Family Medicine Approach to Infertility

Robert F Raspa MD St. Vincents Family Medicine Residency Jacksonville, FL

Objectives:
List the common causes of male and female infertility Begin an infertility evaluation, ordering initial tests Prescribe simple treatments for infertile couples Facilitate appropriate referral to infertility specialists

Infertility:
Inability to conceive after 12 months of frequent, unprotected intercourse Some however begin initial work-up after 6 months as the fecundability (ability to conceive) decreases as times passes, particularly if history suggests infertility or if female partner older than 35 (decreased ovarian function)

Is infertility common?
10-15% of couples in the US 1.2 million women visited their primary care doctor for infertility in 2002

Risk Factors
Smokingdecreased conception Alcoholincreased infertility Stress (acupuncture helps) IUD removaltakes longer to conceive Increased agefathers over 40 Gulf war vets Inflammatory bowel disease

Other Factors
No increased risk with male underwear type or Ruptured appendix Unknown effects of environmental estrogensPCBs Nifedipine may decrease male fertility?

Timing Factors
Sperm live 48-72 hours Eggs live 12 hours Fertility Focused Intercourse is important

Etiology:
Male: 20% Female: 38% Mixed: 27% Unexplained: 15%

Importance of evaluation of both partners

WHO 1982-1985 multi-center study

Causes of Female Infertility

Ovulation disorders-25% Endometriosis-25% Pelvic Adhesions-12% Tubal Blockage-11% Other Tubal Factors-11% Hyperprolactinemia-7%
WHO Technical Report Series 1992

Female Causes:
Cervical factorsbad mucus, antibodies, infection Uterine Factorssubmucosal fibroids, bicornuate uterus, Ashermans syndrome Tubal factorsPID, endometriosis, post-op adhesions Ovary Factorsanovulation, luteal phase defect, toxins (chemotherapy) Bad eggschromosomal (Turners Syndrome)

Female H&P:
Gs and Ps PMH including STD Hx Medications Substance Use Menstrual Hx
Age at onset? Regular? Duration? Premenstral Sx?

Endometriosis Sx: dysmenorrhea, dyspareunia, Endocrine Sx: galactorrhea, hirsuitism, fatigue, constipation, weight gain, etc Exercise

Female H&P:
Physical Exam:
Vitals, BMI Skin: Acne, hirsuitism Thyroid: enlargement Breast: galactorrhea, development Pelvic: uterine size, tenderness, discharge, masses, development

Initial Counseling:
Frequency and timing of intercourse
Fertile Interval: 5 days preceding ovulation and day of ovulation

Smoking Alcohol Caffeine Stress Body weight (Ideal BMI is 20-25) Prenatal vitamins

Initial Female Work-Up:

Ovulation???: Regular Menses with Premenstrual Sx:
Some confirm ovulation by history/charting alone

Irregular Menses or desire confirmation:

Charting Progesterone on cycle day 21 LH surge (home urinary kits)

Charting:

Menstrual Cycle:

Ovulation Disorders:
WHO Classification:
1: Hypogonadotropic Hypogonadal
5-10%

2: Normogonadotropic Normoestrogenic
70-85% Includes PCOS

3: Hypergonadotropic Hypoestrogenic
10-30%

Hyperprolactinemia

Anovulation:
Determination of cause/class:
FSH/LH Estradiol (E2) Progesterone Prolactin/TSH Comprehensive Metabolic Panelliver, renal Testosterone, Androstenedione, DHEA-S, 17-OH Progesterone

Class 1 Anovulation:
Hypogonadotropic Hypogonadal
Low FSH and low estradiol Due to either decreased hypothalamic secretion of GnRH (Kallmans) or pituitary insensitivity to GnRH Results in decreased pituitary release of FSH FSH stimulates follicular maturation and thus estradiol secretion

Class 1 Treatment:
Gonadotropins (FSH/LH) Indications:
Class 1 anovulatory pts Class 2 anovulatory pts who have failed initial tx

Risks:
Multiple gestations Ovarian hyperstimulation

Class 1 Treatment:
Gonadotropins (FSH/LH) Dose:
Step-up vs Step-down protocols

Monitoring:
Transvaginal US q2-3 days to monitor follicles and timing of hCG dose to induce ovulation of dominant follicle

Given by Reproductive Endocrinologists

Class 2 Anovulation:
Normogonadotropic Normoestrogenic:
Normal levels of FSH and estrodiol FSH secretion during follicular phase is subnormal May ovulate intermittently, particularly if have oligomenorrhea Causes: PCOS, Hyperthyroidism, Androgenic hormones from tumors, liver or renal disease, Cushings (work-up is here)

Treatment of Class 2 Anovulation:

Check lab results from anovulatory work up and treat as appropriate
PCOS: increased BMI, hirsuitism, anovulation, 2:1 LH:FSH ratio

Best treatment is achieve ideal body weight or at least a 10% reduction in wt.
Best BMI 20-25

Low body wt or high stress decreases GnRH, can be like WHO 1 .

Class 2 Treatment: Metformin

Improves insulin insensitiviy Restores ovulation in 50% of PCOS Titrate dose to minimize side effects Minimal effect on hirsuitism Trial for 6 months with continued charting to eval for ovulation Not FDA approved for combo with Clomiphene but some trials have shown benefit of combo while others show similar success rates as Clomiphene alonecombined effect 60% preg rate in PCOS

Class 2 Treatment: Clomiphene

Induces ovulation by increased gonadotropin release Dose: 50mg days 5-9; up to 100mg daily if needed Intercourse timing and frequency; +/- urine LH kit +/- Metformin (PCOS) +/- Intrauterine Insemination (cervical factors) 6 cycles max Letrazole is alternative with similar efficacy to Clomiphene

Class 2 Treatment: Aromatase Inhibitors

Block final step of estrogen synthesis Letrozol 2.5 - 5mg daily on days 3-7 (anastazol) or 25mg once day 3. Intercourse timing and frequency; +/- urine LH kit Similar efficacy to clomiphene Minimal side effects Lower incidence of multiple gestations

Class 3 Anovulation:
Hypergonadotropic Hypoestrogenic:
High FSH and low estradiol FSH is inappropriately high due to lack of negative feedback from estradiol Causes: Premature ovarian failure or Ovarian resistance Resistant to treatment

Class 3 Anovulation:
Rare Poor Prognosis--best test is Antimullerian Hormonehigh is good, less than 2.5 is bad Clue given with Clomiphene Challenge Test
Test FSH on Day 3 Clomiphene Day 5-9 Test FSH on Day 10 If either FSH greater than 10, reduced ovarian function.

Anovulatory Treatment Overview:

WHO Class 1: GnRH problemtreat with GnRH pump and support (Not available in US) or Gonadotropins (Refer) WHO Class 2: Most patients herewe can treat WHO Class 3: Ovarian failurelittle hope with any therapy (Refer) Hyperprolactinemia: RxDrugs or Surgery

Regular Menses:
Ovulatory cycles confirmed by:
Charting x 3 months Cycle day 21 Progesterone LH surge

Fertility focused intercourse

Ovulation confirmed:
Lifestyle changes Chlamydia/GC test Male partner testing Good Cervical Mucus
Mucus enhancermucinex, vit B6 Increase mucus with antibiotics day 9-14

Prolactin, TSH Luteal phase defect? < 10 days Fertility focused intercourse x 3 months

Further work-up:
Check Hysterosalpingogram (HSG)
Tubal factors: patency Uterine factors: anatomy, submucosal fibroids

Oil based contrast has a good track record of pregnancy after HSG If 3 more months go by will need laparoscopy to check for endometriosis, adhesions, ovarian problems (hydrosalpinges) Key to treatment is find the problem and treat

Male Infertility
Male factor infertility 20% of couples Contributes to 30-40% Azoospermiano sperm Aspermiano semen Oligospermiadecreased normal sperm Need 2 sperm samples after 48-72 hour abstinence say experts
AUA and ASRM Practice Committee Reports2001

Male Infertility
Pre-testicularendocrinetreatablerare Testicularspermatogenesisuntreatable except varicoceles Post-testicular40% obstruction History
Mumps, Trauma, Infection, Chemo, Radiation, HeatUnderwear doesnt matter Family History? Prior Fertility?

Male Workup
Exam
Male secondary sex characteristics Assure vas deferens bilaterally Testis size Varicocele

Sperm Count
FertileOver 48 million, Over 63% motile, Over 12% normal morphology Likely Not FertileLess than 13.5 million,Less than 32% motile, Less than 9% normal morphology In the middleindeterminate
New England J Med 2001:345:1388

Lab Workup
Abnormal semen--<10 million, decreased sexual function or exam evidence Lab
TSH, FSH/LH, Testosterone If Testosterone is lowdo Free T, LH, Prolactin If FSH upImpaired spermatogenesis If FSH and LH upcomplete testicular failure with testicular atrophy

Male Causes
Absense of vas deferens
Renal agenesis in 10-20% Cystic Fibrosismost will have congenital bilateral absence of vas deferens CFTR mutationif positive, check female

Bilateral testicular atrophy

Low FSH and TKallman or Pituitary tumor Check prolactin and MRI

Duct Obstruction
May be treatable If normal volumeeither disordered spermatogenesis or near testicular obstruction
If FSH upspermatogenesis problem If FSH is normal, biopsy testis

Low sperm volumeejaculatory dysfunction

Consider TRUS

Azoospermia
Check chromosome7% abnormal
2/3 Klinefelters XXY Microdeletions on Y chromosome seen with PCR, not on karyotype Assay when non-obstructive oligospermia with sperm less than 5 million

Unexplained Infertility
Most likely combined male and female factors Treatments are multiple but many unsatisfying Time alone may be treatment or Refer

Advanced Reproductive Technologies (ART)

Most deliver normal infants BUT: Infertility treatment associated with increased risk of adverse pregnancy outcomes Placental abruption, fetal loss 2nd trimester, preeclampsia, previa, C/S, ovarian torsion

Advanced Reproductive Technologies (ART)

Multiple births and birth defects, preterm and low birth weight, cerebral palsey Insufficient evidence regarding risks and benefits for IVF for unexplained infertility 18-22% success per cycle

Other Drugs
Metformin may induce ovulation in anovulatory women without hyperandrogenism ASA doesnt help Testosterone doesnt help for males Ginseng may help increase sperm count and motility Chasteberry associated with increased pregnancy ratelevel 2 evidence

Other considerations
Intrauterine insemination (IUI) better if antibodies or if subfertile male As effective, cheaper, and safer than IVF for idiopathic infertilityLancet 2000 Varicocele repair probably doesnt help FSH (HCG) therapy for subfertilitymixed results

Pregnancy Support:
After conception progesterone supplementation has been shown to be effective in reducing miscarriage, preeclampsia and preterm birthin IVF and without Can use HCG as wellstimulates estrogen and progesterone

Pregnancy Support:
Counselinggroupimproved pregnancy rate Accupuncture works for IVFlikely works for normal conception if stress is an issue

Summary:
Consider causes of infertility Do systematic workupovulatory vs nonovulatory If ovulatory, consider tubal and male factors Find the cause and treat. Refer when unable to find cause or if unable to perform treatment

Questions?