Male and female infertility exam oriented noted

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Male and Female Infertility - Exam-Oriented Notes

DEFINITION

Infertility = failure to achieve pregnancy after 12 months of regular, unprotected intercourse (or 6 months if female age >35 years).

Affects ~15-20% of all couples
Distribution of causes: 1/3 male factors only | 1/3 female factors only | 1/3 combined
Unexplained infertility (no identifiable cause): ~20% of couples

PART 1: MALE INFERTILITY

Causes (by frequency)

Diagnostic Category	Incidence
Idiopathic infertility	50-60%
Varicocele	15-35%
Primary testicular failure (Klinefelter syndrome, Y microdeletions, cryptorchidism, irradiation, orchitis, drugs)	10-20%
Other (sperm autoimmunity, drugs, toxins, systemic illness)	5%
Genital tract obstruction (congenital absence of vas deferens, vasectomy, epididymal obstruction)	5%
Hypogonadotropic hypogonadism (pituitary adenoma, panhypopituitarism, idiopathic HH, hyperprolactinemia)	3-4%
Coital disorders	<1%

(Textbook of Family Medicine 9e)

History and Physical Examination

History: puberty/growth milestones, erectile function, STD history, medications, surgical history, prior successful pregnancies, drug/alcohol use, family history of genetic diseases, androgen use (testosterone products, anabolic steroids must be stopped).

Physical exam:

Secondary sex characteristics: body hair (face, axilla, chest, pubic)
Gynecomastia
Testicular volume (Prader orchidometer): normal 12-25 mL (3.5-5.5 cm length)
- Klinefelter syndrome: markedly reduced (1-2 mL)
Eunuchoid proportions: arm span >2 cm > height (suggests pre-epiphyseal androgen deficiency)
Varicocele palpation (patient standing) - more common on the LEFT side

(Harrison's Principles of Internal Medicine 22E)

Investigations

1. Semen Analysis (WHO Criteria) - FIRST AND MOST IMPORTANT TEST

Collected after 2-7 days of abstinence. If abnormal, repeat after 4-6 weeks (two consecutive analyses needed).

Parameter	Normal (WHO)
Volume	≥1.5 mL
Sperm concentration	≥15 million/mL
Total motility	≥40%
Progressive motility	≥32%
Normal morphology (Kruger strict)	≥4%
Vitality	≥58% live
pH	≥7.2

Terminology:

Oligospermia = sperm count <15 million/mL
Asthenospermia = reduced motility (<40%)
Teratospermia = abnormal morphology (<4%)
Oligoasthenoteratozoospermia (OAT) = all three abnormal
Azoospermia = no sperm in ejaculate
Aspermia = no ejaculate
Hypospermia = volume <1.5 mL

2. Hormonal Evaluation (if oligospermia/azoospermia on 2 analyses)

Testosterone (low = hypogonadism)
LH: elevated = primary testicular failure; low/normal = secondary (hypothalamic-pituitary)
FSH: selectively elevated = seminiferous tubule damage
Prolactin: elevated = hyperprolactinemia (prolactinoma)
TSH: thyroid disease
Inhibin B: reduced with seminiferous tubule damage (Sertoli cell marker)

3. Genetic Testing (if severe oligospermia <5 million/mL or azoospermia)

Karyotype: Klinefelter syndrome (47,XXY)
Y chromosome microdeletion analysis (AZF regions)
- AZFa + AZFb deletions: associated with Sertoli cell only syndrome - poor prognosis for sperm retrieval
- AZFc deletion: most common Y microdeletion; associated with oligospermia - better prognosis for sperm retrieval
- 6-15% of men with non-obstructive azoospermia/severe oligozoospermia harbor a Y microdeletion
CFTR mutations: bilateral absence of vas deferens (obstructive azoospermia)

4. Imaging

Scrotal ultrasound: evaluate testicular volume, varicocele (dilated pampiniform plexus), epididymal cysts/obstruction
- Varicocele: venous diameter >2 mm; demonstrate with Valsalva maneuver on Doppler
MRI: evaluates vas deferens, prostate, seminal vesicles (ejaculatory duct obstruction)
Transrectal ultrasound (TRUS): ejaculatory duct obstruction (volume <1.0 mL on semen analysis)

NOT Routinely Recommended

Sperm antibody testing
Scrotal ultrasound routinely
DNA sperm fragmentation assay (reserved for recurrent pregnancy loss)

Causes of Azoospermia

	Pre-testicular (Hypogonadotropic)	Testicular (Primary)	Post-testicular (Obstructive)
Cause	GnRH/pituitary deficiency, hyperprolactinemia	Klinefelter, Y deletion, orchitis, cryptorchidism, chemo/radiation	Vasectomy, CAVD, ejaculatory duct obstruction
FSH	Low/normal	Elevated	Normal
Testicular volume	Small	Small	Normal
Sperm retrieval	Good with gonadotropins	Variable (AZFc best)	Good (TESE/PESA)

CAVD = Congenital Absence of the Vas Deferens (associated with CFTR mutations / cystic fibrosis)

Varicocele - High-Yield Points

Most common treatable cause of male infertility
Found in ~35% of men with primary infertility; 15% of general male population
Almost invariably left-sided (left testicular vein drains into left renal vein at a right angle - incompetent valves)
Isolated right-sided varicocele in older men: raise concern for intra-abdominal mass
Treatment: varicocelectomy (most commonly performed operation for male infertility) or embolization
Recurrence after embolization: ~20%

Treatment of Male Infertility

Sperm Count	Motility	Treatment
Mild (15-20 × 10⁶/mL)	Normal	Expectant management
Moderate (10-15 × 10⁶/mL)	20-40%	IUI ± clomiphene/gonadotropins in female partner
Severe (<10 × 10⁶/mL)	<10%	IVF + ICSI or donor sperm
Secondary hypogonadism	-	Pulsatile GnRH or gonadotropin therapy

Note: Y microdeletions (AZFc) will be transmitted through ICSI to male offspring.

(Harrison's Principles of Internal Medicine 22E)

PART 2: FEMALE INFERTILITY

Causes

Category	Incidence
Ovarian dysfunction (anovulation)	~40%
Tubal factors	~20-30%
Peritoneal/Endometriosis	10-15%
Uterine factors	5-10%
Cervical factors	5%
Unexplained	10-15%

Fertility timeline: peaks age 20-24 → progressive decline → steep decline after age 40.

Causes of Anovulation

PCOS - most common cause of anovulatory infertility (affects 4-7% of women of reproductive age); associated with hyperinsulinemia and hyperandrogenism
Hyperprolactinemia (prolactinoma)
Thyroid disease (hypo- or hyperthyroidism)
Hypothalamic amenorrhea (low weight, excessive exercise, stress)
Premature ovarian failure/insufficiency
Congenital adrenal hyperplasia (late-onset)
Cushing syndrome

History and Physical Examination

History:

Menstrual history (regularity, cycle length)
Symptoms of hyperandrogenism (hirsutism, acne, voice change)
Galactorrhea (prolactin excess)
Prior pelvic infections (PID - tubal damage)
Endometriosis symptoms (dysmenorrhea, dyspareunia)
Thyroid symptoms
Diet, exercise, BMI
Medications

Exam: signs of PCOS (hirsutism, acne, obesity), galactorrhea, thyroid enlargement, uterine/adnexal tenderness, signs of androgen excess

Investigations

Step 1: Confirm Ovulation

Urinary LH ovulation prediction kits (detect LH surge) - preferred
Mid-luteal phase serum progesterone (day 21, 7 days before expected menses): >3 ng/mL confirms ovulation
Basal body temperature (BBT): NO LONGER RECOMMENDED (only shows ovulation has already occurred)
Transvaginal ultrasound (follicle tracking)

Step 2: Ovarian Reserve (especially age >35 or poor response suspected)

Day 3 FSH (cycle day 2-3): >12 IU/L = poor ovarian reserve - refer to reproductive endocrinologist
Day 3 Estradiol (cycle day 2-3)
Anti-Müllerian Hormone (AMH): best marker of ovarian reserve - does not vary with menstrual cycle phase; used for gonadotropin dosing
Antral follicle count (AFC) on transvaginal ultrasound

Step 3: Hormonal Screen (if irregular cycles)

TSH - thyroid dysfunction
Prolactin - hyperprolactinemia
Androgens (total + free testosterone, DHEA-S) - hyperandrogenism/PCOS/CAH
Day 3 LH:FSH ratio: >2:1 suggests PCOS

Step 4: Uterine and Tubal Evaluation

Test	Use
Hysterosalpingography (HSG)	First-line for tubal patency assessment; also shows uterine cavity
Sonohysterography (saline infusion)	Better for submucosal myomas, polyps, Asherman syndrome
Laparoscopy + chromotubation	Gold standard for tubal patency; also diagnoses endometriosis, adhesions
Hysteroscopy	Direct visualization of uterine cavity; therapeutic (Asherman, polyps, fibroids)
MRI	Uterine anomalies, deep infiltrating endometriosis
Transvaginal ultrasound	Fibroids, ovarian cysts, antral follicle count, hydrosalpinx

NOT recommended routinely: postcoital test, endometrial biopsy, BBT records, diagnostic laparoscopy as initial test, thrombophilia testing, immunologic testing, karyotype.

Summary Table: Tests by Factor

Factor	Test
Ovulatory	Urinary LH kit, serum progesterone (luteal phase), TVU, TSH, FSH, prolactin, androgens
Cervical	Cervical mucus evaluation; postcoital test (not sensitive)
Uterine	Ultrasonography, HSG, hysteroscopy, sonohysterography, MRI
Tubal	HSG (first choice), laparoscopy + chromotubation, fluoroscopic/hysteroscopic cannulation
Peritoneal	Ultrasound, laparoscopy

(Textbook of Family Medicine 9e; Harrison's 22E)

Progesterone Challenge Test (for amenorrhea workup)

Give medroxyprogesterone (Provera) 10-20 mg/day x 5-10 days
Withdrawal bleed within 10 days = adequate estrogen + patent outflow tract (anovulation likely)
No bleed → give estrogen + progesterone (OCP cycle)
- Bleed → low estrogen state (HH, ovarian failure)
- No bleed → outflow obstruction (Asherman syndrome, Müllerian anomaly)

Tubal Factor Infertility - High Yield

Constitutes 30-35% of female infertility cases
Most caused by sexually transmitted infections (Chlamydia, Gonorrhea - PID causing tubal damage/hydrosalpinx)
Treatment: IVF (first choice - bypasses tubes); tubal repair NOT recommended if infection-related or hydrosalpinx
Asherman syndrome: intrauterine adhesions following D&C or endometritis - presents with hypomenorrhea/amenorrhea

Treatment of Female Infertility (by cause)

Cause	Treatment
Hyperprolactinemia/prolactinoma	Bromocriptine (dopamine agonist) or cabergoline
PCOS (anovulation)	Letrozole (aromatase inhibitor - first line); Clomiphene citrate (SERM); Metformin (insulin sensitizer, especially if insulin resistant); Gonadotropins (FSH/LH injections)
Hypothalamic hypogonadism (HH)	Pulsatile GnRH or exogenous FSH + LH
Adrenal hyperplasia (elevated androgens)	Clomiphene + glucocorticoids
Infection	Antibiotics
Tubal obstruction	IVF
Uterine fibroids/polyps	Hysteroscopic resection
Endometriosis	Medical (GnRHa) ± surgical ± IVF

(Textbook of Family Medicine 9e; Harrison's 22E; Goodman & Gilman's)

PART 3: ASSISTED REPRODUCTIVE TECHNOLOGIES (ART)

Procedure	Indication	Detail
IUI (Intrauterine Insemination)	Mild-moderate male factor, unexplained infertility, cervical factor	Washed concentrated sperm deposited into uterine cavity via catheter
IVF (In Vitro Fertilization)	Tubal factor (primary), moderate-severe male factor, endometriosis, unexplained	Oocytes harvested transvaginally; fertilized in lab; embryo transferred at day 3 (cleavage) or day 5 (blastocyst)
ICSI (Intracytoplasmic Sperm Injection)	Severe oligospermia, azoospermia (with sperm retrieval), failed fertilization in IVF	Single sperm injected directly into oocyte
TESE (Testicular Sperm Extraction)	Non-obstructive azoospermia	Surgical sperm retrieval from testis
PESA (Percutaneous Epididymal Sperm Aspiration)	Obstructive azoospermia	Sperm aspirated from epididymis

PART 4: PRECONCEPTION COUNSELING - EXAM HIGHLIGHTS

Smoking: decreases fertility (oocyte DNA damage, reduced ovarian reserve, accelerates menopause by 1-4 years); increases miscarriage and ectopic pregnancy risk
Obesity (female): increases anovulatory cycles, miscarriage rate, maternal/fetal complications
Obesity (male): abnormal sperm parameters
Caffeine: restrict to ≤2 cups/day when trying to conceive
Testosterone products: must be STOPPED (suppresses spermatogenesis via negative feedback on HPG axis)
Fertile window: 5-6 days prior to ovulation; intercourse every 1-2 days during this period
Advanced maternal age (>35 years): higher risk of aneuploidy
Advanced paternal age (>40 years): adverse health outcomes in offspring

EXAM MNEMONICS

STOP for male infertility workup:

Semen analysis (first test)
Testosterone/hormone panel (if abnormal semen)
Orchidometer/physical exam
Prolactin (if LH/FSH low - pituitary cause)

Causes of female anovulation - "PHAT Chances":

PCOS
Hyperprolactinemia
Adrenal (CAH, Cushing)
Thyroid disease
Central/Hypothalamic (HH, weight loss, exercise)
hypogonadism (premature ovarian failure)
aging (ovarian reserve decline)
neoplasm
cysts (ovarian)
endocrine (DM)
stress

QUICK COMPARISON TABLE

Feature	Male	Female
First test	Semen analysis	Urinary LH kit / mid-luteal progesterone
Most common cause	Idiopathic / Varicocele	Ovulatory dysfunction (PCOS)
Genetic test indication	Severe oligo/azoospermia	POI, recurrent miscarriage
Gold standard tubal test	N/A	HSG (first) / Laparoscopy (gold standard)
Key hormone panel	T, LH, FSH, PRL, TSH	FSH, LH, PRL, TSH, AMH, androgens
Age effect cutoff	Paternal age >40	Maternal age >35 (referral), steep decline >40
Primary ART for severe defect	IVF + ICSI	IVF

Sources: Harrison's Principles of Internal Medicine 22E; Textbook of Family Medicine 9e; Grainger & Allison's Diagnostic Radiology; Goodman & Gilman's Pharmacological Basis of Therapeutics; Harrison's Chapter 408 (Fertility Evaluation and Treatment)

Sexual dysfunction and Infertility Order and interpret relevant investigations of Sexual dysfunction and Infertility 2. Describe differential diagnosis of Sexual dysfunction and Infertility

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Sexual Dysfunction & Infertility: Investigations and Differential Diagnosis

Exam-Oriented Comprehensive Notes

SECTION A: SEXUAL DYSFUNCTION

1. DEFINITION AND DSM-5 FRAMEWORK

Sexual dysfunction = a clinically significant disturbance in a person's ability to respond sexually or to experience sexual pleasure. Key DSM-5 principles:

Must cause clinically significant distress to the individual
Duration: symptoms persist for ≥6 months
Not better explained by another mental disorder, a medical condition, or a substance/medication
Subtypes: Lifelong vs. Acquired | Generalized vs. Situational | Mild/Moderate/Severe

(Textbook of Family Medicine 9e)

2. DSM-5 CLASSIFICATION OF SEXUAL DYSFUNCTIONS

MALE SEXUAL DYSFUNCTIONS

Disorder	Definition
Erectile Disorder (ED)	Inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance in ≥75% of sexual encounters
Premature (Early) Ejaculation (PE)	Ejaculation occurring within ~1 minute of vaginal penetration, before the person wishes it
Delayed Ejaculation	Marked delay in, infrequency of, or absence of ejaculation
Male Hypoactive Sexual Desire Disorder	Persistent/recurrent deficiency of sexual thoughts/fantasies and desire for sexual activity

FEMALE SEXUAL DYSFUNCTIONS

Disorder	Definition
Female Sexual Interest/Arousal Disorder	Absent/reduced sexual interest OR arousal for ≥6 months (≥3 of 6 criteria) - DSM-5 merged hypoactive sexual desire + arousal
Female Orgasmic Disorder	Marked delay in, infrequency of, or absence of orgasm, or reduced intensity, despite adequate stimulation
Genito-Pelvic Pain/Penetration Disorder (GPPPD)	Persistent difficulty with vaginal penetration; vulvovaginal/pelvic pain during intercourse; fear/anxiety about pain (merges prior dyspareunia + vaginismus)

3. DIFFERENTIAL DIAGNOSIS OF SEXUAL DYSFUNCTION

A. Erectile Dysfunction (ED)

Prevalence by age: 2% (age 40-49) → 6% (50-59) → 17% (60-69) → 39% (≥70 years)

Category	Causes
Vascular	Atherosclerosis, hypertension, hyperlipidemia, diabetes mellitus (most common organic cause), peripheral arterial disease, Leriche syndrome, pelvic radiation/surgery
Neurological	Spinal cord injury, MS, Parkinson's disease, stroke, peripheral neuropathy (diabetic), pelvic nerve damage from radical prostatectomy, disc herniation
Endocrine	Hypogonadism (low testosterone), hyperprolactinemia, hypothyroidism, hyperthyroidism, Cushing's syndrome, Addison's disease
Psychogenic	Performance anxiety, depression, anxiety disorders, relationship conflict, sexual abuse history, spectator effect, guilt/religious conflict
Structural/Local	Peyronie's disease (fibrous plaques causing painful curved erection), phimosis, priapism (complication)
Drug-induced	Antihypertensives (beta-blockers, thiazides, methyldopa, clonidine), SSRIs, TCAs, antipsychotics, spironolactone, ketoconazole, 5-alpha reductase inhibitors (finasteride), opioids, statins, alcohol, anabolic steroids
Systemic disease	Chronic kidney disease, liver cirrhosis, COPD, cardiovascular disease

Key teaching point: ED and cardiovascular disease share the same vascular pathophysiology - men with ED often develop cardiac symptoms LATER. ED should trigger cardiac risk assessment. "What is bad for the heart is bad for the penis."

(Textbook of Family Medicine 9e; Harrison's 22E)

Organic vs. Psychogenic ED - Distinguishing Features

Feature	Organic	Psychogenic
Onset	Gradual, progressive	Sudden
Nocturnal/morning erections	Absent	Present
Masturbatory erections	Impaired	Usually preserved
Situational (with certain partners)	Generalized	Often situational
Associated depression/anxiety	May be secondary	Often primary
Age	Usually older	Often younger
Nocturnal penile tumescence (NPT) test	Absent/reduced	Normal

B. Premature Ejaculation (PE)

DSM-5: ejaculation within ~1 minute of vaginal penetration; prevalence 1-3% (DSM-5 definition), up to 20-30% (broader definition)
Primary (lifelong): since first sexual encounter - likely neurobiological (low serotonin threshold)
Secondary (acquired): follows normal function - consider prostatitis, hyperthyroidism, anxiety, relationship issues, infrequent intercourse

C. Delayed Ejaculation

Least common male sexual dysfunction
Causes: SSRIs/SNRIs (most common drug cause), alcohol, spinal cord injury, radical pelvic surgery, diabetes, hypothyroidism, psychological factors

D. Female Sexual Interest/Arousal Disorder (Low Desire)

Category	Causes
Hormonal	Menopause (estrogen deficiency), surgical menopause (more severe), androgen deficiency, hyperprolactinemia, thyroid disease
Psychological	Depression, anxiety, past sexual trauma/abuse, body image issues, relationship discord
Medical	Diabetes, cardiovascular disease, chronic pain, urinary incontinence, neurological disease
Medications	SSRIs/SNRIs (most common), antipsychotics, antihypertensives, antiandrogens (cimetidine, spironolactone), antiestrogens, GnRH agonists, anticholinergics, opioids, alcohol
Situational	Partner factors, life stressors, unemployment, childcare burden, communication failure

E. Genito-Pelvic Pain/Penetration Disorder (GPPPD)

Prevalence: 12-21% in the United States.

Type	Description
Vaginismus	Involuntary contraction of pelvic floor/vaginal muscles preventing penetration; primarily psychological/fear-based; no structural cause
Dyspareunia	Recurrent genital pain before, during, or after intercourse; organic or psychological; NOT exclusively from lack of lubrication or vaginismus

Differential Diagnosis of Dyspareunia:

Superficial (introital) dyspareunia:

Vulvodynia / vulvar vestibulitis
Atrophic vaginitis (menopause)
Vaginal infection (Candida, Trichomonas, BV)
Bartholin's cyst/abscess
Lichen sclerosus
Imperforate hymen / hymenal remnants

Deep dyspareunia:

Endometriosis (most important cause)
Pelvic inflammatory disease (PID)
Uterine fibroids
Ovarian cysts
Pelvic adhesions
Irritable bowel syndrome (IBS)
Interstitial cystitis

F. Female Orgasmic Disorder

Causes: SSRIs (most common drug cause - delay/inhibit orgasm), spinal cord injury (requires intact sympathetic outflow for orgasm), neurological disease, inadequate stimulation, psychological inhibition, menopausal changes

4. RISK FACTORS TABLE (Both Sexes)

Shared Risk Factors
Cardiovascular disease / hypertension
Diabetes mellitus
Neurological disorders (stroke, spinal cord injury, Parkinsonism)
Endocrinopathies (diabetes, hyperprolactinemia)
Liver and/or renal failure
Psychological: sexual abuse, life stressors, depression
Medications (see drug table above)
Smoking, alcohol, obesity

(Harrison's Principles of Internal Medicine 22E)

5. INVESTIGATIONS FOR SEXUAL DYSFUNCTION

A. All Patients - History (MOST IMPORTANT)

Onset and duration (lifelong vs. acquired, gradual vs. sudden)
Situational vs. generalized (all partners/situations vs. specific)
Libido - is sexual desire present? (if absent = desire disorder or hypogonadism)
Nocturnal/morning erections (males)
Masturbatory function
Partner and relationship factors
Substance use (alcohol, recreational drugs, anabolic steroids)
Full medication review - drugs implicated in up to 25% of ED cases
Psychiatric history (depression, anxiety, past abuse)
Surgical history (radical prostatectomy, pelvic surgery, vascular surgery)
Medical history: DM, CVD, neurological disease, thyroid, renal, liver disease

Validated Tools:

SHIM (Sexual Health Inventory for Men) = International Index of Erectile Function (IIEF-5) - 5-question validated questionnaire for ED severity
FSFI (Female Sexual Function Index) - validated tool for female sexual dysfunction

B. Physical Examination

Male:

Secondary sexual characteristics (body hair, testicular volume, gynecomastia)
Peripheral pulses (femoral, popliteal) - assess vascular disease
Carotid auscultation for bruits
Penile shaft - Peyronie plaques (fibrous induration)
Testicular - atrophy (hypogonadism), varicocele
Genitourinary - phimosis, chordee
Neurological - anal sphincter tone, perianal sensation, bulbocavernosus reflex (S2-S4)
Thyroid exam
Prostate (DRE)

Female:

External genitalia - clitoris, vulvar atrophy, lichen sclerosus, vestibulitis
Pelvic floor - hypertonicity (vaginismus), prolapse, tenderness
Bimanual exam - uterine/adnexal tenderness, masses (endometriosis, fibroids)
Cervix (infection signs)
Signs of estrogen deficiency (vaginal atrophy, dryness, pallor)

C. Laboratory Investigations

Test	Purpose / Indication
Fasting glucose / HbA1c	Diabetes (most common organic cause of ED)
Lipid profile	Cardiovascular/vascular risk
Total testosterone (AM sample, 8-10 AM)	Hypogonadism; threshold for ED: <300 ng/dL
Free testosterone / SHBG	Total T may be misleadingly normal; ~2% free bioavailable (useful if SHBG abnormal)
LH + FSH	Distinguish primary (↑LH/FSH) vs. secondary (↓/normal) hypogonadism
Prolactin	Hyperprolactinemia (causes ↓libido, ↓T, ED, galactorrhea); check if low T found; <2% of ED cases
TSH	Hypo/hyperthyroidism (affects both sexes)
PSA	Before testosterone replacement in males >40 yrs
Renal function (BUN/creatinine)	Chronic kidney disease
Liver function tests	Cirrhosis (altered sex hormone metabolism)
CBC	Anaemia, haematological causes
Estradiol (E2)	Female: menopausal status, ovarian failure
DHEA-S	Female: reflects adrenal androgen secretion; low in adrenal insufficiency
Androgens (female) - total + free testosterone	PCOS, androgen deficiency, adrenal disorders; measure on days 8-10 of cycle
Urinalysis	Renal disease, glycosuria

For females specifically (FSD evaluation):

Thyroid function, fasting glucose, lipid profile, liver function
If hormonal problem suspected: prolactin, total + free testosterone, SHBG, DHEA, estrogen levels

(Textbook of Family Medicine 9e; Harrison's 22E)

D. Specialized Investigations (Erectile Dysfunction)

Test	What it shows	Indication
Nocturnal Penile Tumescence (NPT) test (RigiScan)	Measures erections during sleep; present = psychogenic cause; absent = organic	Distinguishing psychogenic from organic ED
Penile Duplex Doppler Ultrasonography	Assesses arterial inflow and venous outflow of cavernous arteries; after intracavernosal injection of prostaglandin E1	Suspected vasculogenic ED; pre-surgical planning
Intracavernosal injection test	Intracarvernosal PGE1/papaverine; erection = adequate arterial supply	Differentiates arterial vs. neurogenic/venous
Penile arteriography	Gold standard for penile arterial anatomy	Pre-revascularization surgery (young trauma patients)
Cavernosometry/cavernosography	Assesses venous leak (veno-occlusive dysfunction)	Suspected venous leak
Bulbocavernosus reflex latency	Neurological integrity of S2-S4 pudendal nerve	Suspected neurogenic cause
SSEP (Somatosensory Evoked Potentials)	Central and peripheral nerve function	Neurological ED
Pelvic MRI/CT	Structural lesions	If pituitary tumor or pelvic pathology suspected

Note: Clitoral Doppler ultrasonography and biothesiometry for female sexual dysfunction exist but require expensive equipment and are of uncertain clinical utility (Harrison's 22E).

E. Investigations for Infertility (Recap with Integration)

Male Infertility Investigations - Ordered Approach

Step	Investigation	Interpretation
1st	Semen analysis x2 (2-7 days abstinence, 4-6 weeks apart)	See WHO criteria (normal: count ≥15M/mL, motility ≥40%, morphology ≥4%)
2nd	Testosterone, LH, FSH, Prolactin, TSH	If oligo/azoospermia confirmed
3rd	Karyotype + Y chromosome microdeletion (AZF regions)	If severe oligospermia <5M/mL or azoospermia
3rd	CFTR mutation testing	If bilateral absence of vas deferens on exam
4th	Scrotal ultrasound	Varicocele, testicular atrophy, epididymal cysts
4th	Transrectal ultrasound (TRUS)	If ejaculatory duct obstruction suspected (semen volume <1 mL)
Specialized	Testicular biopsy / TESE	Differentiates obstructive vs. non-obstructive azoospermia

Female Infertility Investigations - Ordered Approach

Step	Investigation	Interpretation
1st	Urinary LH ovulation prediction kit / Mid-luteal progesterone (day 21)	Confirm ovulation; P4 >3 ng/mL = ovulated
1st	TSH, Prolactin, Pregnancy test	Exclude common endocrine causes
2nd	Day 3 FSH + Estradiol	Ovarian reserve; FSH >12 IU/L = poor reserve → refer to RE specialist
2nd	AMH (Anti-Müllerian Hormone)	Best ovarian reserve marker; cycle-independent; determines gonadotropin dosing
2nd	Androgens (total T, DHEA-S, 17-OH progesterone)	Hyperandrogenism (PCOS, CAH, Cushing)
3rd	HSG (Hysterosalpingography)	First-line for tubal patency + uterine cavity
3rd	Sonohysterography (SIS)	Better for submucosal fibroids, polyps, Asherman syndrome
4th	Laparoscopy + chromotubation	Gold standard for tubes; also diagnoses endometriosis, adhesions
4th	Hysteroscopy	Direct uterine cavity visualization + therapeutic
Antral follicle count (AFC)	Transvaginal ultrasound	Ovarian reserve assessment
If amenorrhea	Progesterone challenge test → Estrogen-Progesterone challenge	Determine level of outflow/hormonal defect

6. INVESTIGATIONS INTERPRETATION SUMMARY - SEXUAL DYSFUNCTION

Erectile Dysfunction - Interpretation Logic

Low Testosterone?
    ├── HIGH LH/FSH → PRIMARY hypogonadism (testicular failure)
    │       e.g., Klinefelter, orchitis, radiation
    └── LOW/NORMAL LH/FSH → SECONDARY hypogonadism (hypothalamic-pituitary)
             ├── High Prolactin → Prolactinoma → MRI pituitary
             └── Normal Prolactin → Hypogonadotropic hypogonadism

Normal Testosterone, no medical cause?
    └── Check NPT (nocturnal penile tumescence)
             ├── NPT PRESENT → Psychogenic ED (psychological/relationship cause)
             └── NPT ABSENT → Organic ED → Penile Doppler ultrasonography

Female - Interpretation Logic (Desire/Arousal Disorder)

↓ Estradiol + ↑ FSH/LH → Menopause/POI (ovarian failure)
↑ Prolactin → Prolactinoma → MRI pituitary
Abnormal TSH → Thyroid disease
↑ Androgens + Irregular cycles → PCOS, CAH
Normal hormones + situational → Psychogenic/relationship
Medications review → SSRIs, antihypertensives, antipsychotics

SECTION B: DIFFERENTIAL DIAGNOSIS TABLES

Male Sexual Dysfunction - Differential Diagnosis

Symptom	Key Differentials
ED + DM	Diabetic autonomic neuropathy + vasculopathy
ED + absent morning erections + cardiovascular risk	Vasculogenic ED (most common)
ED + low libido + gynecomastia + small testes	Hypogonadism (Klinefelter, hypopituitarism)
ED + galactorrhea + visual field defects	Prolactinoma → pituitary MRI
ED + sudden onset + normal NPT	Psychogenic ED
Painful curved erection	Peyronie's disease
ED + neurological symptoms	Spinal cord injury, MS, Parkinson's
PE + hyperthyroidism symptoms	Hyperthyroid-associated PE
Delayed ejaculation	SSRIs, diabetes, post-prostatectomy, alcohol

Female Sexual Dysfunction - Differential Diagnosis

Symptom	Key Differentials
Low desire + hot flushes + irregular cycles	Perimenopause/Menopause (↑FSH, ↓E2)
Low desire + galactorrhea	Hyperprolactinemia
Low desire + cold intolerance + weight gain	Hypothyroidism
Low desire + hirsutism + irregular cycles	PCOS
Low desire on SSRIs	Drug-induced sexual dysfunction
Vaginismus (no penetration)	Psychological, prior sexual trauma, vaginismus
Deep dyspareunia + dysmenorrhea	Endometriosis
Deep dyspareunia + vaginal discharge	PID, cervicitis
Superficial dyspareunia + dryness + atrophy	Genitourinary Syndrome of Menopause (GSM)
Superficial dyspareunia + vulvar burning	Vulvodynia / Vulvar Vestibulitis
Anorgasmia on antidepressants	SSRI-induced orgasmic disorder
Anorgasmia + spinal cord injury	Neurological (requires intact S2-S4 for orgasm)

Infertility - Complete Differential Diagnosis

Male Infertility Differential

Category	Specific Causes
Pre-testicular (Hypogonadotropic)	Kallmann syndrome, pituitary tumor, hyperprolactinemia, exogenous androgen/steroid use, hemochromatosis, systemic illness
Testicular (Primary)	Klinefelter syndrome (47,XXY), Y chromosome microdeletions (AZFa/b/c), cryptorchidism, orchitis (mumps), testicular torsion, varicocele, radiation, chemotherapy (alkylating agents), heat exposure
Post-testicular (Obstructive)	Vasectomy, CBAVD (CF-related), epididymal obstruction, ejaculatory duct obstruction, retrograde ejaculation (DM, post-TURP, alpha-blockers)
Sperm dysfunction	Sperm antibodies (post-vasectomy reversal), immotile cilia syndrome (Kartagener), globozoospermia
Coital/Sexual	ED, PE, timing/frequency issues, lubricant use (spermicidal effect)

Female Infertility Differential

Category	Specific Causes
Ovulatory (40%)	PCOS (most common), hyperprolactinemia, thyroid disease, hypothalamic amenorrhea (low BMI, exercise, stress), premature ovarian insufficiency, CAH, Cushing syndrome
Tubal (20-30%)	PID sequelae (Chlamydia/Gonorrhea-related), endometriosis, tubal ligation, previous ectopic pregnancy, tubal torsion, hydrosalpinx
Uterine (5-10%)	Asherman syndrome (intrauterine adhesions), fibroids (submucosal), endometrial polyps, uterine septum, DES exposure
Cervical (5%)	Cervical stenosis, anti-sperm antibodies, abnormal cervical mucus, post-LEEP/cone biopsy
Peritoneal	Endometriosis, pelvic adhesions
Diminished Ovarian Reserve	Advanced age (>35), prior chemotherapy, radiation, prior ovarian surgery (endometrioma)
Unexplained	~10-20% (diagnosis of exclusion)

SECTION C: TREATMENT HIGHLIGHTS (Exam Quick Reference)

Sexual Dysfunction Treatment

Condition	First-Line	Second-Line/Notes
ED (organic/mixed)	PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil)	Vacuum erection device, intracavernosal alprostadil, intraurethral MUSE, penile prosthesis
ED (psychogenic)	Psychosexual counseling, sensate focus	PDE-5 inhibitors + psychotherapy (better than either alone)
ED (hypogonadal)	Testosterone replacement (if T <300 ng/dL)	Then add PDE-5 inhibitor if needed
PE	Dapoxetine (short-acting SSRI, FDA-approved) + behavioral (squeeze technique, stop-start)	SSRIs (paroxetine, sertraline - off-label), tramadol, topical anesthetics
Delayed ejaculation	Remove/switch offending drug (SSRI)	Psychotherapy
Female low desire (menopausal)	Estrogen ± progestogen therapy	Testosterone (investigational, no FDA-approved formulation)
Female low desire (premenopausal)	Treat underlying cause (TSH, prolactin, SSRI switch to bupropion)	Flibanserin (FDA-approved for HSDD in premenopausal women)
Dyspareunia (atrophic)	Vaginal estrogen (local)	Non-hormonal lubricants
Dyspareunia (endometriosis)	GnRH analogues, COC, surgery	IVF if infertile
Vaginismus / GPPPD	Pelvic floor physiotherapy, vaginal dilators, CBT	Botulinum toxin injection (severe cases)

KEY EXAM POINTS - MNEMONICS

Causes of ED - "VENT + P":

Vascular (most common organic cause)
Endocrine (DM, hypogonadism, hyperprolactinemia)
Neurological
Toxins/Drugs (25% of cases)
Psychological

Distinguishing Organic vs Psychogenic ED:

"Morning glory = Psychogenic" - if morning erections are present, psychogenic is more likely

Female Desire Loss - "SHAME":

SSRIs/medications
Hormones (menopause, hyperprolactinemia, thyroid)
Abuse/psychological
Medical illness (DM, CVD)
Estrogen deficiency

Infertility investigations order:

Male: Semen → Hormones → Genetics → Imaging
Female: Ovulation confirm → Reserve → Hormones → Anatomy (HSG → Laparoscopy)

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