InfertilityInfertility Zeev Blumenfeld, M.D. Reproductive Endocrinology, Dept. Obstetrics & Gynecology Dept. Obstetrics & Gynecology Rambam Health Care Campus, Faculty of Medicine, Technion- Israel Institute of Technology (IIT) Haifa, Israel Zeev Blumenfeld, M.D. Reproductive Endocrinology, Dept. Obstetrics & Gynecology Dept. Obstetrics & Gynecology Rambam Health Care Campus, Faculty of Medicine, Technion- Israel Institute of Technology (IIT) Haifa, Israel

DefinitionsDefinitions Infertility –Inability to conceive after one year of unprotected intercourse (6 months for women over 35?) Fertility –Ability to conceive Fecundity –Ability to carry to delivery Infertility –Inability to conceive after one year of unprotected intercourse (6 months for women over 35?) Fertility –Ability to conceive Fecundity –Ability to carry to delivery

StatisticsStatistics 80% of couples will conceive within 1 year of unprotected intercourse ~86% will conceive within 2 years ~14-20% of US couples are infertile by definition (~3 million couples) Origin: –Female factor ~40% –Male factor ~30% –Combined ~30% 80% of couples will conceive within 1 year of unprotected intercourse ~86% will conceive within 2 years ~14-20% of US couples are infertile by definition (~3 million couples) Origin: –Female factor ~40% –Male factor ~30% –Combined ~30%

EtiologiesEtiologies Sperm disorders 30% Anovulation/oligo-ovulation 30% Tubal disease 15% Unexplained 15% Cx factors 5% Peritoneal factors 5% Sperm disorders 30% Anovulation/oligo-ovulation 30% Tubal disease 15% Unexplained 15% Cx factors 5% Peritoneal factors 5%

Associated Factors PID Endometriosis Ovarian aging Spermatic varicocoele Toxins Previous abdominal surgery (adhesions) Cervical/uterine abnormalities Cervical/uterine surgery Fibroids PID Endometriosis Ovarian aging Spermatic varicocoele Toxins Previous abdominal surgery (adhesions) Cervical/uterine abnormalities Cervical/uterine surgery Fibroids

Emotional & Educational Needs Disease of couples, not individuals Feelings of guilt Where to go for information? Options Feelings of frustration and anger Support groups (e.g. Resolve) Disease of couples, not individuals Feelings of guilt Where to go for information? Options Feelings of frustration and anger Support groups (e.g. Resolve)

Overview of Evaluation Female –Ovary –Tube –Corpus –Cervix –Peritoneum Male –Sperm count and function –Ejaculate characteristics, immunology –Anatomic anomalies Female –Ovary –Tube –Corpus –Cervix –Peritoneum Male –Sperm count and function –Ejaculate characteristics, immunology –Anatomic anomalies

The Most Important Factor in the Evaluation of the Infertile Couple Is:

HISTORYHISTORY

History-GeneralHistory-General Both couples should be present Age Previous pregnancies by each partner Length of time without pregnancy Sexual history –Frequency and timing of intercourse –Use of lubricants –Impotence, anorgasmia, dyspareunia –Contraceptive history Both couples should be present Age Previous pregnancies by each partner Length of time without pregnancy Sexual history –Frequency and timing of intercourse –Use of lubricants –Impotence, anorgasmia, dyspareunia –Contraceptive history

History-MaleHistory-Male History of pelvic infection Radiation, toxic exposures (include drugs) Mumps Testicular surgery/injury Excessive heat exposure (spermicidal) History of pelvic infection Radiation, toxic exposures (include drugs) Mumps Testicular surgery/injury Excessive heat exposure (spermicidal)

History-FemaleHistory-Female Previous female pelvic surgery PID Appendicitis IUD use Ectopic pregnancy history DES (?relation to infertility) Endometriosis Previous female pelvic surgery PID Appendicitis IUD use Ectopic pregnancy history DES (?relation to infertility) Endometriosis

Mechanical/Pelvic factor infertility Distal tubal occlusion  PID - 13% post PIDx1  - 39% post PIDx2  - 75% post PIDx3  Endometriosis  Surgical injury  Peritoneal infection  PID - 13% post PIDx1  - 39% post PIDx2  - 75% post PIDx3  Endometriosis  Surgical injury  Peritoneal infection

History-FemaleHistory-Female Irregular menses, amenorrhea, detailed menstrual history Vasomotor symptoms Stress Weight changes Exercise Cervical and uterine surgery Irregular menses, amenorrhea, detailed menstrual history Vasomotor symptoms Stress Weight changes Exercise Cervical and uterine surgery

When Not to Pursue an Infertility Evaluation Patient not sexually-active Patient not in long-term relationship? Patient declines treatment at this time Couple does not meet the definition of an infertile couple Patient not sexually-active Patient not in long-term relationship? Patient declines treatment at this time Couple does not meet the definition of an infertile couple

Physical Exam-Male Size of testicles Testicular descent Varicocoele Outflow abnormalities (hypospadias, etc) Size of testicles Testicular descent Varicocoele Outflow abnormalities (hypospadias, etc)

Physical Exam-Female Pelvic masses Uterosacral nodularity Abdominopelvic tenderness Uterine enlargement Thyroid exam Uterine mobility Cervical abnormalities Pelvic masses Uterosacral nodularity Abdominopelvic tenderness Uterine enlargement Thyroid exam Uterine mobility Cervical abnormalities

Overall Guidelines for Work-up Work- up can usually be accomplished in 1- 2 cycles [“Cycle Evaluation”] Timing of tests Don’t over test Cut to the chase, i.e. proceed with laparoscopy if adhesive disease is likely Work- up can usually be accomplished in 1- 2 cycles [“Cycle Evaluation”] Timing of tests Don’t over test Cut to the chase, i.e. proceed with laparoscopy if adhesive disease is likely

Work-up by Organ Unit

Ovary

Ovarian Function Document ovulation: –BBT –Luteal phase progesterone –LH surge –Endom. Bx If POF suspected, perform FSH TSH, PRL, adrenal functions if indicated The only convincing proof of ovulation is pregnancy Document ovulation: –BBT –Luteal phase progesterone –LH surge –Endom. Bx If POF suspected, perform FSH TSH, PRL, adrenal functions if indicated The only convincing proof of ovulation is pregnancy

Ovarian Function Three main types of dysfunction –Hypogonadotrophic, hypoestrogenic (central) –Normogonadotropic,normoestrogenic (e.g. PCOS) –Hypergonadotrophic, hypoestrogenic (POF) Three main types of dysfunction –Hypogonadotrophic, hypoestrogenic (central) –Normogonadotropic,normoestrogenic (e.g. PCOS) –Hypergonadotrophic, hypoestrogenic (POF)

BBTBBT Cheap and easy, but…  Inconsistent results  Retrospective  May delay timely diagnosis and treatment  98% of women will ovulate within 3 days of the nadir  Biphasic profiles can also be seen with LUF syndrome Cheap and easy, but…  Inconsistent results  Retrospective  May delay timely diagnosis and treatment  98% of women will ovulate within 3 days of the nadir  Biphasic profiles can also be seen with LUF syndrome

Luteal Phase Progesterone  Pulsatile release, thus single level may not be useful unless elevated  Performed 7 days after presumptive ovulation  Done properly, >15 ng/ml consistent with ovulation  Pulsatile release, thus single level may not be useful unless elevated  Performed 7 days after presumptive ovulation  Done properly, >15 ng/ml consistent with ovulation

Urinary LH Kits  Sensitive and accurate  Positive test precedes ovulation by ~24 hours, so useful for timing intercourse  Downside: price, obsession with timing of intercourse  Sensitive and accurate  Positive test precedes ovulation by ~24 hours, so useful for timing intercourse  Downside: price, obsession with timing of intercourse

Endometrial Biopsy  Invasive, but the only reliable way to diagnose LPD  ??Is LPD a genuine disorder???  Pregnancy loss rate <1%  Perform around 2 days before expected menstruation (= day 28 by definition)  Lag of >2 days is consistent with LPD  Must be done in two different cycles to confirm diagnosis of LPD  Invasive, but the only reliable way to diagnose LPD  ??Is LPD a genuine disorder???  Pregnancy loss rate <1%  Perform around 2 days before expected menstruation (= day 28 by definition)  Lag of >2 days is consistent with LPD  Must be done in two different cycles to confirm diagnosis of LPD

Fallopian Tubes

Tubal Function  Evaluate tubal patency whenever there is a history of PID, endometriosis or other adhesiogenic condition  Kartagener’s syndrome can be associated with decreased tubal motility  Tests  HSG  Laparoscopy  Falloposcopy (not widely available)  Evaluate tubal patency whenever there is a history of PID, endometriosis or other adhesiogenic condition  Kartagener’s syndrome can be associated with decreased tubal motility  Tests  HSG  Laparoscopy  Falloposcopy (not widely available)

Hysterosalpingography (HSG)  Radiologic procedure requiring contrast  Performed optimally in early proliferative phase (avoids pregnancy)  Low risk of PID except if previous history of PID (give prophylactic doxycycline or consider laparoscopy)  Oil-based contrast  Higher risk of anaphylaxis than H 2 O-based  May be associated with fertility rates  Radiologic procedure requiring contrast  Performed optimally in early proliferative phase (avoids pregnancy)  Low risk of PID except if previous history of PID (give prophylactic doxycycline or consider laparoscopy)  Oil-based contrast  Higher risk of anaphylaxis than H 2 O-based  May be associated with fertility rates

Hysterosalpingography (HSG) Can be uncomfortable Pregnancy test is advisable Can detect intrauterine and tubal disorders but not always definitive Can be uncomfortable Pregnancy test is advisable Can detect intrauterine and tubal disorders but not always definitive

LaparoscopyLaparoscopy Invasive; requires OR or office setting Can offer diagnosis and treatment in one sitting Not necessary in all patients Uses (examples): –Lysis of adhesions –Diagnosis and excision of endometriosis –Myomectomy –Tubal reconstructive surgery Invasive; requires OR or office setting Can offer diagnosis and treatment in one sitting Not necessary in all patients Uses (examples): –Lysis of adhesions –Diagnosis and excision of endometriosis –Myomectomy –Tubal reconstructive surgery

FalloposcopyFalloposcopy Hysteroscopic procedure with cannulation of the Fallopian tubes Can be useful for diagnosis of intraluminal pathology Promising technique but not yet widespread Hysteroscopic procedure with cannulation of the Fallopian tubes Can be useful for diagnosis of intraluminal pathology Promising technique but not yet widespread

Uterine Corpus

CorpusCorpus Asherman Syndrome –Diagnosis by HSG or hysteroscopy –Usually s/p D+C, myomectomy, other intrauterine surgery –Associated with hypo/amenorrhea, recurrent miscarriage Fibroids, Uterine Anomalies –Rarely associated with infertility –Work-up: Ultrasound Hysteroscopy Laparoscopy Asherman Syndrome –Diagnosis by HSG or hysteroscopy –Usually s/p D+C, myomectomy, other intrauterine surgery –Associated with hypo/amenorrhea, recurrent miscarriage Fibroids, Uterine Anomalies –Rarely associated with infertility –Work-up: Ultrasound Hysteroscopy Laparoscopy

Cervix

Cervical Function Infection –Ureaplasma suspected Stenosis –S/P LEEP, Cryosurgery, Cone biopsy (probably overstated) Immunologic Factors –Sperm-mucus interaction Infection –Ureaplasma suspected Stenosis –S/P LEEP, Cryosurgery, Cone biopsy (probably overstated) Immunologic Factors –Sperm-mucus interaction

Cervical Function Tests: –Culture for suspected pathogens –Postcoital test (PCT) Scheduled around 1-2d before ovulation (increased estrogen effect) 48 0 of male abstinence before test No lubricants Evaluate 8-12h after coitus (overnight is ok!) Remove mucus from cervix (forceps, syringe) Tests: –Culture for suspected pathogens –Postcoital test (PCT) Scheduled around 1-2d before ovulation (increased estrogen effect) 48 0 of male abstinence before test No lubricants Evaluate 8-12h after coitus (overnight is ok!) Remove mucus from cervix (forceps, syringe)

SpinnbarkeitFerning Late follicular phase Watery, thin & acellular Cervical Mucus

Cervical Function PCT, continued (normal values in yellow) –Quantity (very subjective) –Quality (spinnbarkeit) (>8 cm) –Clarity (clear) –Ferning (branched) –Viscosity (thin) –WBC’s (~0) –# progressively motile sperm/hpf (5-10/hpf) –Gross sperm morphology (WNL) PCT, continued (normal values in yellow) –Quantity (very subjective) –Quality (spinnbarkeit) (>8 cm) –Clarity (clear) –Ferning (branched) –Viscosity (thin) –WBC’s (~0) –# progressively motile sperm/hpf (5-10/hpf) –Gross sperm morphology (WNL) Male factors

Problems with the PCT Subjective Timing varies; may need to be repeated In some studies, “infertile” couples with an abnormal PCT conceived successfully during that same cycle Subjective Timing varies; may need to be repeated In some studies, “infertile” couples with an abnormal PCT conceived successfully during that same cycle

Peritoneum

Peritoneal Factors Endometriosis –2x relative risk of infertility –Diagnosis (and best treatment) by laparoscopy –Can be familial; can occur in adolescents –Etiology unknown but likely multiple ones Retrograde menstruation Immunologic factors Genetics Lymphatic or Hematogenic spread –Medical options remain suboptimal Endometriosis –2x relative risk of infertility –Diagnosis (and best treatment) by laparoscopy –Can be familial; can occur in adolescents –Etiology unknown but likely multiple ones Retrograde menstruation Immunologic factors Genetics Lymphatic or Hematogenic spread –Medical options remain suboptimal

Male Factors

Serum T, FSH, PRL levels Semen analysis Testicular biopsy Sperm penetration assay (SPA) Serum T, FSH, PRL levels Semen analysis Testicular biopsy Sperm penetration assay (SPA)

Male Factors-Semen Analysis Collected after 48 0 of abstinence Evaluated within one hour of ejaculation If abnormal parameters, repeat twice, 2 weeks apart Collected after 48 0 of abstinence Evaluated within one hour of ejaculation If abnormal parameters, repeat twice, 2 weeks apart

Normal Semen Analysis

Male factor evaluation Spermiogram

Sperm Penetration Assay “Zona-free Hamster Ova Assay” Dynamic test of fertilization capacity of sperm Failure to penetrate at least 10% of zona- free ova consistent with male factor False positives and negatives exist “Zona-free Hamster Ova Assay” Dynamic test of fertilization capacity of sperm Failure to penetrate at least 10% of zona- free ova consistent with male factor False positives and negatives exist

Male factor Endocrine evaluation

Male Factor Evaluation Genetics CBAVD, CUAVD Epididymal obstruction Ejaculatory duct obstruction Non-obstructive AZO Severe OTA Non-Obstructive AZO Severe OTA  CF gene mutations  Karyotype  Y-microdeletions

Treatment Options

Ovarian Disorders  Anovulation  Clomiphene Citrate ± hCG  FSH, hMG/hCG  Induction + IUI (often done but unjustified)  PRL  Bromocriptine [ Parlodel,Parilac mg/day, bid],  Cabergoline [Dostinex 0.5 mg/week]],  Octahydrobenzoquinoline [Norprolac  g/day]  TSR if macroadenoma  POF  ?high-dose hMG (not very effective)  Anovulation  Clomiphene Citrate ± hCG  FSH, hMG/hCG  Induction + IUI (often done but unjustified)  PRL  Bromocriptine [ Parlodel,Parilac mg/day, bid],  Cabergoline [Dostinex 0.5 mg/week]],  Octahydrobenzoquinoline [Norprolac  g/day]  TSR if macroadenoma  POF  ?high-dose hMG (not very effective)

Ovulatory Disorders Central amenorrhea –CC first, then hMG –Pulsatile GnRH LPD –Progesterone suppositories during luteal phase –CC ± hCG Central amenorrhea –CC first, then hMG –Pulsatile GnRH LPD –Progesterone suppositories during luteal phase –CC ± hCG

Ovarian Matrix

Ovulatory factor Endocrine evaluation FSH LH E 2 PRL Hypothalamic Insufficiency ↓ ↓ ↓ N Pituitary adenoma/ N/↓ N/↓ N/↓ N/↑ HyperPRLemia PCO N/low ↑ N N/↑ Ovarian failure ↑ ↑ ↓ N

Ovulation Induction CC –70% induction rate, ~40% pregnancy rate –Patients should typically be normoestrogenic –Induce menses and start on day 3-5 –With dosages, antiestrogen effects dominate –Multifetal rates 5-10% –Monitor effects with PCT, pelvic exam CC –70% induction rate, ~40% pregnancy rate –Patients should typically be normoestrogenic –Induce menses and start on day 3-5 –With dosages, antiestrogen effects dominate –Multifetal rates 5-10% –Monitor effects with PCT, pelvic exam

Clomiphene Citrate Mechanism of Action

Response to clomiphene No response Ovulation & pregnancy & pregnancy Ovulation - no pregnancy 33%

Clomiphene Citrate Side Effects  Dysmucorrhea - 15%  Hot flushes - 10%  Abdominal pain - 5.5% (OHSS usually mild)  Breast discomfort - 2%  Nausea and vomiting - 2.2%  Visual symptoms - 1.5%  Headache - 1.3%  Emotional liability and depression  Dysmucorrhea - 15%  Hot flushes - 10%  Abdominal pain - 5.5% (OHSS usually mild)  Breast discomfort - 2%  Nausea and vomiting - 2.2%  Visual symptoms - 1.5%  Headache - 1.3%  Emotional liability and depression

CC- Mechaniam of Action

hMG (Pergonal,Menogon,Menopur) LH +FSH (also FSH alone = Gonal-F,Puregon) For patients with hypogonadotrophic hypoestrogenism or normal FSH and E 2 levels Close monitoring essential, including estradiol levels 60-80% pregnancy rates overall, lower for PCOS patients 10-15% multifetal pregnancy rate LH +FSH (also FSH alone = Gonal-F,Puregon) For patients with hypogonadotrophic hypoestrogenism or normal FSH and E 2 levels Close monitoring essential, including estradiol levels 60-80% pregnancy rates overall, lower for PCOS patients 10-15% multifetal pregnancy rate

hMG- Mechanism of Action

Human Gonadotropins Results Group I Cumulative pregnancy rate after 6 months 90% Group II Cumulative pregnancy rate after 6 months 40% Group I Cumulative pregnancy rate after 6 months 90% Group II Cumulative pregnancy rate after 6 months 40%

RisksRisks CC  Vasomotor symptoms  Head Ache  Ovarian enlargement  Multiple gestation  NO risk of SAb or malformations CC  Vasomotor symptoms  Head Ache  Ovarian enlargement  Multiple gestation  NO risk of SAb or malformations hMG  Multiple gestation  OHSS (~1%) –Can often be managed as outpatient –Diuresis –Severe cases fatal if untreated in ICU setting hMG  Multiple gestation  OHSS (~1%) –Can often be managed as outpatient –Diuresis –Severe cases fatal if untreated in ICU setting

Fallopian Tubes  Tuboplasty  IVF  GIFT, ZIFT not options  Tuboplasty  IVF  GIFT, ZIFT not options

CorpusCorpus Asherman syndrome –Hysteroscopic lysis of adhesions (scissor) –Postop Abx, E 2 Fibroids (rarely need treatment) –Myomectomy ( hysteroscopic, laparoscopic, open) Uterine anomalies (rarely need treatment) –Metroplasty, Hysteroscopy Asherman syndrome –Hysteroscopic lysis of adhesions (scissor) –Postop Abx, E 2 Fibroids (rarely need treatment) –Myomectomy ( hysteroscopic, laparoscopic, open) Uterine anomalies (rarely need treatment) –Metroplasty, Hysteroscopy

CervixCervix Repeat PCT to rule out inaccurate timing of test If cervicitisAbx If scant mucuslow-dose estrogen Sperm motility issues (? Antisperm AB’s) –Steroids? –IUI Repeat PCT to rule out inaccurate timing of test If cervicitisAbx If scant mucuslow-dose estrogen Sperm motility issues (? Antisperm AB’s) –Steroids? –IUI

Peritoneum (Endometriosis) From a fertility standpoint, excision beats medical management Lysis of adhesions GnRH-a (not a cure and has side effects, expense) Danazol (side effects, cost) Continuous OCP’s (poor fertility rates) Chances of pregnancy highest within 6 m’s-1 year after treatment From a fertility standpoint, excision beats medical management Lysis of adhesions GnRH-a (not a cure and has side effects, expense) Danazol (side effects, cost) Continuous OCP’s (poor fertility rates) Chances of pregnancy highest within 6 m’s-1 year after treatment

Male Factor Hypogonadotrophism –hMG –GnRH –CC, hCG results poor Varicocoele –Ligation? (no definitive data yet) Retrograde ejaculation –Ephedrine, imipramine –AIH with recovered sperm Hypogonadotrophism –hMG –GnRH –CC, hCG results poor Varicocoele –Ligation? (no definitive data yet) Retrograde ejaculation –Ephedrine, imipramine –AIH with recovered sperm

Male Factor Idiopathic oligospermia –No effective treatment –?IVF –donor insemination Idiopathic oligospermia –No effective treatment –?IVF –donor insemination

Unexplained Infertility 5-10% of couples Consider PRL, laparoscopy, other hormonal tests, cultures, ASA testing, SPA if not done Review previous tests for validity Empiric treatment: –Ovulation induction –Abx –IUI –Consider IVF and its variants Adoption 5-10% of couples Consider PRL, laparoscopy, other hormonal tests, cultures, ASA testing, SPA if not done Review previous tests for validity Empiric treatment: –Ovulation induction –Abx –IUI –Consider IVF and its variants Adoption

SummarySummary Infertility is a common problem Infertility is a disease of couples Evaluation must be thorough, but individualized Treatment is available, including IVF, but can be expensive, invasive, and of limited efficacy in some cases Consultation with a expert reproductive endocrinologist is advisable Infertility is a common problem Infertility is a disease of couples Evaluation must be thorough, but individualized Treatment is available, including IVF, but can be expensive, invasive, and of limited efficacy in some cases Consultation with a expert reproductive endocrinologist is advisable

Thank you!