04/19/23

Infertility

Edward Illions, M.D.Associate Professor

Division of Reproductive Endocrinology & Infertility

Department of Obstetrics, Gynecology & Women’s Health

Albert Einstein College of Medicine

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Definition• Failure to conceive after 12 months

of regular coital activity in the absence of contraception.

• Classification :– Primary– Secondary

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Epidemiology of Infertility

Affects 10-15% of couples of reproductive age.

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Terminology• Fecundability: Probability of

achieving pregnancy within one menstrual cycle-approximately 25%

• Fecundity: The ability to achieve a live birth within one menstrual cycle

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Natural FertilityTime Required for Conception

Time of Exposure % Pregnant

1 month 30%3 months 57%6 months 72%1 year 85%2 years 93%

Guttmacher AF, Factors affecting normal expectancy of conception, JAMA 161:855, 1956.

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Female Reproductive Anatomy

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Integral Components to Fertility

• Gamete availability– Production– Deposition

• Sperm transport• Cervical hospitality• Patency of fallopian tubes • Fertilization• Normal embryonic development and cleavage• Endometrial receptivity• Implantation • Embryonic growth and development

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Integral Components to Fertility

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Etiology of Infertility• Male factors 35%• Female factor/s 55%

• Tubal factor 40%• Ovulatory disturbances 40%• Unexplained infertility 10%• Miscellaneous 10%

– Uterine factor– Cervical factor

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Male Infertility- etiology

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Male Infertility-diagnostic tests

• Semen Analysis-WHO criteria– Volume 2-5ml– Viscosity viscous/liquefies in 30 min.– Color opalescent– Sperm count 20 million/ml– Motility 50% motile (≥20µm/sec)– Morphology 30% normal (>14% Kruger)

– Head/neck piece/tail

– WBC’s < 1 million/ml

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Male Infertility-Terminology

• Oligospermia <20 Million per ml• Asthenospermia <50% motile sperm• Teratospermia >70% abnormal

sperm• Oligo-astheno-teratospermia• Azoospermia No sperm seen

• Obstructive Cystic Fibrosis/Infections• Non-Obstructive Kleinfelter’s Syndrome (47 XXY)

Sertoli Cell Only Syndrome

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Male Infertility-diagnostic tests

• Karyotype– Klinefelter syndrome (1:500 males)

• Y microdeletion– AZFa, AZFb, AZFc (= DAZ)

• Cystic Fibrosis– Congenital bilateral absence of vas

deferens (1-2% infertile males)– 5T allelle

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Male Infertility-diagnostic tests

• NOT utilized anymore (really)– Sperm Penetration Assay– Human Zona Binding Assay/Hemizona

Assay– Hypo-osmotic Swelling Test

• Hypo-osmotic sodium citrate and fructose solution

– Sperm Antibodies

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Female Infertility- etiology

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Female Infertility

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Female Infertility- ovarian reserve testing

Cycle Day 3 FSH / Estradiol (E2)FSH > 10 IU/L associated with poor pregnancy rates with IVFE2 > 80 pg/mL

Clomiphene Challenge Test (CCCT)FSH > 10 IU/L on CD3 or CD10

Ultrasound ovarian volume

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Female Infertility- ovulation testing

• Average menstrual cycle – approximately 28 days (range is 21-35 days).

• Ovulation occurs approximately the 14th day of a 28 day cycle.

• Ovulatory disorders– Oligo-ovulation and Oligomenorrhea– Anovulation and amenorrhea

• Missed periods for 6 months OR for a 3 cycles

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Female Infertility- ovulation testing

• Menstrual history (cycle length)• Symptoms consistent with ovulation

– Mid cycle mucus changes– Pre-menstrual molimina– Mittleschmertz

• Mid-luteal serum progesterone ≥ 3ng/mL – < 10 ng/mL associated lower pregnancy rate

• BBT (basal body temperature)• Endometrial biopsy in luteal phase• Urinary LH surge monitoring• Serial ultrasound follicular tracking

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Basal Body Temperature (BBT) Chart

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Pulsatility of GnRH secretion, the frequency as well as amplitude, are critical for effects

on pituitary gonadotrophs

Frequency and amplitude of GnRH pulses change during the course of menstrual cycle.

FP: 1 in 60-90minLP: 1 in 2-6 hours

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Ovulatory disorders- PCOS– 5-10% reproductive aged women– Oligo-anovulation and Hyperandrogenism.– Features of hyperandrogenism

– Hirsuitism– Acne– Android obesity

– Metabolic profile• Insulin resistance• Obesity• Metabolic syndrome – Hyperlipidemia, hypertension• Increased risk for type II diabetes mellitus

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Ovulatory Disorders- Hyperprolactinemia

• Prolactin (normal <20 ng/ml)– Diurnal variation-highest during sleep– Increase seen with:

– Food intake– Sleep– Stress– Coitus/pelvic exam– Breast stimulation

» Thoracic lesions/dermatological disorders• Iatrogenic

– Psychotropic medications – Dopamine antagonists, phenothiazines, etc

• Hypothyroidism– Secondary to TRH

• Pituitary adenomas– Microadenomas < 10mm– Macroadenomas >10mm

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Ovulatory Disorders- Hypothalamic amenorrhea

– Anorexia nervosa– Excessive exercise

• Ballet dancers• Competitive athletes

– Stress– Chronic illness– Exogenous opiods

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Female Infertility- cervical hospitality testing

• Post coital test (PCT) – 8 - 12 hrs post coitus– Mid follicular cervical mucus

• Clarity• Spinbarkeit (stretchability) 8-10 cm • Ferning• Sperm - > 10 motile sperm per HPF

– Shaking phenomenon-antisperm antibodies

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Post-coital test

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Post-coital test

NOT DONE ANYMORE(rare exceptions)

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Female Infertility- tubal factor– Pelvic Inflammatory Disease (PID)

– Pathogens-Gonorrhea, Chlamydia, Anaerobes

– Pelvic adhesive disease– Endometriosis– Post-surgical adhesions– Ruptured appendix

– Pelvic Tuberculosis– Salpingitis Isthimica Nodosa (SIN)– In-Utero-exposure to DES

(diethylstylbesterol)

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Female Infertility- tubal factor testing: Hysterosalpingogram (HSG)

– Early follicular phase of cycle• Rule out STD’s

– Advantages: • Outpatient procedure• Reveals contour of the uterine cavity and tubal

patency.• May provide information regarding peritubal disease.• May be therapeutic-especially using oil based media.

– Disadvantages:• Risk of PID-1%• False positive –air bubbles/tubal spasm• Discomfort

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Assessment of tubal patency

Hysterosalpingogram (HSG)

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Hysterosalpingogram (HSG)

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Filling defects

Evaluating uterine cavity by HSG

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Female Infertility- endometrial receptivity testing

• Luteal Phase Endometrial Biopsy – Luteal phase defect

• >2 day lag on >1 biopsy

– Chronic endometritis• presence of plasma cells in the endometrium

– Endometrial function test (EFT)(NOT REALLY DONE ANYMORE, with specific exceptions)

• Anatomical abnormalities evaluation (Fibroids/polyps/adhesions-Asherman’s Syndrome)

= HSG, HSN, Hysteroscopy

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Sonohysterogram (HSN)

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Sonohysterogram (HSN)

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Female Infertility- fertilization and embryo development testing

• With treatment by IVF (in vitro fertilization) and/or ICSI (intracytoplasmic sperm injection)

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Female Infertility- some additional tests…

• Thrombophilia screening– Family or personal history of thrombosis– Recurrent pregnancy loss

• Screening for medical disorders:– Diabetes, renal disease,anemia– STD’s

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All tests negative???Unexplained Infertility

• No obvious etiology unmasked by conventional assessment

• 70% of patients with unexplained infertility will conceive over 2 years

• Fecundity is reduced to 1-3% in the remainder

• Still treatment options

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Evaluation of the Infertile Couple

History Female Male

– Menstrual - Medical– Dietary - Sexual– Medical - Occupational– Gyn/Ob - Family– Sexual – Family

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Physical examFemale

• Height• Sexual Development• Breasts/Galactorrhea• Thyroid • Hirsutism• Acanthosis nigricans • Anosmia

Male• Height • Sexual Development• Breasts• Genitalia• Thyroid • Anosmia

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Investigations1. Semen analysis2. Ovulatory status

– Menstrual history– Symptoms consistent with ovulation

» Mid cycle mucus changes» Pre-menstrual molimina» Mittleschmertz

– Luteal serum progesterone ≥ 6ng/ml – BBT (basal body temperature)– Endometrial biopsy in luteal phase– Urinary LH surge monitoring– Serial ultrasound follicular tracking

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Assessment of Tubal Patency by Laparoscopy

– Advantages• Direct exam of pelvic structures and tubal

patency• Other diagnoses-endometriosis/pelvic

adhesions• Opportunity for correction of anatomical

abnormalities– Lysis of adhesions/endometriosis ablation or

resection

– Disavantages:• Risks of surgery• Uterine cavity not assessed

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Mid cycle cervical mucus smear demonstrates a “ferning”

pattern on drying

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Management……. Male factor

– Intrauterine insemination (IUI)– Intracytoplasmic sperm injection

(ICSI)– Donor sperm

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Management……. Ovulation disorders

• Hyperprolactinemia– Medical therapy– Treat hypothyroidism

• PCOS– Ovulation induction

• Medical – Clomid– Gonadotrophins

• Surgical– Ovarian drilling– Wedge resection

• Insulin sensitizers– Metformin– Weight loss and life-style modifications

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Management……. • Tubal disease:

– Surgical- tuboplasty; lysis of adhesions– IVF (in-vitro fertilization)

• Uterine factors:– Correct anatomical distortions– Treatment of LPD with progesterone

supplementation, clomiphene, gonadotropins

• IVF may be diagnostic for some couples!• IVF with donor eggs

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Additional tests for infertile couples anticipating fertility

treatment• Screening tests offered to high risk

populations:– Cystic Fibrosis– Ashkenazi Jews

• Bloom syndrome, Canavan disease, Gaucher disease, Niemann-Pick disease, Tay-Sachs disease, Fanconi anemia, Familial dysautonomia, Cystic fibrosis, Mucolipidosis Type IV

– Hemoglobin electrophoresis

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THANK YOU!