1. Genital Tuberculosis

Definition and Pathogenesis

Pathology

Clinical Features

• Women: Primary infertility is the most common presentation (60-70% of cases). Menstrual irregularities including amenorrhea, oligomenorrhea, or hypomenorrhea occur due to endometrial involvement. Chronic pelvic pain, low-grade fever, and constitutional symptoms may be present. Ascites from peritoneal involvement can mimic ovarian carcinoma.
• Men: Painless nodular thickening of the epididymis, scrotal sinus formation, beaded vas deferens, infertility.

Diagnosis

• Endometrial biopsy (curettage) during the premenstrual phase for AFB smear, culture, and histopathology (caseating granulomas with Langhans giant cells).
• Laparoscopy with direct biopsy of tubal lesions.
• Hysterosalpingography (HSG) showing "tobacco-pouch" or "pipe-stem" appearance of tubes.
• PCR of endometrial or peritoneal tissue is highly sensitive.
• Tuberculin skin test (PPD) or IGRA (QuantiFERON).
• Chest X-ray - may show old healed primary complex.
• CA-125 may be elevated, mimicking ovarian malignancy.

Treatment

• Standard regimen: Isoniazid (INH) + Rifampin (RIF) + Pyrazinamide (PZA) + Ethambutol (EMB) for 2 months (intensive phase), followed by INH + RIF for 4 months (continuation phase) - total 6 months.
• Some authorities recommend 9 months for genital TB given the deep tissue involvement.
• Surgical intervention is reserved for persistent pelvic masses, treatment failures, or complications (e.g., fistulas, frozen pelvis).

2. HIV and TB in Pregnancy

Epidemiology

Effect of Pregnancy on TB

HIV-Specific Considerations

• Pneumocystis jiroveci pneumonia (PJP) - occurs when CD4+ count is <200 cells/mm³; historically 100% maternal mortality, now ~50% mortality. P. jiroveci is the #1 cause of pregnancy-associated AIDS deaths in the US. Treatment: trimethoprim-sulfamethoxazole (TMP-SMX).
• Bacterial pneumonias - S. pneumoniae and H. influenzae are most common; Pseudomonas aeruginosa is a significant pathogen in HIV-infected individuals.
• Latent TB reactivation - risk highest in the first 2 years after conversion; BCG vaccination history complicates PPD interpretation.

Diagnosis in Pregnancy

• PPD/Mantoux test - women from endemic areas with BCG vaccination: use PPD unless previously known positive; reaction ≥10 mm after BCG given >10 years ago should be treated as latent TB infection.
• Asymptomatic gravidas with positive PPD: thorough physical examination, chest X-ray after first trimester.
• Active TB symptoms (cough 74%, weight loss 41%, fever 30%, malaise/fatigue 30%, hemoptysis 19%) prompt immediate chest X-ray.
• AFB smear and culture of three early-morning sputum samples; if sputum cannot be produced - induction, gastric washings, or bronchoscopy.

Obstetric Complications

• Severe preeclampsia and eclampsia
• Placenta previa
• Postpartum hemorrhage
• Sepsis
• Anemia

Congenital TB

1. Demonstration of primary hepatic complex or cavitating hepatic granuloma on percutaneous liver biopsy at birth
2. Infection of the maternal genital tract or placenta
3. Lesions seen in the first week of life
4. Exclusion of postnatal transmission

Treatment in Pregnancy

• Ethambutol is teratogenic in animals but not shown to be in humans; most common side effect is optic neuritis.
• Streptomycin is contraindicated - causes cranial nerve VIII damage (sensorineural deafness) in neonates.
• Drugs to avoid: ethionamide, streptomycin, capreomycin, kanamycin, cycloserine.
• Latent TB: INH 300 mg/day starting after first trimester for 6-9 months, with pyridoxine (B6) supplementation to prevent peripheral neuropathy.
• MDR-TB in pregnancy: individualized management; counsel about teratogenicity risk; untreated TB carries greater morbidity/mortality than treatment.

3. Amenorrhea

Definition

• Primary amenorrhea: Absence of menses by age 13 when no secondary sexual characteristics have developed, or by age 15 in the presence of normal secondary sexual characteristics.
• Secondary amenorrhea: Absence of menses for 3 or more consecutive months in a woman who has previously menstruated, or 6 months in a woman with previously irregular cycles.

Physiology

Classification and Causes

Primary Amenorrhea

• Turner syndrome (45,X) - streak gonads, short stature, somatic stigmata
• Pure gonadal dysgenesis (46,XX or 46,XY - Swyer syndrome)
• Congenital lipoid adrenal hyperplasia (StAR protein deficiency)
• 17α-hydroxylase/17,20-lyase deficiency (CYP17 mutations) - primary amenorrhea, no secondary sex characteristics, hypertension, hypokalemia

• Kallmann syndrome (GnRH deficiency + anosmia)
• Other hypothalamic/pituitary dysfunction

• Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome)
• Androgen insensitivity syndrome (46,XY; female phenotype, absent uterus, testes)

• Imperforate hymen, transverse vaginal septum

Secondary Amenorrhea

• Pregnancy - must be ruled out first (hCG)
• Hypothalamic-pituitary dysfunction - weight loss, exercise (hypothalamic amenorrhea), stress, hyperprolactinemia, hypopituitarism
• PCOS - most common endocrine cause
• Thyroid disorders - hypothyroidism causes hyperprolactinemia → amenorrhea
• Premature ovarian insufficiency (POI) - high FSH, low estradiol before age 40
• Outflow tract obstruction - Asherman syndrome (intrauterine adhesions)
• Premature menopause

Diagnostic Evaluation

1. Physical exam for secondary sexual characteristics and anatomic abnormalities
2. Serum beta-hCG (rule out pregnancy)
3. Serum prolactin and TSH
4. Serum FSH + estradiol (differentiates hypergonadotropic from hypogonadotropic)
5. Anti-Müllerian hormone (AMH) - can be helpful
6. Dehydroepiandrosterone sulfate (DHEA-S) >7.0 µg/mL → adrenal neoplasm evaluation; 5.0-7.0 µg/mL → evaluate for adult-onset congenital adrenal hyperplasia

Treatment

• Treat the underlying cause
• Hormone therapy to establish/maintain secondary sexual characteristics and bone protection (calcium + Vitamin D + estrogen for hypoestrogenic states)
• Ovulation induction (FSH + LH for hypogonadotropic; letrozole/clomiphene/gonadotropins for PCOS) for fertility
• Multidisciplinary approach for functional hypothalamic amenorrhea (behavioral health + nutrition)

4. Endometriosis

Definition

1. Superficial peritoneal endometriosis
2. Ovarian endometriosis (endometrioma/"chocolate cyst")
3. Deep infiltrating endometriosis (risk of malignant transformation mainly confined to this type)

Pathogenesis

1. Regurgitation (Sampson's) theory - endometrial tissue implants at ectopic sites via retrograde flow of menstrual endometrium through the fallopian tubes (most widely accepted).
2. Benign metastasis theory - endometrial tissue spreads to distant sites (bone, lung, brain) via blood vessels and lymphatics.
3. Metaplastic theory - endometrium arises directly from coelomic epithelium (mesothelium of pelvis/abdomen), from which the Müllerian ducts originate during embryogenesis.
4. Extrauterine stem/progenitor cell theory - bone marrow-derived stem cells differentiate into endometrial tissue.

Morphology

Clinical Features

• Dysmenorrhea - secondary, progressively worsening (key distinguishing feature from primary dysmenorrhea)
• Chronic pelvic pain - often cyclical, worsening before/during menses
• Dyspareunia - especially deep dyspareunia
• Infertility - through distorted pelvic anatomy, impaired sperm transport, altered peritoneal environment, impaired implantation
• Dyschezia (pain on defecation) - with rectovaginal/bowel involvement
• Dysuria - with bladder involvement
• Cyclic hemoptysis/pneumothorax - rare thoracic endometriosis
• Asymptomatic - found incidentally in a significant proportion

Staging

Diagnosis

• Clinical suspicion based on symptoms and examination (tender nodules in the posterior fornix/uterosacral ligaments; fixed retroverted uterus).
• Laparoscopy with biopsy - gold standard for definitive diagnosis.
• Transvaginal ultrasound (TVUS) - useful for detecting endometriomas but misses peritoneal implants.
• MRI - superior to TVUS for deep infiltrating endometriosis.
• CA-125 may be elevated but is non-specific.

Management

• Combined oral contraceptive pills (continuous use preferred)
• Progestins (medroxyprogesterone acetate, norethindrone, dienogest)
• GnRH agonists (leuprolide) ± add-back estrogen/progesterone
• Danazol (androgenic side effects limit use)
• Aromatase inhibitors (for refractory disease)
• NSAIDs for pain

• Conservative (laparoscopic excision/ablation of lesions) - for fertility preservation
• Definitive (hysterectomy ± bilateral salpingo-oophorectomy) - for completed family and severe disease

5. Polycystic Ovary Syndrome (PCOS)

Definition and Epidemiology

Diagnostic Criteria (Rotterdam Consensus + 2023 International Guidelines)

1. Irregular menses (oligo-ovulation/anovulation, typically <8-9 cycles/year)
2. Clinical or biochemical hyperandrogenism - elevated total or free testosterone; modified Ferriman-Gallwey score ≥4-6 (ethnicity-dependent); or clinical acne/hirsutism
3. Polycystic-appearing ovaries on ultrasound - ≥20 antral follicles or ovarian volume ≥10 cm³ in at least one ovary; OR elevated serum AMH (proposed cutoff >35 pmol/L / 5 ng/mL)

Pathophysiology

• Abnormal GnRH pulsatility → disproportionately elevated LH relative to FSH → increased ovarian androgen (theca cell) production; relatively low FSH impairs follicle maturation and ovulation.
• Insulin resistance (present in ~60-80%) - in skeletal muscle and adipose tissue - leads to compensatory hyperinsulinemia, which stimulates ovarian androgen production directly. Insulin also suppresses hepatic sex hormone-binding globulin (SHBG), increasing free androgen levels.
• Elevated 11-oxygenated androgens - alternate source of androgens may be elevated.
• Obesity worsens insulin resistance and the overall phenotype.
• Genetics - ~19 loci identified by GWAS; familial clustering is common.
• AMH - significantly elevated in PCOS (produced by granulosa cells of small antral follicles); ongoing research into using AMH as a diagnostic criterion.

Clinical Features (frequency data from Tietz Textbook)

• Typically begins at or near puberty with hirsutism and irregular menses from menarche
• LH levels elevated in ~2/3 of cases; LH:FSH ratio often elevated (but not recommended as diagnostic criterion given LH pulsatility)
• Rare presentation as primary amenorrhea

Long-term Metabolic Risks

• Metabolic syndrome
• Type 2 diabetes mellitus
• Dyslipidemia and cardiovascular disease (hypercholesterolemia)
• Endometrial hyperplasia and endometrial cancer (2-6 fold increased risk due to unopposed estrogen from anovulation)
• Obstructive sleep apnea
• Metabolic dysfunction-associated steatotic liver disease (MSDLD), independent of BMI
• Depression, anxiety, disordered eating, body image distress (high prevalence)

Pregnancy-Related Risks

Treatment

• First-line: Combined hormonal contraceptives (CHCs) - regulate cycles, reduce androgens by increasing SHBG, treat acne/hirsutism; use lowest effective estrogen dose.
• If inadequate response after 6 months: add antiandrogens (spironolactone, flutamide).
• Endometrial protection in women not using CHCs: cyclic progestins (medroxyprogesterone acetate 10 mg or progesterone 200 mg for 10-14 days every 3 months) or levonorgestrel IUD.
• Lifestyle management (all women with PCOS): weight reduction improves virtually all features.
• Metformin: consider for cardiometabolic risk prevention in overweight/obese women; not recommended alone for hyperandrogenic symptoms, endometrial protection, or pregnancy loss prevention.
• Screen at diagnosis and regularly: obesity, hypertension, glycemic control, depression/anxiety, and fasting lipid profile.

• First-line: Letrozole (aromatase inhibitor) - superior to clomiphene for ovulation and live birth rates in PCOS.
• Second-line: Clomiphene citrate ± metformin.
• Third-line: Injectable gonadotropins (risk of ovarian hyperstimulation syndrome - OHSS - is higher in PCOS; use low-dose step-up protocols for monofollicular growth).
• IVF as last resort.

6. Asherman's Syndrome (Intrauterine Synechiae)

Definition and Pathogenesis

Etiology

• Dilatation and curettage (D&C) following incomplete pregnancy loss (miscarriage), pregnancy termination, or postpartum hemorrhage - this is by far the most common cause in Western countries.
• Infected pregnancy (endometritis at time of curettage dramatically increases risk).
• Postpartum curettage for retained placenta.

• Myomectomy
• Hysteroscopic surgery
• Diagnostic curettage
• Cesarean section
• Uterine packing

• Genital tuberculosis - a very common cause; these patients have a particularly poor prognosis after surgery.
• Caustic abortifacients.

Clinical Features (correlate with severity)

• Amenorrhea or hypomenorrhea - hallmark of severe disease; results from obliteration of the endometrial cavity or destruction of functional endometrium.
• Menstrual irregularities - partial synechiae cause scanty or irregular bleeding.
• Cyclic pelvic pain - if the adhesions obstruct menstrual outflow (cryptomenorrhea).
• Infertility - due to disrupted endometrial receptivity and mechanical obstruction of implantation.
• Recurrent pregnancy loss / spontaneous abortion - due to inadequate endometrial surface for implantation.

Diagnosis

• Clinical suspicion: history of preceding uterine instrumentation + amenorrhea or menstrual changes.
• Hysterosalpingography (HSG) - irregular filling defects within the uterine cavity.
• Hysteroscopy - gold standard; directly visualizes adhesions (classified as filmy, fibromuscular, or connective tissue/dense based on severity).
• Saline infusion sonohysterography (SIS) - can suggest adhesions.
• MRI - useful in complex cases.

Treatment

• Hysteroscopic resection (adhesiolysis) is the preferred treatment to restore fertility. Using hysteroscopic scissors or energy devices to divide adhesions under direct vision.
• Patients with genital tuberculosis as the etiology have a very poor prognosis even after successful surgery, because the endometrial basalis may be irreversibly destroyed.

• Estrogen therapy × 1 month alone: oral conjugated estrogens 2.5 mg/day overlapping with progestin; or E2 valerate 2 mg injections daily.
• Mechanical separation: intraoperative placement of an intrauterine device (small Malecot catheter or pediatric Foley catheter) for 1-2 weeks post-operatively to keep uterine walls apart.
• Combination of both mechanical + estrogen approaches is commonly used.

Prognosis

• Mild-to-moderate synechiae treated with hysteroscopy have reasonable pregnancy rates (~45-60% in some series).
• Severe/complete synechiae, particularly from genital TB, carry a very poor reproductive prognosis.
• Surrogate/gestational carrier pregnancy may be the only option in cases of permanent endometrial destruction.