---

Male and Female Infertility - Comprehensive Notes

---

PART 1: DEFINITIONS AND EPIDEMIOLOGY

• Infertility = failure to achieve pregnancy after 1 year of unprotected intercourse
• 15-20% of all couples are affected
• Causes are distributed roughly:
  • 1/3 male factors alone
  • 1/3 female factors alone
  • 1/3 combination of both
  • ~20% unexplained (idiopathic)
• Female fertility peaks at ages 20-24, declines progressively after 32, steep decline after 40
• In female couples desiring conception, donor sperm is needed - they are not "infertile" in the traditional sense

Workup should begin after 6 months (not 1 year) if the woman is over 35, has irregular menses, known history of pelvic inflammatory disease (PID), STI, or exposure to gonadotoxic agents.

---

PART 2: MALE INFERTILITY

Causes / Differential Diagnosis

• Hypothalamic dysfunction (Kallmann syndrome)
• Pituitary failure (tumor, radiation, surgery)
• Hyperprolactinemia (drug-induced, tumor)
• Androgen insensitivity syndrome (AIS)
• Exogenous androgens (anabolic steroids)
• Thyroid disorders
• Adrenal hyperplasia
• Testicular failure

• Congenital absence of vas deferens (associated with CFTR mutations)
• Obstructed vas deferens
• Congenital abnormalities of ejaculatory system
• Varicocele
• Retrograde ejaculation

• Unexplained azoospermia
• Chromosomal abnormalities (e.g., Klinefelter 47,XXY)
• Mumps orchitis
• Cryptorchidism
• Chemical or radiation exposure

• Absent cilia - Kartagener syndrome (Primary Ciliary Dyskinesia)
• Antisperm antibody formation

• Unexplained impotence
• Decreased libido

---

Investigations for Male Infertility

• Reproductive history, STD history, contraception
• Medications (especially anabolic steroids, chemotherapy, antihypertensives)
• Recreational drug, alcohol, and environmental toxin exposure
• Sexual history: erectile function, ejaculatory technique, lubricant use
• Surgical history (vasectomy, hernia repair, pelvic surgery)
• Family history of genetic diseases
• Physical: external genitalia for androgenization, hair pattern (virilization), gynecomastia, neurologic findings (anosmia, visual impairment), testicular atrophy

• Most important laboratory test in male fertility evaluation
• Semen analyzed within 1 hour of collection
• Two consecutive abnormal results required before proceeding to further workup

• Azoospermia = no sperm in ejaculate
• Oligospermia = low sperm count (<15 million/mL)
• Asthenospermia = reduced motility
• Teratospermia = abnormal morphology

• Testosterone (total) - assess Leydig cell function
• LH - distinguishes primary vs. secondary hypogonadism
• FSH - marker of spermatogenesis integrity (elevated = testicular failure)
• Prolactin - rule out hyperprolactinemia
• TSH - rule out thyroid disease

• Karyotype / Chromosomal analysis - rule out Klinefelter (47,XXY), Y chromosome microdeletions
• CFTR mutation testing - if bilateral congenital absence of vas deferens
• Testicular biopsy - differentiate obstructive from non-obstructive azoospermia
• Scrotal Doppler ultrasound - confirm varicocele
• Post-ejaculate urinalysis - rule out retrograde ejaculation
• Anti-sperm antibodies - immunologic cause
• Transrectal ultrasound (TRUS) - evaluate ejaculatory ducts
• MRI pituitary - if hyperprolactinemia confirmed

Management of Male Infertility

• Treat underlying infection with appropriate antibiotics
• Varicocelectomy for varicocele
• Counseling about environmental factors (avoid heat, toxins)
• IUI (Intrauterine Insemination) for mild male factor
• ICSI (Intracytoplasmic Sperm Injection) for severe male factor - outcomes comparable to conventional IVF
• Referral to infertility specialist

---

PART 3: FEMALE INFERTILITY

Causes / Differential Diagnosis

• Polycystic Ovarian Syndrome (PCOS) - most common cause of anovulation
• Primary Ovarian Insufficiency (POI) / premature menopause
• Hypergonadotropic hypogonadism (gonadal dysgenesis, resistant ovary syndrome)
• Hypogonadotropic hypogonadism (Kallmann syndrome, pituitary/hypothalamic insufficiency)
• Hyperprolactinemia (tumor, drugs)
• Luteal phase deficiency
• Thyroid disorders (hypothyroidism, hyperthyroidism)
• Liver disease, obesity, androgen excess
• Anorexia, excessive exercise, stress

• Tubal occlusion or scarring from PID
• Salpingitis isthmica nodosa
• Infectious salpingitis (Chlamydia, Gonorrhea)
• Previous ectopic pregnancy
• Post-surgical adhesions

• Leiomyomata (fibroids, esp. submucosal)
• Congenital malformation (Mullerian anomalies)
• Intrauterine adhesions (Asherman syndrome)
• Endometritis / abnormal endometrium

• Cervical stenosis
• Inflammation or infection
• Abnormal mucous viscosity

• Endometriosis (30-40% when combined with tubal)
• Pelvic adhesions

• Antisperm antibodies

• Decreased libido, anorgasmia

---

Investigations for Female Infertility

• Menstrual history: regularity, cycle length, dysmenorrhea
• Obstetric history: prior pregnancies, miscarriages
• History of PID, STIs, pelvic surgery
• Medications and gonadotoxin exposure
• Physical: external genitalia for androgen excess (clitoromegaly, hirsutism), thyroid exam, galactorrhea, uterine and adnexal pathology

• Urinary LH ovulation predictor kits (detect LH surge) - recommended
• Mid-luteal serum progesterone (7 days before anticipated menses) - value >3 ng/mL indicates ovulation; >10 ng/mL = adequate luteal phase
• Transvaginal ultrasound - follicular tracking
• Note: Basal body temperature (BBT) is no longer routinely recommended

• Serum FSH on Day 3 of menstrual cycle - value >12 IU/L = poor ovarian reserve
• Serum Estradiol (E2) on Day 3 - elevated E2 with normal FSH can still suggest poor reserve
• Anti-Mullerian Hormone (AMH) - best single marker of ovarian reserve; not cycle-dependent
• Antral Follicle Count (AFC) on transvaginal ultrasound
• Women >35 should always have ovarian reserve testing

• Serum AMH - most reliable ovarian reserve marker
• 17-OH Progesterone - elevated in follicular phase suggests congenital adrenal hyperplasia (CAH)
• Androgens (total testosterone, DHEA-S) - if androgen excess suspected
• Karyotype - if primary ovarian insufficiency (Turner syndrome 45,X)
• MRI pituitary - if hyperprolactinemia confirmed
• Pelvic/transvaginal ultrasound - ovarian morphology (PCOS), fibroids, polyps
• HSG (Hysterosalpingography) - tubal patency, uterine cavity
• Diagnostic laparoscopy - gold standard for endometriosis and pelvic adhesions
• Hysteroscopy - direct visualization of uterine cavity

• Serum E2 <40 pg/mL
• LH <10 IU/L, FSH <10 IU/L
• No withdrawal bleeding on progestin challenge (thin endometrium)
• Causes: pituitary/hypothalamic failure, hyperprolactinemia, Kallmann syndrome

• Elevated FSH and LH, low E2
• Causes: POI, gonadal dysgenesis, menopause, resistant ovary syndrome

---

PART 4: SEXUAL DYSFUNCTION

Definition & DSM-5 Framework

• Sexual dysfunction = persistent problem causing clinically significant distress
• Subtypes:
  • Lifelong (since sexual debut) vs. Acquired (after period of normal function)
  • Generalized (all situations) vs. Situational (specific contexts/partners)
  • Severity: mild / moderate / severe

1. Partner factors (partner's response, partner's involvement)
2. Relationship factors (communication, emotional abuse)
3. Individual vulnerability (body image, psychiatric comorbidity - depression, anxiety; life stressors)
4. Cultural/religious factors
5. Medical factors (physical disability, medications)

---

Female Sexual Dysfunction

A. Female Sexual Interest/Arousal Disorder (FSIAD)

• Most common female sexual problem - affects 4 in 10 women
• Diagnosed when lacking/reduced sexual interest for ≥6 months, with at least 3 of 6 criteria:
  1. Absent/reduced interest in sexual activity
  2. Absent/reduced sexual/erotic thoughts or fantasies
  3. No/reduced initiation; unreceptive to partner's initiation
  4. Absent/reduced sexual excitement/pleasure during activity
  5. Absent/reduced sexual interest in response to any erotic cues
  6. Absent/reduced genital/nongenital sensations during activity

B. Female Orgasmic Disorder

• Delay, infrequency, or absence of orgasm; reduced intensity
• SSRIs delay/inhibit orgasm in women

C. Genito-Pelvic Pain/Penetration Disorder

• Prevalence: 12-21% in the United States
• Persistent difficulty with penetration, pelvic/vaginal pain, fear/anxiety, pelvic floor tightening
• History: pain on tampon insertion before sexual activity is an important risk factor
• Exam: visible pelvic floor muscle contraction, anatomical abnormalities

D. Differential Diagnosis of Female Sexual Dysfunction

• Depression, anxiety disorders
• Relationship conflict
• History of sexual trauma/abuse (PTSD)
• Endocrine: hypothyroidism, hyperprolactinemia, menopause (low estrogen)
• Pelvic pathology: vulvodynia, vestibulodynia, endometriosis, vaginismus
• Neurological disease
• Medication-induced (SSRIs, antipsychotics, OCPs)
• Substance use (alcohol, opioids)

---

Male Sexual Dysfunction

A. Erectile Dysfunction (ED)

• Parasympathetic stimulation → nitric oxide (NO) release → increases intracellular cGMP → cavernosal smooth muscle relaxation → rapid blood inflow → occlusion of emissary veins → erection
• PDE-5 degrades cGMP; PDE-5 inhibitors prolong erection
• Requires intact vascular, neurologic, endocrine, and psychological systems

• 2% at ages 40-49
• 6% at ages 50-59
• 17% at 60+ years

B. Differential Diagnosis of ED

"What is bad for the heart is bad for the penis" - vascular risk factors are the most common modifiable cause

C. Premature (Early) Ejaculation (PE)

• Defined as intravaginal ejaculatory latency of <1 minute
• Most common male sexual complaint

D. Differential Diagnosis of Male Sexual Dysfunction

• Vascular disease (commonest)
• Diabetes mellitus
• Hypogonadism / low testosterone
• Hyperprolactinemia
• Neurological disorders
• Peyronie's disease
• Post-surgical (radical prostatectomy, pelvic surgery)
• Medications (see below)

• Anxiety, depression
• Performance anxiety
• Relationship problems
• Post-traumatic stress

---

Investigations for Sexual Dysfunction

Male Sexual Dysfunction Workup

• Nature of ED (complete vs. partial, situational vs. generalized, morning erections present?)
• Cardiovascular risk factors (DM, HTN, dyslipidemia, smoking)
• Medications and substance use
• Psychiatric symptoms (depression, anxiety)
• Relationship/partner issues

• Peripheral pulses (carotid auscultation for bruits)
• Thyroid exam
• Genitourinary: penile shaft (Peyronie plaques), testicular size/atrophy
• Neurological: anal sphincter tone, perianal sensation, bulbocavernosus reflex
• Secondary sexual characteristics assessment

• Fasting glucose / HbA1c - rule out diabetes
• Fasting lipid profile - vascular risk
• Total testosterone (morning sample) - hypogonadism
• LH and FSH - if testosterone low (distinguish primary vs. secondary)
• Prolactin - if hypogonadism or visual symptoms
• TSH - thyroid disease
• BUN and creatinine - renal disease
• Serum transaminases - hepatic disease
• PSA - before testosterone therapy

• Nocturnal penile tumescence (NPT) testing - differentiates psychogenic from organic ED (erections during sleep preserved in psychogenic ED)
• Penile Doppler ultrasound with intracavernous injection - assesses arterial flow and venous leak
• Pudendal nerve conduction studies - neurogenic ED
• Pituitary MRI - if hyperprolactinemia confirmed

Female Sexual Dysfunction Workup

• Onset, context, and duration of symptoms
• Relationship and partner factors
• Prior sexual trauma or abuse
• Psychiatric history (depression, anxiety)
• Medications (especially SSRIs, antipsychotics, OCPs, anticonvulsants)
• Menopausal status and hormonal symptoms
• Pelvic pain history

• External genitalia, vaginal mucosa (atrophy = low estrogen)
• Pelvic floor tone and tenderness
• Evidence of infection, anatomical abnormalities (vaginal septa)

• TSH, FSH, LH, Estradiol - hormonal evaluation
• Prolactin - if galactorrhea or amenorrhea
• Androgens (total testosterone, DHEA-S) - androgen insufficiency
• Fasting glucose - if diabetes suspected
• Pelvic ultrasound - if anatomical cause suspected
• Psychological screening tools - PHQ-9 (depression), GAD-7 (anxiety)

---

Medications Affecting Sexual Function

---

PART 5: SUMMARY TABLE - INVESTIGATIONS AT A GLANCE

---

PART 6: KEY TREATMENT HIGHLIGHTS

• Varicocelectomy improves sperm parameters
• Treat infections; avoid gonadotoxins
• IUI for mild factor; ICSI for severe factor

• PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) = first-line (SOR: A)
• Sildenafil onset 30-60 min (3-5 hr effect); Tadalafil onset 16-30 min (24-72 hr effect)
• Prostaglandin E1 (intracavernous or intraurethral alprostadil) = second-line
• Vacuum erection devices (VEDs) = adjunct
• Testosterone replacement if hypogonadal (see routes in Table 42-5)
• Psychotherapy + sildenafil superior to sildenafil alone

• SSRIs delay ejaculation (SOR: A); dapoxetine is the only SSRI approved specifically for PE

• Psychosocial interventions for FSIAD
• Vaginal dilators + pelvic floor physiotherapy for genito-pelvic pain
• If SSRI-induced: add bupropion (SOR: C) or switch to bupropion/mirtazapine
• Treat underlying hormonal causes (hypothyroidism, hyperprolactinemia)

---