Reproductive · PANCE / PANRE

Infertility (Workup and Approach)

Inability to conceive after 12 months of regular unprotected intercourse (6 mo if >=35).

Also known as: infertility, subfertility, infertility workup, male infertility, female infertility

Overview

Failure to achieve clinical pregnancy after 12 months of regular unprotected intercourse in women <35, or 6 months in women >=35. Earlier evaluation if known risk factors (oligomenorrhea, prior pelvic surgery or PID, endometriosis, known male factor).

Epidemiology

Affects ~10-15% of reproductive-age couples. Causes are roughly distributed: female factor 30-40% (ovulatory 25%, tubal/peritoneal 20%, uterine/cervical 5%), male factor 30-40%, combined 10-15%, unexplained 10-15%.

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Risk factors

  • Female: advancing age, PCOS, endometriosis, PID, prior pelvic surgery, smoking, obesity or underweight, prior chemotherapy/radiation, thyroid disease, hyperprolactinemia
  • Male: varicocele, undescended testis, prior testicular trauma/surgery/torsion, mumps orchitis, chemotherapy/radiation, anabolic steroid use, hypogonadism, genetic (Klinefelter, Y-chromosome microdeletion), obesity, heat exposure, smoking

Pathophysiology

Reproductive success requires ovulation, sperm production and transport, fallopian tube patency, normal uterine cavity, and synchronized fertilization and implantation. Disruption at any step impairs fertility. Age-related decline in fertility is driven primarily by oocyte quality and quantity, accelerating after 35.

Clinical presentation

Symptoms

  • Inability to conceive over the defined interval
  • Menstrual history is critical — regular cycles 21-35 days suggest ovulation; irregular cycles suggest ovulatory dysfunction
  • Dyspareunia, dysmenorrhea, pelvic pain (endometriosis)
  • Galactorrhea (prolactinoma), visual symptoms (pituitary mass)

Signs / physical exam

  • BMI extremes, hirsutism, acne (PCOS); thyroid enlargement; galactorrhea
  • Pelvic exam: uterine size/contour, adnexal masses, nodularity in cul-de-sac (endometriosis), cervical motion tenderness

Differential diagnosis

  • Anovulation (PCOS, hypothalamic, hyperprolactinemia) — Irregular or absent menses, signs of hyperandrogenism (PCOS) or low BMI/stress (hypothalamic)
  • Tubal disease — Prior PID, chlamydia/gonorrhea, endometriosis, prior pelvic surgery or ectopic — HSG shows blockage or hydrosalpinx
  • Uterine factor (fibroids, polyps, intrauterine adhesions/Asherman, mullerian anomaly) — Abnormal bleeding, recurrent loss; saline-infusion sonohysterography or hysteroscopy
  • Endometriosis — Cyclic dyspareunia, dysmenorrhea, dyschezia; nodularity on exam; laparoscopy diagnostic
  • Male factor — Abnormal semen analysis — first-line male evaluation
  • Unexplained infertility — Normal workup; treatment options include expectant, IUI with ovulation induction, or IVF

Diagnostic workup

Diagnostic criteria

Clinical: failure to conceive over the defined interval with sufficient evaluation to identify ovulation, tubal patency, uterine cavity, and male factor.

Labs

  • Female ovulatory: mid-luteal progesterone (day ~21) >3 ng/mL confirms ovulation; menstrual history (regular cycles strongly suggest ovulation)
  • Ovarian reserve: AMH, day-3 FSH and estradiol, antral follicle count by transvaginal ultrasound — used to counsel regarding response to ovarian stimulation, NOT to predict spontaneous fertility
  • TSH, prolactin (universal); testosterone, DHEA-S, 17-OHP if hyperandrogenism suspected
  • Male: semen analysis after 2-5 days of abstinence — repeat if abnormal (volume >=1.5 mL, concentration >=15 million/mL, total motility >=40%, normal morphology >=4% by Kruger or >=30% WHO criteria)
  • Male further workup if abnormal: FSH, LH, testosterone (morning), prolactin, TSH; karyotype and Y-microdeletion if severe oligospermia or azoospermia

Imaging

  • Transvaginal pelvic ultrasound: ovaries, uterine cavity, follicle count
  • Hysterosalpingogram (HSG) — assesses tubal patency and uterine cavity; performed days 5-12 of the cycle
  • Saline-infusion sonohysterography (SIS) — superior for cavity (polyps, submucosal fibroids, septum)
  • Scrotal ultrasound in men with abnormal exam or semen analysis (varicocele)

Diagnostic algorithm

flowchart TD
  A[Couple presents with infertility] --> B[Detailed history + exam]
  B --> C[Semen analysis]
  B --> D[Ovulation assessment<br/>menstrual hx, mid-luteal P4]
  B --> E[Tubal/uterine: HSG or SIS]
  B --> F[Ovarian reserve: AMH, AFC]
  C --> G{Semen abnormal?}
  G -->|Yes| H[Repeat + endocrine + scrotal US<br/>Urology referral]
  D --> I{Ovulatory?}
  I -->|No| J[Identify cause<br/>PCOS, HPRL, hypothalamic, thyroid]
  J --> K[Ovulation induction<br/>letrozole > clomiphene; cabergoline if HPRL]
  E --> L{Tubal/cavity normal?}
  L -->|No| M[Hysteroscopic repair or IVF]
  G & I & L -->|All normal| N[Unexplained infertility]
  N --> O[IUI + stimulation x 3-4 cycles, then IVF]
Initial workup and treatment pathway for the infertile couple.

Treatment

First-line

  • Lifestyle: optimize BMI, smoking cessation, limit alcohol, manage chronic disease (diabetes, thyroid)
  • Anovulation:
  • - PCOS: letrozole (first-line per ASRM; superior to clomiphene for live birth in PCOS); clomiphene citrate alternative; metformin alone or adjunctive in insulin-resistant patients
  • - Hypogonadotropic hypogonadism: pulsatile GnRH or exogenous gonadotropins (FSH/LH); restore weight/reduce exercise stress in hypothalamic amenorrhea
  • - Hyperprolactinemia: dopamine agonist (cabergoline preferred over bromocriptine)
  • Tubal disease: in vitro fertilization (IVF); salpingectomy of hydrosalpinx improves IVF success
  • Uterine factor: hysteroscopic polypectomy, myomectomy, septum resection, lysis of adhesions
  • Endometriosis-associated infertility: laparoscopic ablation/excision and/or IVF
  • Male factor:
  • - Mild-moderate oligospermia: intrauterine insemination (IUI) with ovarian stimulation
  • - Severe oligospermia or azoospermia: IVF with ICSI; surgical sperm retrieval (TESE/microTESE) for non-obstructive azoospermia
  • - Varicocelectomy improves semen parameters and may improve fertility in selected men
  • Unexplained infertility: 3 cycles of IUI + ovarian stimulation, then IVF if unsuccessful

Second-line / adjunct

  • IVF indications: tubal disease, severe male factor, advanced age, diminished ovarian reserve, failed IUI, fertility preservation, preimplantation genetic testing
  • Donor egg, donor sperm, gestational carrier as appropriate

Complications

  • Ovarian hyperstimulation syndrome (OHSS) — capillary leak with ascites/pleural effusion; risk higher with PCOS and high estradiol levels
  • Multiple gestation with assisted reproduction (especially gonadotropins without IVF; mitigated by single embryo transfer)
  • Ectopic pregnancy (higher in tubal disease and ART)
  • Psychological burden — depression, anxiety, relationship strain

PANCE pearls

  • Always do a semen analysis early — male factor accounts for 30-40% and is inexpensive to screen.
  • AMH and antral follicle count predict OVARIAN RESPONSE to stimulation, not natural fertility. Do not use to deny treatment.
  • Letrozole is first-line ovulation induction in PCOS (PPCOS II trial); higher live birth rates than clomiphene.
  • Hydrosalpinx significantly reduces IVF success — salpingectomy or proximal tubal occlusion before IVF improves outcomes.
  • Counsel women >=35 to seek evaluation after 6 months and women >=40 after 3 months, given accelerating age-related decline.

References

  • ASRM 2021 — ASRM Committee Opinion: Definitions of Infertility (Fertil Steril 2021)
  • PPCOS II — Legro et al., NEJM 2014 — letrozole vs clomiphene in PCOS
  • WHO 2021 — WHO Laboratory Manual for the Examination and Processing of Human Semen, 6th ed
  • AUA/ASRM 2021 — AUA/ASRM Guideline on Diagnosis and Treatment of Infertility in the Male

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