Resident Editors:  Carine Davila, MD

                        Faculty Editor: Cindy Lai, MD

Background

• Inability of a couple to conceive after 12 months of regular intercourse without contraception in women < 35 years; and after six months > 35 years 
• Affects 10-15% of reproductive age couples in the United States
• Condition with unique and profound psychological and emotional impact. Feelings of frustration, anger, depression, grief, guilt, and anxiety are common and should be anticipated.

Signs and Symptoms

• General History: couples' ages, length of time attempting conception, frequency of intercourse, occupation, life stressors
• Obstetric History: previous pregnancies and potential complications, results of prior infertility evaluation
• Menstrual History: cycle length, frequency. Regular, cyclic bleeding is >98% diagnostic of ovulation. Irregular cycle lengths of <25 days or >35 days, or a variation of >7 days in consecutive cycles are suggestive of ovulation defects. Moliminal symptoms suggest ovulation: breast tenderness, ovulatory pain, mood changes, bloating
• Gynecologic History: hx PID, pelvic surgeries, hx ectopic pregnancy, abnormal pap smear and treatments, prior methods of contraception, dyspareunia, dysmennorhea or cyclic pelvic pain, hx pelvic radiation
• Exposures: cytotoxic drugs, tobacco, alcohol, pelvic radiation, review medications
• Endocrine: autoimmune conditions, signs/sx hypothyroidism, galactorrhea, hot flashes, significant weight changes
• Family History: infertility, genetic defects, developmental delay, early menopause, other reproductive problems
• Male Factor: paternity history, history of testicular surgery or injury, genitourinary infection, post-pubertal mumps, STIs, genital radiation, chemotherapy, hypospadias, or retrograde ejaculation. Excessive exposure to heat (hot tubs, saunas), toxic chemicals, pesticides, marijuana, nicotine 

Differential Diagnosis

1) Male Causes: multifactorial. Note: male factor is solely responsible in ~20% of infertile couples and contributes in another 30-40% of couples. Both partners should be evaluated in parallel! If partner is not your patient, please counsel to request PCP referral to urology or reproductive specialist. 

Examples: azospermia, hypogonadism, toxin exposure, ejaculatory duct obstruction

Test: Semen Analysis

2) Ovulatory Disorders: WHO Classification Four Types

• Hypogonadotropic Hypogonadism: Hypothalamic or Pituitary failure

Examples: Kallman’s Syndrome, Functional (secondary to low body weight/anorexia/intense athletics), GnRH insensitivity

Test: Day 3 FSH, estradiol (both will be low)

Treatment: GnRH agonist

• Hypergonadotropic Hypogonadism: Primary Gonad Failure

Examples: Premature Ovarian Failure, Turner’s Syndrome, Radiation exposure

Test: Day 3 FSH, estradiol (FSH high, estradiol low)

Treatment: IVF with egg donor, clomiphene (if some ovarian reserve)

• Eugonadotropic Eugonadism: Chronic Anovulation

Examples: PCOS

Test: Confirmation of ovulation → menstrual calendar, FSH, LH, serum progesterone one week prior to expected menstruation date

Treatment: Metformin, weight loss, clomiphene (Clomid)

• Hyperprolactinemia: High Prolactin suppresses GnRH

Examples: Medications (neuroleptics), Pituitary tumors, Hypothyroidism 

Test: Prolactin, TSH

Treatment: Medication change, Bromocriptine (prolactinoma), Thyroid replacement (hypothyroidism)

3) Pelvic Causes: Uterine or Tubal Anomalies

Examples: PID, hx ectopic pregnancies, endometriosis, leiomyomas, uterine polyps, Asherman’s Syndrome, Mullerian defects, Fibroids, endometrial polyps, intrauterine adhesions

Test: Hysterosalpingogram (HSG), Saline sonohystogram, Diagnostic Hysteroscopy

Treatment: Hysteroscopy (Asherman’s, uterine septum); tubal surgery (PID/endometriosis); Myomectomy, IVF

4) Unknown and Rare Causes: coital problems, cervical problems (except as marker of chronic cervicitis that should be treated, unexplained

Evaluation

A. Physical Exam (female)

• General: BMI (>30 or <22), weight distribution (central obesity)
• Thyroid: Enlarged thyroid or presence of nodules or tenderness
• Prolactin Excess: visual field exam, breast excretions
• Evidence of Excess Androgens: acne, male pattern baldness, facial hair, acanthosis nigricans
• Pelvic Factor: pelvic tenderness, pelvic mass, uterosacral nodularity, decreased uterine mobility, cervical abnormalities
• Secondary Sex Characteristics: breast development, hair distribution, genital development

B. Initial Studies/Interventions

• Emotional Needs: primary care physicians are uniquely positioned to address couples’ stress regarding infertility
• Semen Analysis: Men should abstain from ejaculation at least 48 hours. Analysis should occur within 1 hour. Study measures volume, concentration, motility and morphology. Most important prognostic indicator: Total Motile Count (TMC).  Abnormal studies should prompt referral.
• Document Ovulation: Regular menstrual cycles suggest ovulation and this can be confirmed with serum progesterone testing at day 21 of a 28-day cycle or one week prior to expected menstruation (low progesterone suggests ovulatory disorder). Other appropriate options including: accurate menstrual calendar with documented pre-menstrual symptoms (breast tenderness, ovulatory pain, bloating), home urine ovulation kits, corpus luteum on ultrasound.
• If Anovulatory: TSH, Prolactin to investigate treatable causes

High TSH: evaluate and treat hypothyroidism

High Prolactin/normal TSH: refer to specialist, consider discontinuing any possible medication culprits as indicated

• If Ovulatory: Check Day 3 FSH, LH, estradiol (considered indicator of ovarian reserve), consider hysterosalpingogram to rule out pelvic factor, and refer to infertility clinic.
• Hysterosalpingogram (HSG): Radio-opaque dye injected through cervix, filling the uterus and fallopian tubes, which are observed under fluoroscopy. Performed in the 2nd week of the menstrual cycle (i.e. after menses, before ovulation). Offered to those with infertility who have no history of pelvic infections, endometriosis or ectopic pregnancies. Abnormal findings include congenital malformations of the uterus, submucosal leiomyomata, intrauterine synechiae (Asherman's Syndrome), intrauterine polyps, and proximal or distal tubal block (hydrosalpinx).  Laparoscopy may be performed if endometriosis is highly suspected. If patients undergo HSG prior to referral, they should be instructed to bring their films to their infertility appointment.

Treatment

• Take prenatal vitamins
• Reduce sources of life stress, tobacco, alcohol, caffeine and drug use
• Recommend <4 alcohol drinks per week for women, <250 mg caffeine
• Men are encouraged to avoid heat damage from hot tubs, biking, saunas
• Maintain a healthy weight, or lose weight if BMI> 30 kg/m²; this may restore ovulation 
• Maximal pregnancy rates with coital frequency approximately every other day. Coital frequency < 1x week associated with prolonged conception interval. Best time is 1-2 days prior to ovulation.

When to Refer

• Anyone age 35 or older with 6 months attempted fertility
• Anyone with >1 year infertility
• Women with known uterine/tubal disease, risk factors for premature ovarian failure (cytotoxic drugs, pelvic radiation, autoimmune disease, strong family history of early menopause), oligo/amennorhea, hyperprolactinemia
• Male partner with risk factors for subfertility or abnormal semen analysis
• Recurrent early pregnancy loss: 3 or more miscarriages <20 weeks gestation
• Anyone with previous intrauterine insemination or IVF use

References:

Koroma L, Stewart L. Infertility: evaluation and initial management. J Midwifery Women’s Health 2012; 24:221.

Lindsey T and K Vitrikas. Evaluation and treatment of infertility. Am Fam Physician 2015; 91(5): 308-314.

McLaren J. Infertility evaluation. Obstet Gynecol N Am 2012; 39:453.

The American College of Obstetricians and Gynecologists Committee on Gynecology Practice and the Practice Committee of the American Society for Reproductive Medicine. Female age-related fertility decline. Fertil Steril 2014; 101:633.

The Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013; 99:63.

The Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2015; 103:e44-50.

The Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2015; 103:e18-25.

Thoma, M et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril 2013; 99(5): 1324. 

UptoDate: Overview of Infertility, Evaluation of Female Infertility, accessed 29 May 2018.