FEMALE INFERTILITY, pelvic organ prolapse

Medical related

1. FEMALE INFERTILITY

2. DEFINITION- Infertility is a disease which generates disability as an impairment of function Defined as inability to establish clinical pregnancy after 12 months of regular, unprotected sexual intercourse i.e. without use of contraception in women <35 years of age, and after 6 months of regular intercourse without contraception in >35 years of age.

3. SUBFERTILITY- Any form of reduced fertility with prolonged time of unwanted non-conception FECUNDITY- the capacity to have a live birth FECUNDABILITY- the probability of achieving a pregnancy in a single menstrual cycle with adequate sperm exposure and no contraception that results in a live birth STERILITY – permanent state of infertility TIME TO PREGNANCY- the length of time that it takes a couple to conceive NORMAL FERTILITY- Most pregnancies occur during the first six cycles of attempted conception

4. NORMAL FERTILITY- Most pregnancies occur during the first six cycles of attempted conception TIME OF EXPOSURE % PREGNANT 3 MONTHS 57% 6MONTHS 72% 1 YEAR 85% 2 YEARS 93%

5. INCIDENCE In a WHO study of 8500 infertile couples- Female factor infertility – 37% Male factor infertility – 8% Male + female factor infertility – 35% Unexplained infertility – 20%

6. Female factors (81%) - Ovulatory disorders – 25% Endometriosis – 15% Pelvic adhesions – 12% Tubal blockage – 11% Other tubal abnormalities – 11% Hyperprolactemia – 7%

7. As a woman gets older, her chances of infertility increases INFERTILITY RATES- Aged – 15 to 34 years ----- 7.3 to 9.1% 35 to 39years ---- 25% 40 to 44years ---- 30% More in eastern Europe, north Africa, the middle east

8. PATHOPHYSIOLOGY

9. 1) ANOVULATION Ovulatory disorders – 25% of female infertility Oligo /anovulation-

10. WHO classification of ovulatory disorders- Hypogonadotropic hypogonadal i.e hypothalamic amenorrhea Normogonadotropic normoestrogenic i.e. PCOS Hypergonadotropic hypoestrogenic i.e. premature ovarian failure Hyperprolactenemic anovulation i.e. pituitary adenoma

11. I) HYPOTHALAMIC AMENORRHEA / FUNCTIONAL HYPOTHALMIC AMENORRHEA Associated with eating disorders or excessive exercises ( inc. cortisol) decrease in the hypothalamic GnRH secretion Decrease or absent pulsatility of GnRH Decrease in release of gonadotropins and FSH, LH from anterior pituitary gland Abnormal follicle growth, anovulation, decreased estrogen levels

12. FSH and LH will have variations from low to normal but, Hormone ratio resembles a prepubertal female with— FSH > LH

13. II) NORMOGONADOTROPIC NORMOESTROGENIC ANOVULATION Most common – PCOS (80-85% of all anovulatory pts & affects 8% of all reproductive age females ) PCOS diagnosed by- ROTTERDAM’S CRITERIA oligoovulation / anovulation Clinical signs of hyperandrogenism or serological elevations of androgens Polycystic ovaries on USG Atleast 2 out of 3 are present for PCOS

14. Infertility in PCOS – Due to dysfunction in developing a mature follicle thus anovulation. FSH and LH are normal LH can be normal or elevated Pathophysiology of PCOS- Abnormal pulsatality of GnRH

15. III) HYPERGONADOTROPIC HYPOESTROGENIC Premature ovarian insufficiency & ovarian resistance associated with female age Steady decline in the quality and quantity of oocytes 20 wks female fetus – 6 million follicles Newborn – 1 million follicles approx. Onset of puberty – 300000 follicles Rate of follicle loss max. increases in mid-thirties

16. External factors- cigarette smoking, radiation, chemotherapy Fecundibility and follicular quantity inverserly proportional to cigarette smoking Ovarian quality loss is due to MEIOTIC NON-DISJUNCTION ANEUPLOIDY Due to age related changes in the granulosa cells Increase age – increase no. of meiotic nondisjunction thus, chromosomally abnormal oocytes and embryos Women with depleted ovarian follicle pool may ovulate regularly, but have infertility due to poor quality of oocytes remaining in the terminal pool

17. IV) HYPERGONADOTROPIC HYPOGONADISM Primary ovarian insufficieny before 40 years of age Characterised by- Lack of folliculogenesis Decreased estrogen Loss of oocytes Infertility Most common cause of POI- TURNER SYNDROME ( monosomy of sex chromosome 45X karyotype)

18. PROLACTEMIA Prolactin suppression of hypothalamic GnRH secretion Decrease LH Thus, anovulation / oligomenorrhea / amenorrhea Prolactin values – 50 to 100 ng /ml Causes amenorrhea or oligoamenorrhea d/t abnormal feedback on hypothalamic – pituitary – ovarian axis >100 ng /ml causes hypogonadism , amenorrhea, pituitary adenomas

19. 2) ENDOMETRIOSIS Endometrial tissue outside the uterine cavity diagnosed by histological identification of endometrial glands or stroma outside the uterus M.c. site – pelvis (can spread throughtout the entire abdomen) Affects 10-15% reproductive age women Infertility – 40-50% women with endometriosis Accoring to ASRM, Stage 1 & stage 2- infertility d/t inflammation ( inc. PGs, cytokines, NK cell) inflammation impairs ovarian & tubal function Defective follicular formation, fertilization & implantation

20. STAGE III & STAGE IV- associated with pelvis adhesions or masses distorting pelvic anatomy Thus impaired tubal motility, oocyte release, sperm motility Advanced endometriosis- impaired folliculogenesis Decreased fertilization potential

21. 3) PELVIC / TUBAL ADHESIONS Infectious processes within the abdomen leading cause M.C.C– PID Microorganism with max risk of infertility associated with PID- CHLAMYDIA TRACHOMATIS One in 4 women with tubal factor infertility will have positive antibodies to Chlamydia These are inversely proportional to pregnancy rates

22. No. of PID episodes & severity associated with infertility. One study shows pregnancy rates following PID- 1 episode – 80% 2 episodes – 77% 3 episodes – 46% In terms of severity- Mild – 90% live birth rate Moderate – 82% Severe – 57%

23. HYDROSALPINGES Tubal abnormality d/t acute & chronic inflammation Damage to structural integrity of fallopian tubes Tubal obstruction Blocks distribution of physiological fluid in fallopian tubes Thus accumulation of fluid

24. Hydrosalpinges impair the fertility through Retrograde flow of toxins and PGs into endometrium Creates a hostile environment for implantation by impairing endometrial receptivity Studies show that pts undergoing IVF have a 50% decrease in pregnancy if hydrosalpinx is present

25. Other conditions interfering with tubal transport- Adhesions from previous surgery Non tubal infections ( appendicitis, IBD) Pelvis tuberculosis Salpingitis isthmica nodosa ( diverticulosis of fallopian tube)

26. 4) UTERINE ANOMALIES IMPAIRED implantation – Mechanical i.e. space occupying lesions Decreased endometrial receptivity Uterine fibroid- submucosal / intracavitary component can lower pregnancy and implantation rates Uterine anomalies- interferes with normal implantation Mullerian anomalies RPL ( septate uterus- poorest reproductive outcome) Others– endometrial polyps -- synechiae from prior pregnancy related curettage

27. Accoring to study, congenital uterine abnormalities account for 8% of female cause of infertility 25% of women will have late 1 st trimester or 2 nd trimester abortions

28. LUTEAL PHASE DEFECT- Abnormal corpus luteum results in inadequate production of progesterone which is necessary for making the endometrium receptive to implantation

29. CERVICAL FACTORS Normal mid-cycle cervical mucus facilitates transport of sperm Congenital malformations or trauma to cx- Stenosis and inability to produce normal mucus Thus impairing fertility

30. AUTOIMMUNE DISEASES Increased risk of infertility due to effect of antibodies on fertilization and implantation Example- premature ovarian failure in women with SLE and MG Celiac disease- if untreated increased frequency of reproductive abnormalities including infertility, abortions and IUGR

31. GENETIC CAUSES Infertile couples have high prevalence of karyotype abnormalities ( trisomies , mosaics, translocations) than the general population M.C. aneuploidies with infertility- 45 X (turner syndrome in women) 47 XXY ( kleinfelters syndrome in male) Genes affecting fecundity- KAL 1 ( kallman’s syndrome) GnRH receptor FSH receptor Beta subunit of FSH LH receptor FMR 1 (fragile X syndrome) LEP receptor TUBB8

32. TUBB8 – TUBB8 mutation disrupts microtubule function during oocyte division Thus arrests oocyte maturation and prevents fertilization Clinical testing is available for abnormality of FMR 1 that causes fragile X syndrome

33. LIFESTYLE FACTORS Tobacco use – accounts for 13% of cases Overweight and obesity Alcohol intake Stress Environmental factors

34. UNEXPLAINED When no cause is revealed after a thorough evaluation

35. HISTORY AND PHYSICAL EXAMINATION

36. Fertility history Current conception attempts      Length of time of unprotected intercourse     Coital frequency     Use of ovulation monitoring     Partner status and are they contributing sperm or oocytes to the patient’s reproductive efforts     Presence of sexual dysfunction, including:  - Decreased libido  - Erectile dysfunction  - Ejaculatory dysfunction  - Dyspareunia  - Vaginismus   Prior fertility history      History of previous conception attempts     Prior periods of intercourse without contraception or with low efficacy contraception     Any prior fertility evaluation or treatment  Gynecologic history Menstrual history      Age at menarche     Cycle length (range), duration, and amount of bleeding     Presence of intermenstrual bleeding     Presence of dysmenorrhea     Presence of molimina   General gynecologic history      Cervical screening history including related treatments    Contraceptive use including type and duration     Sexually transmitted infections and/or pelvic inflammatory disease     Dyspareunia or chronic pelvic pain     History of abnormal cervical screening (pap smear human papillomavirus testing) 

37. Obstetrical history Total number of pregnancies and outcomes, including: - Biochemical miscarriage - Clinical miscarriage - Pregnancy of unknown location - Terminations - Ectopic pregnancy - Stillbirth - Live birth Conceived with current vs. prior partner(s) Details of any fertility treatment required Obstetrical complications, including: - Gestational diabetes - Hypertensive disorders - Preterm delivery - Placental disease - Intrauterine growth restriction Congenital disease or birth defects in offspring Past medical and surgical history Medical disorders with particular attention to endocrine, autoimmune, genetic, psychiatric, or malignant disorders Endocrine history should include evaluation of the thyroid, and the presence of galactorrhea and hirsutism Prior hospitalizations Surgical procedures Medications and allergies Use of gonadotoxic medications or radiotherapy Current medications including any supplements

38. Family history Any family members with known history of: - Inherited disorders - Endocrinopathies - Birth defects - Developmental delay - Infertility - Early menopause (<40 years of age) - Multiple spontaneous abortions Heritable cancer syndromes Social history Occupation and potential exposure to toxic agents Use of tobacco, alcohol, or recreational drugs History of psychological, physical, and/or sexual trauma Gender identity Race and ethnicity Diet and exercise habits

39. PHYSICAL EXAMINATION Vital signs and BMI- extremes of BMI associated with reduced fertility In primary amenorrhea- incomplete development of secondary sexual characteristics is sign of hypogonadotropic hypogonadism Body habitus – short , squarely shaped chest, suggest turner syndrome in pt with absent menses Abnormalities of thyroid gland, galactorrhea or signs of androgen excess ( hirsutism , acne, male pattern baldness, virilisation) suggest endocrinopathy eg . Hyper- or hypothyroidism, hyperprolactinemia , PCOS , adrenal disorder)

40. Tenderness or masses in the adnexae or posterior cul-de-sac – PID or endometriosis Palpable tender nodules in the post cul-de-sac, uterosacral ligaments or rectovaginal septum – suggestive of endometriosis Vaginal/cervical structural abnormalities or discharge – suggest mullerian anomaly, infection, or cervical factor Uterine enlargement, irregularity, or lack of mobility – s/o uterine leiomyoma, endometriosis, or pelvis adhesive disease

41. DIAGNOSTIC EVALUATION

42. Infertility evaluation is indicated for couples who seek help because they have not been able to conceive. 1. Initiate evaluation after 12 months of unprotected and frequent intercourse: Women under age 35 years without risk factors for infertility 2. Initiate evaluation after six months of unprotected and frequent intercourse: Women age 35 to 40 years 3. Initiate evaluation upon presentation despite less than six months of unprotected and frequent intercourse: Women over age 40 years Women with oligomenorrhea /amenorrhea Women with a history of chemotherapy, radiation therapy, or advanced stage endometriosis Women with known or suspected uterine/tubal disease Women whose male partner has a history of groin or testicular surgery, adult mumps, impotence or other sexual dysfunction, chemotherapy and/or radiation, or a history of subfertility with another partner

43. The 5 diagnostic evaluation categories are- Semen analysis – to detect male factor infertility Assessment of ovarian function and reserve Assessment of uterine cavity Assessment of fallopian tubes Endocrinological serum studies

44. ASSESSMENT OF OVULATORY FUNCTION Women with regular menstrual cycles every 28 days with molimina are most likely ovulatory Ovulation is easily documented by a mid-luteal phase serum progesterone level, obtained approx. 1 week before expected menses i.e day-21 Progesterone >3ng/mL s/o recent ovulation Urinary ovulation prediction kit- detects mid-cycle LH surge that precedes ovulation within 1-2 days (5-10% false positive and false negative rate) Thus, serum LH confirmation useful in pts unable to detect a urinary LH surge

45. Other methods, daily ultrasounds to follow development and ultimately the disappearance of the follicle (most accurate method of documenting ovulation) Endometrial biopsy to document secretory changes in endometrium Too expensive and invasive for routine diagnostic assessment of ovulation Mid-luteal progesterone <3ng/mL or highly irregular cycles pt evaluated for anovulation includes— Serum prolactin TSH FSH Assessment for PCOS

46. ASSESSMENT OF OVARIAN RESERVE Diminished ovarian reserve refers to diminished oocyte quality, quantity or reproductive potential Tests for ovarian reserve- Day 3 FSH and estradiol levels CCCT AMH levels

47. Cycle day 3 FSH and estradiol - Women with good ovarian reserve have early sufficient ovarian hormones from small follicles to allow FSH to remain at lower level Women with reduced follicle count produced insufficient hormones, causing lack of inhibition, thus elevated FSH FSH <10IU/mL– normal ovarian reserve FSH 10-20IU/mL – intermediate FSH >20 IU/mL – poor prognosis for spontaneous ovulation d/t low ovarian reserve Accoring to a study,day 3 estradiol value > 80pg/mL – low pregnancy rates Value >100pg/mL – 0% pregnancy rate

48. Elevated basal estradiol levels are due to advanced premature follicle recruitment that occur in women with poor ovarian reserve Day -3 estradiol level reflects the follicular growth rather than no. of antral follicles High estradiol level inhibit pituitary FSH production thus mask one of the signs of decreased ovarian reserve in perimenopausal women Measurement of both FSH and estradiol levels helps to avoid false negative FSH testing (day 1 is the first day of full menstrual flow)

49. CLOMIPHENE CITRATE CHALLENGE TEST- Oral administration of 100mg clomiphene citrate on cycle day-5 through day-9 with measurement of day -3 FSH & estradiol and day 10- FSH FSH < 10IU/mL on day-3 and day-10 – s/o Adequate ovarian reserve FSH 10-15 IU/mL and elevated FSH level on either day-3 or day-10 s/o decreased ovarian reserve

50. ANTI- MULLERIAN HORMONE Member of the TGF-beta family , it’s a glycoprotein Expressed by small (<8mm) preantral and early antral follicles AMH level reflects the size of the primordial follicle pool Can be measured anytime during a woman’s cycle Best biochemical marker of ovarian function Early, reliable, direct indicator of declining ovarian function It gradually declines as the primordial pool declines with age, AMH undetectable at menopause

51. AMH levels seem to be a good predictor of exogenous gonadotropin response- < 0.5ng/mL, predicts difficulty getting more than 3 follicles to grow <0.1 ng /mL, shows limited egg supply that may require more aggressive ovulation induction protocols 1.0 to 3.5 ng /mL, shows normal values >3.5 shows ample supply and may require mild induction to prevent ovarian hyperstimulation syndrome

52. ANTRAL FOLLICLE COUNTS- Measuring the number of follicles measuring 2-10 mm in the ovaries with transvaginal ultrasound in the early follicular phase Predictive of ovarian response to ovulation induction Total AFC (2-10mm size) is usually between 10 to 20 in a redproductive aged woman Count <4 s/o poor response to gonadotropin stimulation & higher cancellation rate in IVF

53. SERUM INHIBIN A peptide hormone produced by granulosa cells starting at preantral follicle stage & reflects size of the developing follicle Low level < 45pg/mL of early follicular phase, s/o poor ovarian response Not preferred as no additional information gained over FSH & d/t its intercycle variability

54. OVARIAN VOLUME & OVARIAN VASCULARITY Decreased ovarian vol > 3cc & decreased stromal blood flow are implicated for poor response & poor treatment outcome Perifollicular vascularity indicates increase of mature oocytes & fertilizability Follicles graded by degree of vascular perfusion Grade 1 < 25% Grade 2 <50% Grade 3 <75% Grade 4 > 75% Vascularity > 50% indicates good outcome

55. ASSESSMENT OF FALLOPIAN TUBE PATENCY rubin’s test HSG first line test – therapeutic + diagnostic benefits Sonohysterosalpingogram HyCoSy Laparoscopy with chromopertubation

56. HYSTEROSALPINGOGRAM- Done within 5-10 days of cycle after cessation of menses Water or lipid soluble radiopaque dye ( Urografin or Conray 420) of 5-10ml is used to fill the uterine cavity with HSG cannula or HSG catheter and fallopian tubes which are then imaged using fluoroscopy (ionizing radiation) X-ray is taken as permanent record- 1 st prilimary view before injection, 2 nd shows filling of ut cavity, 3 rd shows spilling of dye in the cavity Patency determined by spillage of the dye in pelvic cavity Also provides information about the uterine cavity Prophylactically doxycycline 100mg BD given for 5 days to start 2 days before HSG Increase in pregnancy and live birth rates with oil suitable media

57. ADVANTAGES – OPD procedure, a permanent record can be kept, Site & side of block determined & any uterine abnormality like synechiae , septate or subseptate ut can be diagnosed Hydrosalpinges (tobacco-pouch appearance) Beaded appearance in genital TB d/t loculation of dye near fimbriae d/t peritubal adhesions Pregnancy rates increased with oil based dye d/t dislodgement of mucous & debris from tubes.

58. DISADVANTAGES Outer contour of uterus not visualised Chance of embolism & drug recation , vasovagal attack, intravasation of dye through lymphatic or venous channel Perforation of uterus & haemorrhage False negative test occassionally (50-60% with proximal tubal occlusion on HSG had patent tubes on subsequent laparoscopy) Contraindicated in known or suspected cases of PID for fear of flaring up of infection, in AUB or pregnancy

59. Hysterosalpingogram                                                                                                                 Hysterosalpingogram demonstrates occlusion at the isthmus of both fallopian tubes (arrows) in patient with infertility.

60. SONOHYSTEROSALPINGOGRAM Instead of radiopaque dye normal saline is pushed with help of balloon catheter ( foley’s catheter- size 8) inside the uterine cavity Specially designed HSG cathter can be used Fluid in peritoneal cavity seen by sonographic view Presence of fluid in POD confirms spillage To fix the catheter & prevent leakage bulb is inflated beforehand & slight traction given Before instillation of saline baseline USG done

61. ADVANTAGES - Noninvasive , abnormality of uterine cavity can also be diagnosed & no radiation exposure As saline used also called saline infusion sonography (SIS) by which uterine cavity seen very well to diagnose other pathology like polyp

62. HYSTEROSALPINGO-CONTRAST SONOGRAPHY- Uses ultrasound to view uterus, tubes and adnexa before and after transcervical injection of echogenic contrast media i.e. Echovist containing galactose microparticles ( microbubble contrast or agitated saline) Safe, well tolerated , easy method to know tubal status, uterine cavity, the ovaries and myometrium

63. LAPROSCOPIC CHROMOPERTUBATION TEST With the help of laproscope abdominal cavity & pelvic structure visualised A color dye usually methylene blue pushed transcervically with HSG cannula If tubes patent, dye seen coming out through the frimbrial ends of tubes visualized through laproscopy Usually done in premenstrual phase. Couple asked to be abstinent or use barrier contraceptive to avoid conception in that cycle which may be disturbed by the test

64. ADVANTAGES – Any pelvic pathology like endometriosis, PID, polycystic ovary can be diagnosed Outer contour of uterus- any abnormality can be seen False negative less t/t can be done in same sitting if prior planning & consent is taken DISADVANTAGES – More invasive procedure & uterine cavity could not be seen without hysteroscopy Many advocate to do combinely with hysteroscopy ( Hlscopy ) in same sitting

65. FALLOSCOPY – diagnose tubal patency in conjunction with hysteroscope but not used routinely due to fear of tubal perforation SALPINGOSCOPY – during laproscopy tubal patency can be seen through salpingoscopy through fimbrial end

66. ASSESSMENT OF UTERINE CAVITY Saline infusion sonohysterography - information abt endometrial cavity, myometrium, adnexa, intrauterine adhesions, polyps and congenital uterine anomalies HSG- identifies submucous fibroids, a T-shaped cavity, polyp. Synechiae , Congenital mullerian anomalies MRI- to distinguish between a uterine septum and a bicornuate uterus Hysteroscopy- definitive method for evaluation of abnormalities of endometrial cavity with TT at time of diagnosis

67. TEST OF LIMITED CLINICAL UTILITY Postcoital test Endometrial biopsy Basal body temperature records Mycoplasma cultures Testing for antibodies Karyotype

68. TREATMENT

69. LIFESTYLE CHANGES- BMI< 17kg/m2 with history of intense exercise or with eating disorders BMI > 27 kg/m2 with anovulation can improve ovulation with weight loss alone Studies show loss of 10% of body weight restore normal ovulation in 50 to 100% of women in less than 1 year

70. OVULATION INDUCTION It’s a procedure by which ovulation is induced by use of drugs Indications – Anovulation or oligoovulation In ovulatory women to induce more follicular development in cases of infertility

71. Superovulation & ovulation enhancement are synonyms where ovulation induction done with medication even in ovulatory women to get more follicles Controlled ovarian hyperstimulation – applied in ART where follicles are stimulated to retrieve multiple eggs

72. MEDICAL INDUCTION OF OVULATION SERM ( antiestrogens ) – Clomiphene citrate & tamoxifen Gonadotrophins Gonadotropin releasing hormones Aromatase inhibitor – letrozole Adjuvant therapy – Dopamine agonist Insulin sensitizing agents Thyroxin dexamethasone

73. RISK WITH OVULATION INDUCTION – Multiple gestation OHSS Cancer risk

74. OVULATION INDUCTION AGENTS CLOMIPHENE CITRATE- SERM with both estrogen antagonist and agonist thus release gonadotrophins release Effective for inducing ovulation is WHO class 2 Studies show, it is often ineffective in WHO class 1 and class 3 patients Dose starting at 50mg on day 2, 3,4,5 or for 5 sequential days Couple advised to have intercourse every other day for 1 week starting 5 days after the last pill More chances to conceive if combined with IUI

75. MOLECULE & MECHANISM – Nonsteroidal triphenylethylene derivative with both estrogenic & antiestrogenic properties. It binds to estrogen receptor on both hypothalamus & pituitary glands, thus blocking negative feedback of circulating estradiol Thus, increase in FSH from pituitary which induces follicle maturation, estrogen production, midcycle LH surge & finally ovulation En-clomiphene better than Zu -clomiphene d/t shorter half-life

76. DOSE, REGIME & DURATION - CC given a daily dose of 50mg for 5 days starting from day 2 Can be increased by 50mg monthly if no ovulation occurs upto max dose 250mg (rarely used) Dose >100 mg not approved by FDA Should be given for 3-4 months after effective dose is achieved before considering failure Monitoring with midluteal serum progesterone or TVS folliculometry ideally done to determine exact dose & to minimise complications. Standard duration is 6 cycles. (>12 cycles increased risk of ovarian malignancy)

77. RESULT – Ovulation rate with CC is 60-85% with pregnancy rate of 30-40% This discrepancy explained by antiestrogenic effect on cervix & endometrium & d/t presence of other associated factors like tubal factor & endometriosis, etc SIDE EFFECTS- Risk of multiple pregnancy as high as 10% & OHSS is 13% . Chance of miscarriage is 20% slightly higher than normal Hot flushes, nausea, vomiting, pain abdomen, headache, breast tenderness, hair loss

78. TAMOXIFEN Structurally similar to CC, widely used in breast cancer Has no antiestrogenic effect on endometrium or vaginal mucosa Used as 2 nd line in women who has side effects or nonresponsive to CC Dose – 20-80mg/day from day 2 to day 6 of cycle

79. AROMATASE INHIBITORS- Letrozole prevents estrogen production by preventing conversion of androstenedione and testosterone to estrone and estradiol Dose starting at 2.5 , 5 or 7.5mg/day on cycle 3,4,5,6,7 with intercourse every other day 5 days after completing the medications Anovulatory WHO class 2 with poor response to clomiphene (no ovulation or thin endometrium) Advantages over clomiphene- Production of fewer follicles and lower estradiol level, thus decrease risk of multiple gestation Shorter half life (50 hrs vs 5 days) thus reduced antiestrogen effects on endometrium and cervical mucus

80. Gonadotropin therapy- Used in WHO class 2 anovulatory women who have not ovulated or conceived with multiple cycles of clomiphene Also used in WHO class 1 anovulatory women with hypopituitarism or as a second line therapy in hypothalamic amenorrhea Requires close hormonal and sonographic monitoring, is expensive and higher risk of multiple gestation TVS done every 2 to 3 days to monitor follicular growth in late follicular phase to evaluate mature follicles >18mm diameter & estradiol > 200pg/mL

81. Once a mature follicle is identified , recombinant HCG 250mg given to trigger ovulation f/b IUI – 24 – 36 hrs later

82. PREPARATIONS OF GONADOTROPINS- Urinary human menopausal gonadotropin ( hMG ) – contains both FSH & LH (75 IU each) Urinary FSH – purified FSH contains 75 IU FSH & < 1 IU LH Recombinant FSH – developed by genetic engineering Urinary HCG – extracted from placenta or urine of pregnant women. Used (5000-10,000) for LH surge to trigger ovulation Recombinant hCG 250mg – equivalent to 5000-10,000 IU urinary hCG recombinant

83. REGIMENS & DOSE STEP – UP PROTOCOL : In regular dose ‘step-up protocol’ done in WHO group I, Starting dose – 150 IU daily sc / im , then increasing dose by 75 IU after 4-5 days depending upon response assessed by S.estradiol & TVS When 1-2 follicles attain mean diameter of 18mm, 5000-10,000 hCG is administered to trigger ovulation Ovulation expected to occur 36-48hrs after hCG Couples instructed to do intercourse on the day of injection & next day

84. “Chronic low dose step-up protocol” followed in PCOS pts as PCOS ovaries are highly sensitive In this regimen, low FSH dose (50-75 IU) is started & continued for longer period (14 days) Only small doses maybe increased (25-37.5 IU every 5-7 days) STEP – DOWN PROTOCOL: Larger doses (150 IU) started from day 2 or 3 When dominant follicle formed FSH decreased by 37.5 IU & further decreased to 75 IU and continued Advantage – less duration of t/t

85. SEQUENTIAL PROTOCOL – In this, step – up protocol is started first, f/b step down when dominant follicle (>14mm) is formed RISK – OHSS – mild 20%, moderate 6-7%, severe 1-2% Multiple gestation Monitoring of ovarian response – By serial USG – transervse diameter of follicle – 1mm/day at least 3 follicles > 14mm; ET – 8mm or more; E2 – steady increase 200pg/mL/follicle RESULTS OF GONADOTROPINS – WHO Group 1 – pregnancy rate/cycle : 25%, cumulative preg rate 95% after 6 cycles PCOS women - <5-25% & 30-60%

86. PULSATILE GnRH MECHANISM – Administartion on GnRH in pulses stimulates the pituitary & releases FSH & LH DOSE – 2.5-10mcg, at 60-90mins interval mimicking normal pulse release by a portable mini pump either SC/IV INDICATION – WHO Type 1 anovulation with intact pituitary ADVANTAGES – Multifollicular development & OHSS is less Monitoring with usg pelvis & serum estradiol every 3-4 days interval RESULT – Pre treatment cycle – ovulation rate is 79-93% & preg 18-29%

87. DOPAMINE AGONISTS INDICATION – Infertilty with hyperprolactemia . 30% PCOS pts are hyperprolactenemic TYPES – Bromocriptine & cabergoline commonly used Ergot alkaloids Cabergoline inhibits only D2 receptor & more effective with fewer s/e New agent - quinagolide

88. MECHANISM – Mimic dopamine & binds dopamine receptors Enhance tonic suppression of prolactin synthesis & release from pituitary & cause euprolactinemia that results ovulation in 80% cases Bromocriptine’s half life is short & remains in circulation for 14 hrs Cabergoline is longer acting with higher affinity for receptors & inhibits prolactin secretion for seven days

89. DOSES – Bromocriptine started with 1.25mg daily at bed time for 1 week & then increased 1.25mg twice daily for 1 month. Dose maybe increased if prolactin level doesn’t become normal Daily dose maybe needed 7.5mg Cabergoline started 0.25mg twice a week for 2 months SIDE EFFECTS – More with bromocriptine mainly , GI and Cardiovascular Headache Nasal congestion

90. PREGNANCY RATE OF DOPAMINE AGONISTS – Cabergoline is superior to bromocriptine for euprolactinemia (80% vs 55%), ovulation (72% vs 52%), and conception (72% vs 48%) When preg occurs in microprolactinoma bromocriptine stopped as chance of growth is minimal (2%) but in macroprolactinoma chance of growth is high (25%) and needs continuation

91. METFORMIN- Insulin resistence commonly seen in PCOS Correction of hyperinsulinemia with metformin useful in PCOS & to induce ovulation by increasing SHBG & decreasing insulin resistance at target tissue & decrease glucose absorption in intestine Indicated in PCOS & BMI > 25kg/m2 Dose – 500mg thrice daily s/e - GI

92. DEXAMETHASONE Found beneficial in some CC resistant cases It decreases adrenocorticotropic hormone peak which decreases adrenal androgens 0.5 mg daily at bed time for 5 days starting on 1 st day of CC, 0.5mg for 6 weeks prior to start CC

93. SURGICAL MX IN ANOVULATION/OLIGOOVULATION Laproscopic ovarian drilling Wedge resection in PCOS Laproscopic laser vaporization Surgery for ovarian or pelvic endometriosis

94. LAPROSCOPIC ovarian drilling SURGERY- Laproscopic ovarian drilling by diathermy or laser to induce ovulation in anovulatory PCOS pts ‘RULE OF 4’ – only 4 punctures on each ovary, using 40 watts of energy for 4 sec , upto 4mm depth on ovarian surface Drinning decreases ovarian androgen secreting tissue & promotes ovulation Only used in pts who fail to conceive through alternative tretaments Invasive

95. ADVANTAGES – 52% ovulation induction rate, 26%- 48% pregnancy rate Multiple gestation very low OHSS risk very low DISADVANTAGE – Surgical complications Adhesion formation Recurrence of anovulation Decreased ovarian reserve

96. TUBAL AND PELVIS ADHESIONS PREVENTION – Early detection & mx of pelvic infection, MTP done in strict aseptic measures Medical – antibiotics & antitubercular drugs Hydrotubation Surgery – Macroscopic Microscopic Laparscopy ART : IVF-ET

97. SX FOR TUBAL FACTOR INFERTILITY – Adhesiolysis Frimbioplasty – lysis of frimbrial adhesion with dilatation of frimbrial phimosis Salpingostomy – creation of tubal stroma with completely occulded distal including hydrosalpinx Tubotubal anastomosis Tubocornual anastomosis Cannulation & balloon tuboplasty (through hysteroscopy) in proximal tubal obstruction

98. UTERINE ABNORMALITIES Fibroids that impinge on the endometrium distorting the uterine cavity ( submucosal and submucosal -intramural fibroids) First line treatment for removal of fibroid is operative hysteroscopy Uterine synechiae , septa, congenital anomalies- hysteroscopic resection Endometrial polyps- polypectomy

99. ART vs SURGERY – TUBAL FACTOR INFERTILITY grossly damaged or even absent tube where restorative sx has no role, ART can bring pregnancy IVF & ET is to achieve preg bypassing the damaged or absent tube, but sx does it by treating the abnormality, restoring anatomy of tube to as normal as possible & maintaining patency After tubal reconstructive sx , couple may have permanent ability to conceive in every cycle naturally A single IVF cycle gives only one chance to conceive, several cycles maybe needed to conceive Following reconstructive sx , overall risks are low including risk such as bleeding, infection, anaesthsia

100. Chances of ectopic pregnancy in both cases ART has some potential complications – severe OHSS (0.25-2%) & multiple pregnancies ( upto 25%) Avg live birth rate per cycle of t/t in ART is from 19% to 35% In intrinsic tubal damage, sx results preg at rate ofm10-60% with ectopic preg rate as high as 21%

101. IVF & EMBRYO TRANSFER In this, eggs are removed from the ovaries Fertilized in the lab with the male partner’s sperm Resulting embryos are then replaced back in the womb 3-7 days later INDICATIONS – Tubal factor infertility Cervical hostility Infertility with endometriosis Unexplained infertility Failed ovulation induction

102. BASIC STEPS IN IVF & ET Patient selection Downregulation by GnRH analog Controlled ovarian hyperstimulation Monitoring Oocyte retrieval transvaginally with usg guidance Sperm preparation Insemination : sperm & ova mixed in vitro for fertilization Embryo transfer – viable embryos transferred transcervically into uterine cavity Luteal support

103. CONTROLLED OVARIAN HYPERSTIMULATION To get multiple no of oocytes superovulation done by ovulation-induction drugs Drugs used are CC, gonadptropin , GnRH Gnrh agonists used for downregulation of HPO axis to get multiple no of good quality oocytes, expecting increase in clinical pregnancy rate Gnrh prevents premature ovulation. hCG given for final maturation & trigger ovulation which occurs 36hrs of hCG administration Idea is to get multiple oocytes by aspiration, multiple embryos, multiple embryo transfer, increase success rate

104. MONITORING – Mandatory for fixing of time of hCG administration & to prevent and detect OHSS Monitoring of ovarian response done by serial folliculometry & measurements of serum estradiol PROTOCOLS OF COH – Depends on category of pt Long protocol – for normal responder Short protocol – for poor responder GnRH antagonist protocol Coasting is used for hyper-responder where gonadotropin discontinued in last part to prevent OHSS

105. LONG PROTOCOL – GnRH agonist started from midluteal phase of previous cycle & continued throughout the follicular phase till hCG given Gonadotropins administered after onset of menses, either leuprolide 0.1mg SC daily or nafarelin 200 mcg twice daily used Monitoring done by serial folliculometry & measurements of serum estradiol hCG administered to trigger ovulation when >3 follicles of at least 17mm diameter in USG Ova picked up 36hrs after hCG . Embros transferred to uterus 3-5 days after retrieval Luteal support given by progesterone either vaginal or injectable route

106. SHORT PROTOCOL – Gnrh agonists usually leuprolide 20pg SC twice daily started from day 2 or 3 of cycle F/b administration of gonadotropins after 2 days & continued through follicular phase COASTING – GnRH agonist started from third week of previous cycle & gonadotropin in low dose (75 IU/day) started after menses & if E2 > 3000pg/mL Gonadotropin discontinued irrespective of follicular diameter & GnRH continued. After E2 <3000pg, hCG administered Useful for hyper-responders like PCOS to prevent OHSS

107. GnRH ANTAGONIST PROTOCOL – Gonadotropin started on day 2 or 3 of cycle f/b GnRH antagonist from day 6 or in a flexible manner Adv is less duration of tt cycle, OHSS less, overall less no of injection & less cost

108. OOCYTE RETRIVAL Under transvaginal sonographic guidance using transvaginal transducer mature oocytes are retrieved transvaginally puncturing through vagina and ovary Oocyte with follicular fluid is aspirated. A washing media mixed with heparin is used & examined under microscope

109. MIXING OF SPERM & OVA , AND IVF Sperm preparation is done The oocyte is inseminated by fresh or cryopreserved sperm >50,000 sperms per egg are used The mixture is incubated in a specialised incubator Presence of formation of pronuclei aftr 18-20hrs indicates fertilization & allowed to cleave 2-4 cell stage when its transferred into uterus Transfer in stage of blastocyst (needs more time of culture outside) increasingly practiced as lesser no of embryo transferred to prevent multiple gestation & make it more physiological as at time of transfer synchronization of endometrial bed occurs

110. EMBRYO TRANSFER With help of an embryo transfer catheter 2-3 embryos in 0.15 to 0.3mL of fluid are transferred after 46-48hrs of insemination little below (1cm) the fundus Abdominal sonographic guidance very helpful during transfer LUTEAL SUPPORT – Progesterone in vaginal route of IM injection (50mg IM/day) Inj hCG 2000 IU biweekly used previously is not a good choice

111. RESULTS OF IVF AND ET- Pregnancy rate – 25-30% Multiple pregnancy rate – 30% Take home baby - <20%

112. ADVANTAGES OF IVF- Better per-cycle success rates than other fertility t/t Less surgical invasive than tubal surgery Can overcome other subfertility factors like male factor, cervical factor, decreased ovarian reserve Site and extent of tubal damange are not important for outcome

113. DISADVANTAGES OF IVF- High per cycle cost and possible need for multiple cycles Need for IVF each time a pregnancy is desired Requires frequent injections and monitoring Increase risk of multiple gestation Increase risk of ovarian hyperstimulation syndrome

114. PROGNOSIS Following pregnancy rate collected from a retrospective analysis of 45 separate studies- No treatment– 1.3- 3.8% IUI alone – 4% Clomiphene citrate alone – 5.6% CC with IUI – 8.3% Gonadotropins alone – 7.7% Gonadotropins with IUI – 17.1% IVF – 20.7%

115. COMPLICATIONS THREE PRIMARY COMPLICATIONS- Multiple gestations Ectopic pregnancy Ovarian hyperstimulation syndrome

116. OHSS- Pathology- increased capillary permeability, thus fluid shift into third space Higher risk-- >20 mature follicles who also receive an HCG trigger shot Moderate OHSS – 6% with IVF Severe OHSS – 1% with IVF Symptoms- Abdominal distension, nausea, vomiting Enlarged ovaries Third spacing of fluids Renal failure Venous thrombosis Acute respirator distress syndrome Electrolyte derangements Cardiac arrhythmias sepsis

117. ECTOPIC PREGNANCY- Highest risk with tubal factor infertility- 9% IVF – 1.3% Clomiphene – 4% Letrozole – 6% Gonadotropins – 8%

118. THANK YOU - DR. AISHWARYA N. GHOGARE