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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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
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.
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
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.
- 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
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