for 5 to 7 days Result • A doubling of LH and a 20 to 50% increase in FSH are normal, indicative of an intact hypothalamic-pituitary response Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA. Short- and long-term effects of clomiphene citrate on the pituitary-testicular axis. J ClinEndocrinolMetab. 1971;33:970-979.

  30. Diagnostic criteria (Female Infertility) Burtis CA, et al. Tietz fundamentals of clinical chemistry, 6th ed. Saunders, 2008. Tritos NA. Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism Workup. Medscape. Updated2014.

  31. Frequency of disorders leading to female infertility in literature Dhaliwal LK, Singh A, Sinha S. Determinants of successful outcome in couples consulting Infertility clinic- Postgraduate Institute of Medical Education and Research, Chandigarh, India: A Record-based Analysis. J Postgrad Med Edu Res 2014; 48(4): 164-170. Philippov OS, Radionchenko AA, Bolotova VP, Voronovskaya NI & Potemkina TV. Estimation of the prevalence and causes of infertility in Western Siberia. Bulletin of the World Health Organization, 1998, 76 (2): 183-187.

  32. RECOMMENDATIONS The prevalence of different conditions leading to infertility differ in various regions, and management depends on the cause It is vital to know the frequency of different causes of infertility in our setup

  33. CONCLUSION

  34. Case - 1 • A 19 yr old female. H/O amenorrhea, menarche at age 13 yr, regular menses till age 18 yr. • O/E tense, anxious, thin, low weight 38 kg . • Lab tests HCG < 5 mIu/mL (Negative = <5) LH 1 mIU/mL (1.7 – 15) FSH 2.5 mIU/mL (1.4 – 9.9) E2 95 pmol/l (73 – 550) PRL 450 mIU/L (40 -530) MRI pituitary fossa (Normal)

  35. Case - 1 • Give Diagnosis? • Prolectinoma • Premature ovarian failure • PCOS • Hypogonadotropic hypogonadism (anorexia nervosa)

  36. Case -1 • Answer D • Hypogonadotropic hypogonadism (anorexia nervosa)

  37. Case - 2 • A 27 yr old women. H/O amenorrhea, hirsutism, obesity, menarche at age 13 yr, regular menses till age 20 yr, over last 7 yr irregular menses (oligomen--). • O/E overweight, acne. On USG bil cystic ovaries • Lab tests LH 24 mIU/mL (1.7 – 15) FSH 5.5 mIU/mL (1.4 – 9.9) E2 140 pmol/L (73 – 550) PRL 375 mIU/L (40 - 530) Testosterone 3.7 nmol/L (0.7 – 2.8)

  38. Case - 2 • What is diagnosis? A. POF B. PCOS C. CAH D. Liver disease

  39. Case - 2 • Answer B • PCOS (LH/FSH ratio >2.5, USG bil cystic ovaries, hyperandrogenism)

  40. Case - 3 • A 35-year-old woman. H/O amenorrhea in the previous 6 months, menarche at age 12, two successful pregnancies. Provera (10mg×5 days) challenge with no subsequent withdrawal bleeding. She denied visual changes, hot flashes, or night sweats. No acne, hirsutism, or alopecia. She did describe galactorrhea, migraine headaches, which increased in frequency and intensity. • Laboratory evaluation included HCG negative Prolactin 1050 mIU/L (40–530) FSH 3 mIU/mL (1.4 – 9.9) TSH 3 mIU/L (0.5–5)

  41. Case- 3 MRI of the pituitary fossa-- 2.7cm suprasellar mass, mild compression of the optic chiasm was noted The patient had transphenoidal surgery and subsequently received hormone replacement therapy but her menses did not resume. • What is the best choice? A. Pituitary insufficiency B. Hypothalamic failure C. Amenorrhea was secondary effect of prolactin on ovaries D. Pituitary tumors within the pituitary gland can interfere directly with gonadotrope function by a mass effect

  42. Case - 3 • Answer D • Pituitary masses can cause amenorrhea via a mass effect on the hypothalamus or pituitary stalk as in this case, via elevated prolactin levels, which result in decreased GnRH secretion, or through a mass effect on pituitary gonadotropes

  43. Case - 4 • Which of the following lab tests should you order when a patient presents with secondary amenorrhea? A. HCG B. Prolactin C. TSH D. FSH E. All of the above

  44. Case - 4 • Answer: E • Pregnancy should always be a consideration in the workup of secondary amenorrhea, and it is important to rule out premature ovarian failure. Thyroid dysfunction (either hypo- or hyper-) can cause menstrual cycle abnormalities. Prolactin-secreting microadenomas frequently present in this age group in association with menstrual cycle abnormalities

  45. Case-5 • In a patient with amenorrhea and an elevated prolactin • which of the following would be the next appropriate step? A. Treat with a dopamine against B. Perform a pituitary MRI C. Treat with an oral contraceptive pill D. Perform a mammogram E. Treat with hormone replacement therapy

  46. Case - 5 • Answer: B • It is essential that a patient with a persistently elevated prolactin level have a neuroimaging study to rule out a large hypothalamic or pituitary tumor. Treatment with a dopamine agonist will mask the symptoms and needs to be reserved for use after the cause of the elevated prolactin has been ascertained. Oral contraceptives and hormone replacement will likewise obscure the problem and may mask the appropriate diagnosis

  47. Case-6 • How does hyperprolactinemia cause amenorrhea? A. Increases GnRH pulse frequency B. Decreases GnRH pulse frequency C. Blocks estrogen binding to estrogen receptor D. Accelerates estrogen metabolism

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