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 dysfunction and tubal/peritoneal disease most common, uterine/cervical factors less so), male factor 30-40%, combined 10-15%, unexplained ~15-30%.
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Question 1ReproductiveEasy
A 24-year-old female with prior chlamydia trachomatis cervicitis presents 5 years later with infertility. In the year following that infection she was hospitalized for fever and lower abdominal pain. She and her partner have had regular unprotected intercourse for 18 months without conception. Which of the following complications does this represent?
AEndometriosis from chronic inflammation
BCervical stenosis affecting sperm transport
CAsherman syndrome with endometrial synechiae
DTubal factor infertility
EOvarian insufficiency from pelvic infection
Reveal answer & full explanation
Correct answer: D — Tubal factor infertility
AEndometriosis from chronic inflammation
BCervical stenosis affecting sperm transport
CAsherman syndrome with endometrial synechiae
DTubal factor infertility✓
EOvarian insufficiency from pelvic infection
Why Tubal factor infertility is correct
Untreated chlamydia or gonorrhea ascends to the upper genital tract, causing pelvic inflammatory disease (PID), tubal scarring and adhesions, and tubal factor infertility (the most common cause of infertility from STI).
Each PID episode increases infertility risk: 12% after 1 episode, 25% after 2 episodes, 50% after 3 or more episodes.
PID also increases ectopic pregnancy risk.
Why the others are wrong
Cervical stenosis affecting sperm transport — not a recognized sequela of PID; PID affects the fallopian tubes, not primarily the cervix.
Asherman syndrome with endometrial synechiae — Asherman syndrome is intrauterine adhesion formation that occurs after uterine instrumentation (e.g., dilation and curettage), not from PID.
Endometriosis from chronic inflammation — endometriosis is not caused by chlamydia or PID; it is a separate condition involving ectopic endometrial implants.
Ovarian insufficiency from pelvic infection — tempting because her hospitalization for fever and lower abdominal pain suggests severe PID that can extend to the ovary as a tubo-ovarian abscess, but PID does not typically impair ovarian reserve or ovulation; its infertility results from tubal scarring and adhesions.
Additional high-yield points
Prevention of tubal infertility includes sexually transmitted infection (STI) screening, prompt treatment, and partner notification.
Question 2ReproductiveMedium
A 41-year-old woman and her 39-year-old partner present for evaluation after 8 months of regular unprotected intercourse without conception. Her menstrual cycles occur every 28 to 30 days, and a mid-luteal progesterone level was 11 ng/mL. She has never been pregnant, has no history of pelvic infection or surgery, and reports no dysmenorrhea or dyspareunia. She has a 5 pack-year smoking history and a BMI of 27 kg/m2. Her partner's semen analysis is normal. Which of the following is the strongest risk factor for infertility in this couple?
AHistory of nulliparity
BAdvanced maternal age
COverweight body habitus
DActive tobacco smoking
Reveal answer & full explanation
Correct answer: B — Advanced maternal age
AHistory of nulliparity
BAdvanced maternal age✓
COverweight body habitus
DActive tobacco smoking
Why Advanced maternal age is correct
Female fertility declines with age, driven primarily by falling oocyte quality and quantity, and this decline accelerates sharply after age 35.
At 41 she has the single most powerful risk factor present; her regular cycles with a confirmatory mid-luteal progesterone above 3 ng/mL indicate she is ovulating, and her partner's semen analysis is normal, so age-related diminished oocyte quality is the dominant contributor.
Guidelines (ACOG/ASRM) advise evaluation after 6 months of trying for women 35 and older and more immediate evaluation and treatment for women over 40, precisely because of this accelerating age effect.
Why the others are wrong
Active tobacco smoking — Smoking is a genuine modifiable risk factor that lowers fecundity, but a modest 5 pack-year history is far weaker than her age in this scenario.
Overweight body habitus — A BMI of 27 is only mildly overweight; extremes of weight impair fertility, often through ovulatory dysfunction, but she is clearly ovulating and this confers minimal added risk.
History of nulliparity — Never having been pregnant is a descriptor of her reproductive history, not an independent causal risk factor for infertility, and carries little predictive weight relative to age.
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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
Diminished ovarian reserve (DOR) — Often still regular ovulatory cycles but abnormal reserve markers: low AMH for age (often <1 ng/mL), day-3 FSH >10 IU/L, low antral follicle count (<5-7); contrast premature ovarian insufficiency = age <40 with >=4 months of oligo/amenorrhea and FSH >25 IU/L
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 (WHO 2021 lower reference limits: volume 1.4 mL, concentration 16 million/mL, total motility 42%, progressive motility 30%, normal morphology 4% by strict/Kruger criteria); oligozoospermia = low count, asthenozoospermia = low motility, teratozoospermia = abnormal morphology, azoospermia = no sperm in the ejaculate
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 is not routine in the male evaluation; reserve it for an inadequate or equivocal scrotal exam or a suspected testicular mass (treat only palpable varicoceles, not those detected solely by imaging)
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 eval<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; no ovulation at the maximum letrozole dose (2.5 -> 5 -> 7.5 mg in successive cycles) -> gonadotropins with close ultrasound monitoring (OHSS and multiple-gestation risk), or laparoscopic ovarian drilling in selected patients; IVF third-line
- 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: match the procedure to the lesion; proximal occlusion on HSG (often a false positive from tubal spasm or a mucus plug) -> selective salpingography with tubal cannulation; mild distal disease in a young woman with no other factors -> laparoscopic neosalpingostomy/fimbrioplasty; severe distal disease, true proximal occlusion that fails cannulation, older age, or other infertility factors -> in vitro fertilization (IVF); salpingectomy or proximal occlusion of a hydrosalpinx before IVF improves IVF success
Uterine factor: hysteroscopic polypectomy, myomectomy, septum resection, lysis of adhesions
Endometriosis-associated infertility: stage I-II in a younger woman -> laparoscopic excision/ablation or ovarian stimulation with IUI; IVF for stage III-IV disease in an older woman or with tubal damage, diminished ovarian reserve, male factor, or failed prior surgery (IVF is more effective than repeat surgery); endometrioma cystectomy lowers ovarian reserve (falling AMH), and prolonged GnRH agonist pretreatment before IVF is no longer recommended
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)
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 to have more immediate evaluation and treatment, given accelerating age-related decline.
References
ASRM 2023 — ASRM Practice Committee. Definition of infertility: a committee opinion. Fertil Steril 2023;120:1170
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
ASRM 2021 (tubal surgery) — ASRM Practice Committee. Role of tubal surgery in the era of assisted reproductive technology: a committee opinion. Fertil Steril 2021;115:1143-50
ESHRE 2022 — Becker CM, et al. ESHRE guideline: endometriosis. Hum Reprod Open 2022;2022(2):hoac009
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