Can you make a detailed notes on cutaneous hyperandrogenism , etiology, pathogenesis, approach, clinical features, management for university theory md dermatology examination

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CUTANEOUS HYPERANDROGENISM

Detailed Notes for MD Dermatology University Theory Examination

DEFINITION

Cutaneous hyperandrogenism refers to the clinical manifestations in the skin, hair, and sebaceous glands resulting from excessive androgen activity - either due to elevated circulating androgens or increased end-organ sensitivity to normal androgen levels. The major cutaneous manifestations are:

Acne vulgaris (hormonal)
Hirsutism
Seborrhoea
Androgenetic alopecia (AGA)
Acanthosis nigricans (as a marker of associated insulin resistance)

The constellation of Seborrhoea, Acne, Hirsutism, and Androgenetic alopecia is termed SAHA syndrome.

ETIOLOGY

A. Ovarian Causes

Condition	Notes
Polycystic Ovarian Syndrome (PCOS)	Most common cause; biochemical or clinical hyperandrogenism + chronic anovulation (<9 periods/year) without adrenal or pituitary disease
Functional ovarian hyperandrogenism	Ovarian steroidogenic dysregulation
Ovarian neoplasms	Sertoli-Leydig cell tumors, granulosa-theca cell tumors, hilus cell tumors - low metastatic potential, surgical treatment
Hyperthecosis	Hyperplasia of theca interna cells
Syndromes of extreme insulin resistance	Severe acanthosis nigricans

B. Adrenal Causes

Condition	Notes
Non-classic (late-onset) Congenital Adrenal Hyperplasia (NCAH)	Most commonly 21-hydroxylase deficiency (CYP21A2 mutation); elevated 17-OHP is hallmark
Cushing syndrome	ACTH-driven adrenal androgen excess
Adrenal adenoma	Secretes testosterone
Adrenal carcinoma	Secretes testosterone + DHEA-S + cortisol
Premature adrenarche
Functional adrenal hyperandrogenism

C. Mixed / Other

Condition	Notes
Idiopathic hyperandrogenism	Elevated androgens without identifiable cause
Idiopathic hirsutism	5-15% of cases; normal androgens, regular cycles - increased end-organ sensitivity
Hyperprolactinaemia	Prolactinoma, drugs, hypothyroidism; hirsutism + galactorrhoea
Acromegaly	Elevated GH and IGF-1
Hypothyroidism	Reduces SHBG; increases free androgens
HAIR-AN syndrome	Hyperandrogenism, Insulin Resistance, Acanthosis Nigricans
Pregnancy	Luteoma, hyperreactio luteinalis, aromatase deficiency

D. Drug-Induced Causes

Exogenous androgens / anabolic steroids
Synthetic progestins (norgestrel, norethindrone, norgestimate, desogestrel) - reduce SHBG
Danazol, valproate, minoxidil

PATHOGENESIS

Androgen Physiology in Skin

Sources of androgens in women:

Ovaries (testosterone, androstenedione)
Adrenal cortex (DHEA, DHEA-S, androstenedione)
Peripheral conversion (in skin, fat)

Key hormones involved:

Testosterone - the principal circulating androgen
DHT (5α-dihydrotestosterone) - the most potent intracellular androgen; has greater receptor binding affinity
DHEA / DHEA-S - adrenal androgens; weaker but present in large quantities
Androstenedione - intermediate; converted to testosterone peripherally

Key enzyme - 5α-reductase:

Converts testosterone → DHT within target tissues (sebaceous glands, hair follicles, genital skin)
Two isoforms: Type 1 (sebaceous glands, liver) and Type 2 (hair follicles, genital skin, prostate)

Sex Hormone-Binding Globulin (SHBG):

Binds both testosterone and estrogen; only free (unbound) fraction is biologically active
SHBG is decreased by: synthetic progestins, obesity, acromegaly, hypothyroidism, insulin resistance → increasing free androgen levels
This explains why androgenic findings can appear even with normal total testosterone

Androgen receptor distribution in skin:

Androgen receptors are present throughout the skin: sebaceous glands, hair follicles (site-specific), dermal fibroblasts, keratinocytes
Androgens also regulate wound healing, epidermal differentiation, and dermal fibroblast function

Mechanisms of Cutaneous Effects

1. Seborrhoea:

Androgens (especially DHT) are the primary stimulants of sebaceous gland development and sebum production
Androgen receptors are densely expressed in sebaceous glands
Increased sebum → altered follicular microenvironment → promotes acne

2. Acne:

Androgens stimulate sebaceous gland hypertrophy → excess sebum
Altered keratinisation of the follicular infundibulum → microcomedone formation
Sebum provides substrate for Cutibacterium acnes → inflammation
Pathogenic sequence: androgen excess → ↑ sebum + ↓ linoleic acid → follicular hyperkeratosis → comedone → papule/pustule/nodule

3. Hirsutism:

Androgens (primarily DHT) activate androgen receptors in the hair follicle papilla
Convert vellus hair (short, fine, unpigmented) → terminal hair (long, pigmented, thick)
Transformation occurs in androgen-sensitive areas: upper lip, chin, beard, chest, upper back, lower abdomen
The hair growth cycle (anagen-catagen-telogen) is hormonally regulated in a site-specific pattern

4. Androgenetic Alopecia (AGA):

Paradoxically, the same DHT causes miniaturisation on the scalp
Terminal hair on scalp → vellus hair over successive cycles
Men: bitemporal recession + vertex loss (Hamilton-Norwood pattern)
Women: diffuse thinning of crown; frontal hairline generally preserved (Ludwig pattern)
Primarily autosomal dominant genetic predisposition; worsened by androgen excess

5. Acanthosis Nigricans:

Not a direct androgen effect but a marker of insulin resistance associated with PCOS/HAIR-AN
Insulin and IGF-1 stimulate keratinocyte and fibroblast proliferation
Seen in axillae, neck, groin, under breasts

Idiopathic Hirsutism:

Normal circulating androgens, regular ovulatory cycles
Caused by increased 5α-reductase activity locally in the follicle
Increased end-organ sensitivity of hair follicle to androgens
Higher rate in Mediterranean, South Asian, and Middle Eastern populations

CLINICAL FEATURES

1. Hirsutism

Definition: Excessive hair growth in women in a male-pattern (androgenic) distribution
Differs from hypertrichosis (generalised excess hair, androgen-independent)
Distribution: Upper lip > thighs > lower abdomen > upper back; also chin, cheeks, chest, suprapubic area, perianal area
Ferriman-Gallwey (mFG) Score:
- Scores 9 body areas (upper lip, chin/cheeks, chest, upper abdomen, lower abdomen, upper back, lower back, arms, legs)
- Score 0-4 per area; maximum 36
- Normal: ≤8; Mild: 8-14; Moderate to severe: ≥15
Abrupt/rapid onset → suspect malignancy
Severity of hirsutism does not always correlate with degree of androgen excess

2. Acne

Comedonal acne in early puberty (9-12 years) is normal; does not need workup unless other features
Acne with onset ages 1-7 with virilisation → refer to paediatric endocrinologist
Features suggesting hormonal acne:
- Sudden onset / severe acne
- Refractory to conventional treatment
- Predominantly on lower face, jawline, neck
- Premenstrual flares
- Irregular menstrual periods
- Associated hirsutism or alopecia

3. Seborrhoea

Oily, shiny skin especially of the face and scalp
Scaling and redness (seborrhoeic dermatitis)
Present in 100% of SAHA syndrome cases

4. Androgenetic Alopecia (AGA)

Women: Ludwig pattern - diffuse central/crown thinning, frontal hairline preserved
Men: Hamilton-Norwood pattern - bitemporal + vertex loss
Usually slow and progressive
Can be acquired in androgen excess states or as autosomal dominant genetic disorder

5. Signs of Virilisation (severe hyperandrogenism)

Clitoromegaly
Male-pattern balding (frontal recession in women)
Deepening of voice
Decreased breast size / breast tissue atrophy
Increased muscle mass
Galactorrhoea (if hyperprolactinaemia)

6. SAHA Syndrome

Seborrhoea + Acne + Hirsutism + Androgenetic Alopecia
Four subtypes: idiopathic, ovarian, adrenal, hyperprolactinaemic
Prevalent in 17.7% of PCOS patients; associated with greater insulin resistance

7. HAIR-AN Syndrome

Hyperandrogenism + Insulin Resistance + Acanthosis Nigricans
Severe insulin resistance driving androgen excess
Diagnosis: impaired GTT result

8. PCOS-specific cutaneous findings

Severe truncal hirsutism
Axillary acanthosis nigricans (common)
Skin tags
Associated: obesity, irregular periods, infertility, impaired glucose tolerance, hyperlipidaemia

APPROACH TO DIAGNOSIS

Step 1: History

Age of onset, rate of progression (slow = functional; rapid = tumour)
Menstrual history (oligomenorrhoea, amenorrhoea)
Family history
Medications: anabolic steroids, danazol, valproate, synthetic progestins
Obstetric history
Symptoms of Cushing: weight gain, striae, buffalo hump, easy bruising

Step 2: Physical Examination

mFG scoring for hirsutism
Signs of virilisation
Signs of insulin resistance: acanthosis nigricans, skin tags, central obesity
Signs of Cushing: purple striae, moon facies, buffalo hump
Thyroid palpation
Galactorrhoea (hyperprolactinaemia)

Step 3: Investigation

First-line tests:

Test	Purpose
Free testosterone (or total testosterone)	Best screening marker; most sensitive biochemical marker of hyperandrogenism
DHEA-S	Screens for adrenal androgen source; elevated in adrenal tumours and CAH
LH:FSH ratio	Ratio >2-3 suggests PCOS
Prolactin	Screens for hyperprolactinaemia
TSH	Rules out hypothyroidism
Fasting glucose/GTT	Insulin resistance assessment
17-OHP (early morning)	Elevated in 21-hydroxylase deficiency NCAH (>10 ng/mL after ACTH stimulation)

Note: Laboratory evaluation is most accurate when the patient is off oral contraceptives for 4-6 weeks, and tests are drawn before menses.

Second-line (if indicated):

Test	Indication
ACTH stimulation test	Confirm NCAH (17-OHP >10 ng/mL post-ACTH)
Dexamethasone suppression test	Distinguish adrenal vs. ovarian vs. Cushing origin
24-hour urinary cortisol / late-night salivary cortisol	Rule out Cushing syndrome
Pelvic ultrasound	PCOS (polycystic ovaries), ovarian tumour
CT abdomen	Adrenal mass (if DHEA-S 2-3× upper limit)
Pregnancy test (β-hCG)	Rule out pregnancy if amenorrhoeic
IGF-1, GH	Acromegaly

Red flag values:

Total testosterone >200 ng/dL → suspect adrenal or ovarian tumour → urgent imaging
DHEA-S 2-3× upper limit → adrenal mass → CT adrenal

Diagnostic Algorithm

The approach follows a branching pathway based on menstrual regularity:

Figure: Diagnostic approach to hirsutism - from Fitzpatrick's Dermatology

Regular cycles + normal T → Idiopathic hirsutism
Regular cycles + elevated T → Idiopathic hyperandrogenism
Irregular cycles, no sudden onset → Exclude secondary causes (PCOS, NCAH, SAHA, hypothyroidism, acromegaly, hyperprolactinaemia, HAIR-AN)
Sudden onset + virilisation → Suspect malignancy; T >200 ng/dL → imaging for adrenal/ovarian tumour

MANAGEMENT

Management is directed at the underlying cause and at the specific cutaneous manifestation. It involves pharmacological and non-pharmacological approaches.

A. HORMONAL / ANTI-ANDROGEN THERAPY

1. Oral Contraceptive Pills (OCPs)

Mechanism: Increase SHBG (reducing free testosterone), suppress LH, reduce ovarian androgen production
Preferred formulations: Those containing progestins with low androgenic or antiandrogenic activity (desogestrel, norgestimate) or antiandrogenic progestins (cyproterone acetate, drospirenone)
Indications: Hirsutism, hormonal acne, AGA in women with PCOS or ovarian hyperandrogenism
Improvement in acne within 3-6 months; hirsutism requires 6-9 months
Contraindicated in women >35 years who smoke, or with thromboembolic risk

2. Spironolactone

Mechanism: Aldosterone antagonist (potassium-sparing diuretic) with antiandrogen activity; competes for androgen cytosol receptors; also inhibits 5α-reductase; decreases androgen synthesis
Dose: 50-200 mg/day
Uses: Hirsutism, hormonal acne, AGA in women, seborrhoea
Monitor: serum potassium, blood pressure, menstrual irregularity
Contraindicated in pregnancy (feminisation of male fetus)
Topical spironolactone: Limited evidence for hirsutism

3. Cyproterone Acetate (CPA)

Antiandrogen + progestin
Used as part of oral contraceptive preparations (not available in the USA)
Effective for acne, hirsutism, AGA
Often used in combination as Diane-35 (CPA 2 mg + ethinyl oestradiol 35 μg)

4. Finasteride

Mechanism: 5α-reductase inhibitor; blocks conversion of testosterone → DHT
Dose: 1-5 mg/day
Uses: AGA in men (5 mg for FPHL in post-menopausal women - limited benefit in placebo-controlled trials); hirsutism
Contraindicated in women of childbearing age (risk of hypospadias/feminisation in male fetus)
Side effects in men: decreased libido, erectile dysfunction, depression (may persist after stopping - post-finasteride syndrome); linked to increased risk of high-grade prostate cancer (without increase in absolute risk)

5. Dutasteride

Dual 5α-reductase inhibitor (type 1 + type 2)
More potent than finasteride
Used in hirsutism and AGA

6. Flutamide

Androgen receptor antagonist
Rarely used due to risk of fatal hepatotoxicity (hepatitis)
Risk to male fetus in women of childbearing age

7. Bicalutamide

Non-steroidal pure antiandrogen (developed for prostate cancer)
Dose: 25 mg/day for PCOS-induced and idiopathic hirsutism
Well-tolerated; hepatotoxicity reported at ≥50 mg/day

8. Metformin

Insulin sensitiser; improves insulin responsiveness in PCOS
Indirect antiandrogen effect by reducing insulin-driven androgen production
Improves menstrual irregularity, reduces androgens
Adjunct in PCOS with insulin resistance / metabolic syndrome

9. Glucocorticoids

For adrenal-origin hyperandrogenism (CAH)
Suppresses ACTH, thereby reducing adrenal androgen production
Dexamethasone 0.25-0.5 mg at night (low dose to avoid Cushing side effects)
Prednisolone 5-7.5 mg/day

10. Clascoterone (Winlevi 1%)

Topical antiandrogen (androgen receptor antagonist)
Approved for treatment of acne
Not well-established for hirsutism

B. MANAGEMENT OF SPECIFIC CONDITIONS

Hirsutism

Cosmetic/Physical methods:

Shaving, depilatory creams, waxing, threading - temporary
Eflornithine HCl 13.9% cream (Vaniqa): Topical inhibitor of ornithine decarboxylase; slows hair growth; used on face; not permanent; applied twice daily
Electrolysis: Uses galvanic current or thermolysis; only permanent method; disadvantages: time-consuming, scarring, follicular hyperpigmentation, pain; regrowth ~40%
Laser hair removal:
- 755-nm Alexandrite laser
- 800-nm Diode laser
- 1064-nm Nd:YAG laser (best for darker skin)
- Intense Pulsed Light (IPL)
- Works via selective photothermolysis - targets pigmented follicles; requires 3-6 treatment cycles; less effective for fair hair; adverse effects: PIH, folliculitis, paradoxical hypertrichosis, HSV reactivation

Systemic:

Spironolactone 100-200 mg/day (first-line for idiopathic hirsutism / PCOS in women)
OCP (especially drospirenone or CPA-containing)
Finasteride / Dutasteride
Metformin (for PCOS-associated)

Hormonal Acne

OCP (low-androgenic/antiandrogenic progestins)
Spironolactone 50-150 mg/day
Cyproterone acetate-containing OCP
Clascoterone 1% topical
Plus standard topical therapy: retinoids, benzoyl peroxide, topical antibiotics

Androgenetic Alopecia (AGA)

Women:
- Topical minoxidil 2-5% (first-line)
- Spironolactone (systemic or topical)
- OCP (antiandrogenic)
- Finasteride (post-menopausal only - limited evidence)
- Low-level laser therapy
Men:
- Topical minoxidil 5%
- Finasteride 1 mg/day
- Dutasteride 0.5 mg/day
- Hair transplantation

Seborrhoea

Topical antifungals (ketoconazole shampoo)
Topical low-potency corticosteroids
Antiandrogen therapy if severe / associated with SAHA

Acanthosis Nigricans (in PCOS/HAIR-AN)

Weight loss (primary target in obesity)
Metformin
Lifestyle modification
Topical retinoids / keratolytics

C. MANAGEMENT OF SPECIFIC UNDERLYING CAUSES

PCOS

Lifestyle modification: Weight loss (first-line in obese patients) - even 5-10% weight reduction can restore menstrual cycles and reduce androgen levels
Metformin - improves insulin resistance, menstrual regularity
OCP - regulates menstrual cycles, reduces androgens
Spironolactone - for cutaneous manifestations
Clomiphene citrate - if fertility is desired

Non-Classic CAH (21-hydroxylase deficiency)

Low-dose glucocorticoids (dexamethasone, prednisolone) to suppress ACTH
Antiandrogen therapy (spironolactone, OCP) as alternative or adjunct
Antenatal dexamethasone in homozygous female fetuses (to prevent virilisation of external genitalia)
Diagnosis confirmed by CYP21 genotyping

Adrenal/Ovarian Tumours

Surgical resection (curative)

Cushing Syndrome

Treatment of primary cause (surgery for pituitary adenoma - transsphenoidal, adrenal adenoma, ectopic ACTH source)

Hyperprolactinaemia

Dopamine agonists: cabergoline, bromocriptine

SUMMARY TABLE: ANTIANDROGENS IN DERMATOLOGY

Drug	Mechanism	Main Uses	Key Side Effects	Contraindication
Spironolactone	AR antagonist + 5α-RI + ↓ androgen synthesis	Hirsutism, acne, AGA	Hyperkalaemia, menstrual irregularity, breast tenderness	Pregnancy
Cyproterone acetate	AR antagonist + progestin	Hirsutism, acne, AGA	Hepatotoxicity (high dose), depression	Pregnancy
Finasteride	5α-RI (type 1+2)	AGA (men), hirsutism	Decreased libido, ED, depression, post-finasteride syndrome	Pregnancy (teratogenic)
Dutasteride	5α-RI dual (type 1+2)	AGA, hirsutism	Same as finasteride	Pregnancy
Flutamide	AR antagonist	Hirsutism	Fatal hepatitis	Pregnancy, liver disease
Bicalutamide	AR antagonist (pure non-steroidal)	Hirsutism (PCOS, idiopathic)	Hepatotoxicity at ≥50 mg	Pregnancy
OCP	↑ SHBG, ↓ LH, antiandrogenic	Hirsutism, acne, AGA	Thromboembolism, hypertension	Thrombophilia, age >35 + smoking
Metformin	Insulin sensitiser (indirect)	PCOS	GI side effects, lactic acidosis	Renal failure
Clascoterone	Topical AR antagonist	Acne	Local irritation	-
Eflornithine	Ornithine decarboxylase inhibitor	Facial hirsutism	Local irritation	-

KEY EXAM POINTS

SAHA syndrome = Seborrhoea + Acne + Hirsutism + Androgenetic Alopecia; 4 subtypes (idiopathic, ovarian, adrenal, hyperprolactinaemic)
HAIR-AN syndrome = Hyperandrogenism + Insulin Resistance + Acanthosis Nigricans
Modified Ferriman-Gallwey score: ≤8 normal; 8-14 mild hirsutism; ≥15 moderate-severe
DHT is the most potent intracellular androgen; formed by 5α-reductase from testosterone
SHBG reduction (by obesity, insulin resistance, progestins) → increased free androgens
Free testosterone is the most sensitive biochemical marker of hyperandrogenism
Testosterone >200 ng/dL → suspect androgen-secreting tumour → urgent imaging
17-OHP elevation (especially post-ACTH >10 ng/mL) → NCAH (21-hydroxylase deficiency)
Idiopathic hirsutism = normal androgens + regular cycles + increased 5α-reductase activity locally
Abrupt rapid onset of hirsutism = red flag for malignancy
Finasteride contraindicated in women of childbearing age (feminisation of male fetus)
Flutamide - avoid due to fatal hepatotoxicity
Laser hair removal works via selective photothermolysis; Nd:YAG preferred for dark skin; not effective for light/white hair
Eflornithine - topical; inhibits ornithine decarboxylase; slows facial hair growth; not permanent

Sources: Fitzpatrick's Dermatology, 9th Ed., Vol. 1-2 (Ch. 90: Hirsutism; Ch. 137: Hyperandrogenism); Andrews' Diseases of the Skin, 13th Ed. (Ch. 24: Androgen-Dependent Syndromes); Dermatology 2-Volume Set, 5th Ed.

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mkdir -p /tmp/workspace/cutaneous-hyperandrogenism && ls /tmp/workspace/

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Cutaneous Hyperandrogenism - MD Dermatology Notes PDF Generator
Colourful, well-structured, exam-ready PDF using ReportLab
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    t.setStyle(TableStyle([
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        ('TOPPADDING', (0,0), (-1,-1), 5),
        ('BOTTOMPADDING', (0,0), (-1,-1), 5),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
        ('RIGHTPADDING', (0,0), (-1,-1), 8),
        ('ROUNDEDCORNERS', [4, 4, 4, 4]),
    ]))
    return t

def coloured_box(content_rows, bg_color=BOX_BLUE, border_color=ROYAL_BLUE):
    """Wraps content in a coloured background box."""
    data = [[c] for c in content_rows]
    flat = [[item for sublist in data for item in sublist]]
    inner = []
    for row in content_rows:
        inner.append([row])
    t = Table(inner, colWidths=[PAGE_W - 2*MARGIN - 4])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), bg_color),
        ('BOX', (0,0), (-1,-1), 1, border_color),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
        ('RIGHTPADDING', (0,0), (-1,-1), 8),
    ]))
    return t


# ── Main PDF builder ─────────────────────────────────────────────────────────
def build_pdf(output_path):
    doc = SimpleDocTemplate(
        output_path,
        pagesize=A4,
        leftMargin=MARGIN, rightMargin=MARGIN,
        topMargin=20*mm, bottomMargin=16*mm,
        title="Cutaneous Hyperandrogenism - MD Dermatology Notes",
        author="Orris Medical AI",
        subject="MD Dermatology University Examination Notes"
    )

    s = make_styles()
    story = []
    col_w = PAGE_W - 2*MARGIN

    # ── TITLE PAGE ────────────────────────────────────────────────────────────
    title_bg = Table(
        [[Paragraph("CUTANEOUS HYPERANDROGENISM", s['doc_title'])],
         [Paragraph("Comprehensive Notes for MD Dermatology University Theory Examination", s['doc_sub'])],
         [Spacer(1, 4)],
         [Paragraph("Etiology · Pathogenesis · Clinical Features · Approach · Management", s['doc_sub'])],
         [Spacer(1, 6)],
         [Paragraph("Sources: Fitzpatrick's Dermatology 9e | Andrews' Diseases of the Skin 13e | Dermatology 2-Vol Set 5e", 
                    ParagraphStyle('src', fontName='Helvetica', fontSize=9, textColor=colors.HexColor("#90CAF9"), alignment=TA_CENTER, leading=12))]
        ],
        colWidths=[col_w]
    )
    title_bg.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), DARK_NAVY),
        ('TOPPADDING', (0,0), (-1,-1), 14),
        ('BOTTOMPADDING', (0,0), (-1,-1), 14),
        ('LEFTPADDING', (0,0), (-1,-1), 14),
        ('RIGHTPADDING', (0,0), (-1,-1), 14),
        ('ROUNDEDCORNERS', [8, 8, 8, 8]),
    ]))
    story.append(title_bg)
    story.append(Spacer(1, 10))

    # ── DEFINITION ────────────────────────────────────────────────────────────
    story.append(section_header("1. DEFINITION", s['section'], ROYAL_BLUE))
    story.append(Spacer(1, 4))
    story.append(Paragraph(
        "<b>Cutaneous hyperandrogenism</b> refers to clinical manifestations in the skin, hair, and "
        "sebaceous glands resulting from <b>excessive androgen activity</b> — either due to elevated circulating "
        "androgens <i>or</i> increased end-organ sensitivity to normal androgen levels.",
        s['body']))
    story.append(Spacer(1, 4))

    # SAHA box
    saha_data = [
        [Paragraph("★  SAHA SYNDROME", s['box_title'])],
        [Paragraph("<b>S</b>eborrhoea  +  <b>A</b>cne  +  <b>H</b>irsutism  +  <b>A</b>ndrogenetic Alopecia", s['keypoint'])],
        [Paragraph("Four subtypes: Idiopathic · Ovarian · Adrenal · Hyperprolactinaemic | Prevalence: 17.7% of PCOS patients", s['body'])],
    ]
    story.append(coloured_box([row[0] for row in saha_data], BOX_PURPLE, PURPLE))
    story.append(Spacer(1, 3))

    hair_data = [
        [Paragraph("★  HAIR-AN SYNDROME", ParagraphStyle('ht', fontName='Helvetica-Bold', fontSize=10, textColor=RED_DARK))],
        [Paragraph("<b>H</b>yperandrogenism  +  <b>I</b>nsulin <b>R</b>esistance  +  <b>A</b>canthosis <b>N</b>igricans", s['keypoint'])],
    ]
    story.append(coloured_box([row[0] for row in hair_data], BOX_RED, RED_DARK))
    story.append(Spacer(1, 6))

    # ── ETIOLOGY ─────────────────────────────────────────────────────────────
    story.append(section_header("2. ETIOLOGY", s['section'], ROYAL_BLUE))
    story.append(Spacer(1, 5))

    # Etiology table
    etio_headers = [
        Paragraph("SOURCE", s['tbl_hdr']),
        Paragraph("CONDITION", s['tbl_hdr']),
        Paragraph("KEY FEATURES", s['tbl_hdr'])
    ]

    def ec(txt, bold=False):
        st = s['tbl_cell_bold'] if bold else s['tbl_cell']
        return Paragraph(txt, st)

    etio_data = [
        etio_headers,
        [ec("OVARIAN", bold=True), ec("PCOS ★ Most common", bold=True),
         ec("Biochemical/clinical hyperandrogenism + anovulation; LH:FSH >2-3; polycystic ovaries on USG")],
        [ec(""), ec("Functional ovarian hyperandrogenism"), ec("Ovarian steroidogenic dysregulation")],
        [ec(""), ec("Ovarian neoplasms"), ec("Sertoli-Leydig cell tumour, granulosa-theca cell tumour, hilus cell tumour — low metastatic potential; surgical Rx")],
        [ec(""), ec("Hyperthecosis"), ec("Hyperplasia of theca interna cells; more severe hyperandrogenism than PCOS")],
        [ec(""), ec("HAIR-AN syndrome"), ec("Hyperandrogenism + Insulin Resistance + Acanthosis Nigricans")],
        [ec("ADRENAL", bold=True), ec("NCAH (21-OH deficiency) ★", bold=True),
         ec("CYP21A2 mutation; elevated 17-OHP; late-onset; peripubertal hirsutism, acne, amenorrhoea")],
        [ec(""), ec("Cushing syndrome"), ec("Cortisol excess + ACTH-driven adrenal androgen excess; purple striae, moon facies")],
        [ec(""), ec("Adrenal adenoma"), ec("Secretes testosterone; usually unilateral")],
        [ec(""), ec("Adrenal carcinoma"), ec("Secretes testosterone + DHEA-S + cortisol; rapid-onset virilisation")],
        [ec(""), ec("Premature adrenarche"), ec("Early adrenal androgen secretion before age 8 in girls")],
        [ec("PITUITARY /\nOTHER", bold=True), ec("Hyperprolactinaemia"), ec("Prolactinoma, drugs, hypothyroidism; hirsutism + galactorrhoea")],
        [ec(""), ec("Acromegaly"), ec("Elevated GH + IGF-1; coarsened skin, macroglossia, enlarged hands")],
        [ec(""), ec("Hypothyroidism"), ec("Reduces SHBG → increased free androgens")],
        [ec("IDIOPATHIC", bold=True), ec("Idiopathic hirsutism"), ec("Normal androgens, regular cycles; increased 5α-reductase activity locally (5–15% of cases)")],
        [ec(""), ec("Idiopathic hyperandrogenism"), ec("Elevated androgens, no identifiable source")],
        [ec("DRUGS", bold=True), ec("Androgenic medications"), ec("Exogenous androgens, anabolic steroids, danazol, norgestrel, norethindrone, valproate, minoxidil")],
        [ec("PREGNANCY", bold=True), ec("Pregnancy-related"), ec("Luteoma of pregnancy, hyperreactio luteinalis, fetal aromatase deficiency")],
    ]

    etio_colw = [col_w*0.13, col_w*0.32, col_w*0.55]
    etio_table = Table(etio_data, colWidths=etio_colw, repeatRows=1)
    etio_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_NAVY),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('FONTSIZE', (0,0), (-1,0), 9),
        ('ALIGN', (0,0), (-1,0), 'CENTER'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#EEF2FF"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        # Colour rows by source
        ('BACKGROUND', (0,1), (0,5), colors.HexColor("#E3F2FD")),
        ('BACKGROUND', (0,6), (0,10), colors.HexColor("#E8F5E9")),
        ('BACKGROUND', (0,11), (0,13), colors.HexColor("#F3E5F5")),
        ('BACKGROUND', (0,14), (0,15), colors.HexColor("#FFF3E0")),
        ('BACKGROUND', (0,16), (0,16), colors.HexColor("#FFEBEE")),
        ('BACKGROUND', (0,17), (0,17), colors.HexColor("#FCE4EC")),
    ]))
    story.append(etio_table)
    story.append(Spacer(1, 8))

    # ── PATHOGENESIS ──────────────────────────────────────────────────────────
    story.append(section_header("3. PATHOGENESIS", s['section'], TEAL))
    story.append(Spacer(1, 5))

    story.append(Paragraph("A. Androgen Physiology in Skin", s['subsection']))
    story.append(Paragraph(
        "<b>Sources of androgens in women:</b> Ovaries (testosterone, androstenedione) + "
        "Adrenal cortex (DHEA, DHEA-S, androstenedione) + Peripheral conversion (skin, fat, liver).",
        s['body']))
    story.append(Spacer(1, 3))

    # Key hormones mini table
    horm_headers = [Paragraph("HORMONE", s['tbl_hdr']), Paragraph("POTENCY / ROLE", s['tbl_hdr']), Paragraph("NOTES", s['tbl_hdr'])]
    horm_data = [
        horm_headers,
        [ec("Testosterone"), ec("Principal circulating androgen"), ec("Converted to DHT in target tissues by 5α-reductase")],
        [ec("DHT (5α-dihydrotestosterone)", bold=True), ec("★ Most potent intracellular androgen"), ec("Higher receptor binding affinity than testosterone; acts on sebaceous glands, hair follicles")],
        [ec("DHEA / DHEA-S"), ec("Weak androgens"), ec("Adrenal origin; large quantities; substrate for peripheral conversion")],
        [ec("Androstenedione"), ec("Intermediate"), ec("Converted to testosterone peripherally; ovarian + adrenal source")],
        [ec("Progesterone"), ec("Progestational"), ec("Binds androgen receptor weakly; can have androgenic effects")],
    ]
    horm_colw = [col_w*0.22, col_w*0.30, col_w*0.48]
    horm_table = Table(horm_data, colWidths=horm_colw, repeatRows=1)
    horm_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_TEAL),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#E0F2F1"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        ('BACKGROUND', (0,2), (-1,2), colors.HexColor("#B2DFDB")),
    ]))
    story.append(horm_table)
    story.append(Spacer(1, 5))

    # 5a reductase and SHBG
    story.append(Paragraph("B. Key Regulatory Mechanisms", s['subsection']))

    enzyme_box = [
        Paragraph("<b>5α-Reductase</b>", s['subsubsection']),
        Paragraph("Converts Testosterone → DHT in peripheral target tissues (sebaceous glands, hair follicles, genital skin)", s['body']),
        Paragraph("• <b>Type 1:</b> Sebaceous glands, liver, skin", s['bullet']),
        Paragraph("• <b>Type 2:</b> Hair follicles, genital skin, prostate", s['bullet']),
        Paragraph("Drugs that inhibit this enzyme: Finasteride (Type 1+2) | Dutasteride (dual Type 1+2)", s['body']),
    ]
    story.append(coloured_box(enzyme_box, BOX_TEAL, TEAL))
    story.append(Spacer(1, 3))

    shbg_box = [
        Paragraph("<b>Sex Hormone-Binding Globulin (SHBG)</b>", s['subsubsection']),
        Paragraph("Binds testosterone and estrogen; only <b>free (unbound) fraction</b> is biologically active.", s['body']),
        Paragraph("SHBG is <b>decreased</b> by (→ more free androgens):", s['body']),
        Paragraph("• Synthetic progestins (norgestrel, norethindrone, norgestimate, desogestrel)", s['bullet']),
        Paragraph("• Obesity · Insulin resistance · Hypothyroidism · Acromegaly", s['bullet']),
        Paragraph("SHBG is <b>increased</b> by: Oestrogens · OCPs (oestrogen component) → less free androgen", s['bullet']),
    ]
    story.append(coloured_box(shbg_box, BOX_BLUE, ROYAL_BLUE))
    story.append(Spacer(1, 5))

    story.append(Paragraph("C. Mechanisms of Individual Cutaneous Manifestations", s['subsection']))

    mech_headers = [Paragraph("MANIFESTATION", s['tbl_hdr']), Paragraph("MECHANISM", s['tbl_hdr'])]
    mech_data = [
        mech_headers,
        [ec("Seborrhoea", bold=True),
         ec("DHT stimulates sebaceous gland hypertrophy + sebum production. Type 1 5α-reductase predominates in sebaceous glands. Androgen receptors densely expressed here.")],
        [ec("Acne vulgaris", bold=True),
         ec("Androgens → ↑ sebum + ↓ linoleic acid → follicular hyperkeratosis → microcomedone → Cutibacterium acnes colonisation → inflammation → papule/pustule/nodule/cyst")],
        [ec("Hirsutism", bold=True),
         ec("DHT activates androgen receptors in hair follicle papilla → conversion of vellus hair (short, fine, unpigmented) to terminal hair (long, pigmented, coarse) in androgen-sensitive areas")],
        [ec("Androgenetic Alopecia", bold=True),
         ec("Paradoxical: same DHT causes miniaturisation on scalp follicles. Terminal scalp hair → vellus hair over successive cycles. Primarily autosomal dominant genetic predisposition; exacerbated by androgen excess")],
        [ec("Acanthosis nigricans", bold=True),
         ec("NOT direct androgen effect. Marker of insulin resistance (PCOS/HAIR-AN). Insulin + IGF-1 stimulate keratinocyte and fibroblast proliferation → velvety hyperpigmented plaques")],
        [ec("Idiopathic hirsutism", bold=True),
         ec("Normal circulating androgens + regular cycles. Caused by increased LOCAL 5α-reductase activity in hair follicle → increased end-organ sensitivity. More common in Mediterranean/South Asian/Middle Eastern populations")],
    ]
    mech_colw = [col_w*0.22, col_w*0.78]
    mech_table = Table(mech_data, colWidths=mech_colw, repeatRows=1)
    mech_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TEAL),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#E0F2F1"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
    ]))
    story.append(mech_table)
    story.append(Spacer(1, 8))

    # ── CLINICAL FEATURES ────────────────────────────────────────────────────
    story.append(section_header("4. CLINICAL FEATURES", s['section'], ORANGE))
    story.append(Spacer(1, 5))

    # 1. Hirsutism
    story.append(Paragraph("A. Hirsutism", s['subsection']))
    story.append(Paragraph(
        "<b>Definition:</b> Excessive hair growth in women in a <b>male-pattern (androgenic) distribution</b>. "
        "Distinct from hypertrichosis (generalised, androgen-independent).",
        s['body']))

    hir_items = [
        "<b>Distribution:</b> Upper lip > Thighs > Lower abdomen > Upper back; also chin, cheeks, chest, suprapubic, perianal, intergluteal",
        "<b>Abrupt/rapid onset</b> → suspect malignancy (androgen-secreting tumour)",
        "Severity of hirsutism does not always correlate with degree of androgen excess",
        "<b>Ethnicity:</b> Mediterranean > South Asian > Middle Eastern > Asian (lowest prevalence)",
    ]
    for item in hir_items:
        story.append(Paragraph(f"• {item}", s['bullet']))
    story.append(Spacer(1, 4))

    # mFG scoring
    mfg_box = [
        Paragraph("<b>Modified Ferriman-Gallwey (mFG) Score</b>", s['subsubsection']),
        Paragraph("Scores 9 body areas (upper lip, chin/cheeks, chest, upper abdomen, lower abdomen, upper back, lower back, arms, legs)", s['body']),
        Paragraph("Score 0–4 per area (0 = no hair; 4 = extensive growth)  |  Maximum score: 36", s['body']),
    ]
    mfg_score_data = [
        [Paragraph("SCORE", s['tbl_hdr']), Paragraph("INTERPRETATION", s['tbl_hdr'])],
        [ec("≤ 8"), ec("Normal")],
        [ec("8 – 14"), ec("Mild hirsutism")],
        [ec("≥ 15", bold=True), ec("Moderate to Severe hirsutism", bold=True)],
    ]
    mfg_table = Table(mfg_score_data, colWidths=[col_w*0.25, col_w*0.75])
    mfg_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_PURP),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#F3E5F5"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('ALIGN', (0,0), (-1,-1), 'CENTER'),
        ('BACKGROUND', (0,3), (-1,3), colors.HexColor("#EF9A9A")),
    ]))
    story.append(coloured_box(mfg_box + [mfg_table], BOX_PURPLE, PURPLE))
    story.append(Spacer(1, 5))

    story.append(Paragraph("B. Acne (Hormonal)", s['subsection']))
    acne_box = [
        Paragraph("<b>Features suggesting hormonal/hyperandrogenic acne:</b>", s['body']),
        Paragraph("• Sudden onset or severe acne refractory to conventional treatment", s['bullet']),
        Paragraph("• Predominantly lower face / jawline / neck distribution", s['bullet']),
        Paragraph("• Premenstrual flares", s['bullet']),
        Paragraph("• Irregular menstrual periods", s['bullet']),
        Paragraph("• Associated hirsutism, seborrhoea, or alopecia", s['bullet']),
        Paragraph("• Acne onset ages 1–7 with virilisation → refer to paediatric endocrinologist", s['bullet']),
        Paragraph("• Comedonal acne ages 9–12 without other features → normal puberty, no workup needed", s['bullet']),
    ]
    story.append(coloured_box(acne_box, BOX_ORANGE, ORANGE))
    story.append(Spacer(1, 4))

    story.append(Paragraph("C. Seborrhoea", s['subsection']))
    story.append(Paragraph(
        "Oily, shiny skin on face and scalp. Scaling and erythema (seborrhoeic dermatitis). "
        "Present in <b>100% of SAHA syndrome</b> cases.",
        s['body']))
    story.append(Spacer(1, 4))

    story.append(Paragraph("D. Androgenetic Alopecia (AGA)", s['subsection']))
    aga_data = [
        [Paragraph("PATTERN", s['tbl_hdr']), Paragraph("MALES", s['tbl_hdr']), Paragraph("FEMALES", s['tbl_hdr'])],
        [ec("Hair loss pattern", bold=True), ec("Bitemporal recession + vertex loss (Hamilton-Norwood pattern)"), ec("Diffuse crown thinning; frontal hairline PRESERVED (Ludwig pattern)")],
        [ec("Mechanism", bold=True), ec("DHT-driven miniaturisation of scalp follicles"), ec("Same mechanism; genetic predisposition + androgen excess")],
        [ec("Genetics", bold=True), ec("Autosomal dominant (variable penetrance)"), ec("More commonly acquired in androgen excess states")],
    ]
    aga_table = Table(aga_data, colWidths=[col_w*0.18, col_w*0.41, col_w*0.41], repeatRows=1)
    aga_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), GREEN_DARK),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#E8F5E9"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
    ]))
    story.append(aga_table)
    story.append(Spacer(1, 5))

    story.append(Paragraph("E. Signs of Virilisation (Severe Hyperandrogenism)", s['subsection']))
    vir_box = [
        Paragraph("⚠ Signs indicating severe hyperandrogenism — investigate urgently for androgen-secreting tumour:", s['redbox']),
        Paragraph("• Clitoromegaly  •  Male-pattern frontal balding in women  •  Deepening of voice", s['bullet']),
        Paragraph("• Decreased breast size / breast tissue atrophy  •  Increased muscle mass", s['bullet']),
        Paragraph("• Galactorrhoea (if associated hyperprolactinaemia)", s['bullet']),
    ]
    story.append(coloured_box(vir_box, BOX_RED, RED_DARK))
    story.append(Spacer(1, 5))

    story.append(Paragraph("F. PCOS-Specific Cutaneous Findings", s['subsection']))
    story.append(Paragraph("• Severe truncal hirsutism  •  Axillary acanthosis nigricans  •  Skin tags  •  Seborrhoea  •  Hormonal acne", s['bullet']))
    story.append(Paragraph("Associated systemic features: Obesity, oligomenorrhoea/amenorrhoea, infertility, insulin resistance, dyslipidaemia, sleep apnoea, risk of endometrial cancer", s['body']))
    story.append(Spacer(1, 8))

    # ── APPROACH TO DIAGNOSIS ─────────────────────────────────────────────────
    story.append(section_header("5. APPROACH TO DIAGNOSIS", s['section'], PURPLE))
    story.append(Spacer(1, 5))

    story.append(Paragraph("A. History", s['subsection']))
    hist_items = [
        "Age of onset + rate of progression — <b>slow/gradual</b> → functional cause; <b>rapid/abrupt</b> → tumour",
        "Menstrual history: oligomenorrhoea, amenorrhoea, intermenstrual bleeding",
        "Family history of hirsutism, PCOS, or CAH",
        "Medications: anabolic steroids, danazol, valproate, norgestrel, minoxidil, CsA",
        "Obstetric/reproductive history; desire for fertility",
        "Symptoms of Cushing: central weight gain, easy bruising, purple striae, proximal myopathy",
        "Symptoms of hypothyroidism: cold intolerance, constipation, dry skin, weight gain",
        "Galactorrhoea (suggests hyperprolactinaemia)",
    ]
    for item in hist_items:
        story.append(Paragraph(f"• {item}", s['bullet']))
    story.append(Spacer(1, 4))

    story.append(Paragraph("B. Physical Examination", s['subsection']))
    exam_items = [
        "mFG scoring for hirsutism (score 9 body areas; score ≥8 = hirsute)",
        "Signs of virilisation: clitoromegaly, frontal balding, voice change, muscle bulk",
        "Signs of insulin resistance: acanthosis nigricans (axillae, neck, groin), skin tags, central obesity",
        "Signs of Cushing: purple striae, moon facies, buffalo hump, easy bruising",
        "Thyroid palpation — goitre, nodule",
        "Galactorrhoea on breast examination",
        "Pelvic examination — ovarian enlargement (tumour)",
        "Blood pressure (adrenal tumour / Cushing)",
    ]
    for item in exam_items:
        story.append(Paragraph(f"• {item}", s['bullet']))
    story.append(Spacer(1, 5))

    story.append(Paragraph("C. Investigations", s['subsection']))

    # First-line investigations
    inv1_headers = [Paragraph("TEST", s['tbl_hdr']), Paragraph("PURPOSE / INTERPRETATION", s['tbl_hdr'])]
    inv1_data = [
        inv1_headers,
        [ec("Free testosterone ★\n(most sensitive)", bold=True),
         ec("Best screening marker. Elevated in PCOS, ovarian hyperandrogenism, adrenal disorders")],
        [ec("Total testosterone"), ec("T >200 ng/dL → suspect androgen-secreting tumour → urgent imaging")],
        [ec("DHEA-S"), ec("Screens for adrenal androgen source. Elevated in adrenal tumour and CAH. 2-3× upper limit → CT adrenal")],
        [ec("LH : FSH ratio"), ec("Ratio >2-3 → consistent with PCOS")],
        [ec("Prolactin"), ec("Elevated → hyperprolactinaemia; look for prolactinoma")],
        [ec("TSH"), ec("Rules out hypothyroidism as cause of reduced SHBG")],
        [ec("17-OHP (early morning)"), ec("Elevated in 21-hydroxylase deficiency NCAH; >10 ng/mL post-ACTH stimulation → diagnostic")],
        [ec("Fasting glucose / OGTT"), ec("Insulin resistance assessment; impaired GTT → HAIR-AN or PCOS metabolic syndrome")],
        [ec("Lipid profile"), ec("Dyslipidaemia common in PCOS / metabolic syndrome")],
    ]
    note_txt = "<i>★ Lab evaluation most accurate when patient is off OCPs for 4–6 weeks and tests drawn before menses</i>"

    inv1_colw = [col_w*0.27, col_w*0.73]
    inv1_table = Table(inv1_data, colWidths=inv1_colw, repeatRows=1)
    inv1_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_PURP),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#F3E5F5"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        ('BACKGROUND', (0,2), (-1,2), colors.HexColor("#EF9A9A")),
    ]))
    story.append(Paragraph("First-Line Investigations:", s['subsubsection']))
    story.append(inv1_table)
    story.append(Paragraph(note_txt, s['caption']))
    story.append(Spacer(1, 4))

    # Second-line
    story.append(Paragraph("Second-Line / Confirmatory Investigations:", s['subsubsection']))
    inv2_data = [
        [Paragraph("TEST", s['tbl_hdr']), Paragraph("INDICATION", s['tbl_hdr'])],
        [ec("ACTH stimulation test"), ec("Confirm NCAH: 17-OHP >10 ng/mL post-ACTH → 21-hydroxylase deficiency")],
        [ec("Dexamethasone suppression test (DST)"), ec("Distinguish adrenal vs ovarian vs Cushing origin. Suppressible → adrenal; non-suppressible → Cushing / neoplasm / PCOS")],
        [ec("24-h urine cortisol / late-night salivary cortisol"), ec("Rule out Cushing syndrome")],
        [ec("Pelvic ultrasound (USG)"), ec("PCOS (polycystic ovaries); ovarian tumour; Rotterdam criteria imaging")],
        [ec("CT abdomen / adrenals"), ec("Adrenal mass if DHEA-S 2–3× upper limit; adrenal tumour suspected")],
        [ec("MRI pituitary"), ec("Prolactinoma; Cushing's disease (pituitary source)"),],
        [ec("β-hCG"), ec("Rule out pregnancy if amenorrhoeic")],
        [ec("IGF-1 + GH"), ec("Suspected acromegaly")],
        [ec("CYP21 genotyping"), ec("Confirm diagnosis of NCAH (21-hydroxylase deficiency)")],
    ]
    inv2_table = Table(inv2_data, colWidths=inv1_colw, repeatRows=1)
    inv2_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), PURPLE),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#EDE7F6"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
    ]))
    story.append(inv2_table)
    story.append(Spacer(1, 4))

    # Red flag values box
    rf_box = [
        Paragraph("🔴 RED FLAG INVESTIGATION VALUES", ParagraphStyle('rfh', fontName='Helvetica-Bold', fontSize=10, textColor=RED_DARK)),
        Paragraph("• Testosterone <b>>200 ng/dL</b> → Suspect adrenal or ovarian androgen-secreting tumour → urgent CT/MRI", s['bullet']),
        Paragraph("• DHEA-S <b>2–3× upper limit</b> → Adrenal mass → CT adrenal", s['bullet']),
        Paragraph("• 17-OHP <b>>10 ng/mL</b> post-ACTH stimulation → Non-classic CAH (21-OH deficiency)", s['bullet']),
    ]
    story.append(coloured_box(rf_box, BOX_RED, RED_DARK))
    story.append(Spacer(1, 5))

    # Diagnostic algorithm description
    story.append(Paragraph("D. Diagnostic Algorithm (Approach to Hirsutism)", s['subsection']))
    algo_box = [
        Paragraph("Step 1 — <b>Regular menstrual cycle?</b>", s['body']),
        Paragraph("YES → <b>Normal T</b>: Idiopathic hirsutism  |  <b>Elevated T</b>: Idiopathic hyperandrogenism", s['bullet']),
        Paragraph("NO → Is onset sudden ± virilisation?", s['bullet']),
        Paragraph("     YES → Consider malignancy (imaging for adrenal/pelvic mass); T >200 ng/dL", s['bullet2']),
        Paragraph("     NO → Exclude secondary causes:", s['bullet2']),
        Paragraph("           PCOS · NCAH · Cushing syndrome · Hypothyroidism · Acromegaly ·", s['bullet2']),
        Paragraph("           Hyperprolactinaemia · SAHA syndrome · HAIR-AN · Pregnancy · Medications", s['bullet2']),
        Spacer(1, 3),
        Paragraph("Step 2 — <b>Confirm androgen excess</b> (free testosterone; DHEA-S)", s['body']),
        Paragraph("Step 3 — <b>Localise source</b> (dexamethasone suppression test; ACTH stimulation; imaging)", s['body']),
        Paragraph("Step 4 — <b>Treatment based on aetiology</b> + symptomatic management", s['body']),
    ]
    story.append(coloured_box(algo_box, BOX_YELLOW, AMBER))
    story.append(Spacer(1, 8))

    # ── MANAGEMENT ───────────────────────────────────────────────────────────
    story.append(section_header("6. MANAGEMENT", s['section'], GREEN_DARK))
    story.append(Spacer(1, 5))

    story.append(Paragraph("A. General Principles", s['subsection']))
    story.append(Paragraph(
        "Management is directed at: (1) treating the <b>underlying cause</b>, and (2) managing individual "
        "<b>cutaneous manifestations</b>. Involves pharmacological (hormonal, antiandrogen) and non-pharmacological approaches.",
        s['body']))
    story.append(Spacer(1, 4))

    # Antiandrogen drugs master table
    story.append(Paragraph("B. Antiandrogen and Hormonal Pharmacotherapy", s['subsection']))

    drug_headers = [
        Paragraph("DRUG", s['tbl_hdr']),
        Paragraph("MECHANISM", s['tbl_hdr']),
        Paragraph("DOSE / USES", s['tbl_hdr']),
        Paragraph("KEY SIDE EFFECTS", s['tbl_hdr']),
        Paragraph("CONTRA-\nINDICATION", s['tbl_hdr']),
    ]

    drugs = [
        ["Spironolactone\n★ First-line",
         "AR antagonist + 5α-RI + ↓ androgen synthesis",
         "50–200 mg/day\nHirsutism, acne, AGA, seborrhoea",
         "Hyperkalaemia, menstrual irregularity, breast tenderness, polyuria",
         "Pregnancy; renal failure; hyperkalaemia"],
        ["Oral Contra-\nceptive Pills (OCP)",
         "↑ SHBG, ↓ LH → ↓ ovarian androgen; antiandrogenic progestins",
         "Drospirenone- or CPA-containing preferred\nHirsutism, acne, AGA in women",
         "Thromboembolism, hypertension, nausea, mood changes",
         "Thrombophilia; age >35 + smoking; migraine with aura"],
        ["Cyproterone\nAcetate (CPA)",
         "AR antagonist + progestin",
         "2 mg (in Diane-35) or 50–100 mg\nAcne, hirsutism, AGA",
         "Hepatotoxicity (high dose), depression, decreased libido",
         "Pregnancy; liver disease; meningioma"],
        ["Finasteride",
         "5α-RI (Type 1+2)\nBlocks T → DHT",
         "1 mg/day (AGA men)\n5 mg/day (hirsutism)\nPost-menopausal AGA (limited evidence)",
         "↓ Libido, erectile dysfunction, depression, gynecomastia. Post-finasteride syndrome (persists after stopping)",
         "PREGNANCY (feminises male fetus); women of childbearing age"],
        ["Dutasteride",
         "Dual 5α-RI (Type 1 + Type 2)\nMore potent than finasteride",
         "0.5 mg/day\nAGA in men; hirsutism",
         "Same as finasteride",
         "Pregnancy"],
        ["Flutamide\n⚠ AVOID",
         "Pure AR antagonist",
         "Rarely used\nHirsutism",
         "★ FATAL HEPATOTOXICITY\nRisk to male fetus",
         "Pregnancy; liver disease"],
        ["Bicalutamide",
         "Non-steroidal pure AR antagonist",
         "25 mg/day\nPCOS/idiopathic hirsutism",
         "Hepatotoxicity at ≥50 mg/day",
         "Pregnancy"],
        ["Metformin",
         "Insulin sensitiser\nIndirectly ↓ androgen production",
         "500–1500 mg/day\nPCOS with insulin resistance",
         "GI side effects, lactic acidosis (rare)",
         "Renal failure; contrast procedures"],
        ["Clascoterone\n(Winlevi 1%)",
         "Topical AR antagonist",
         "Topical cream BD\nAcne (FDA-approved)",
         "Local skin irritation",
         "—"],
        ["Eflornithine\n(Vaniqa 13.9%)",
         "Topical ornithine decarboxylase inhibitor\n→ slows hair growth",
         "Apply BD to face\nFacial hirsutism (adjunct; not permanent)",
         "Local irritation, burning, stinging",
         "—"],
        ["Glucocorticoids\n(prednisolone /\ndexamethasone)",
         "↓ ACTH → ↓ adrenal androgen production",
         "Prednisolone 5–7.5 mg/day or\nDexamethasone 0.25–0.5 mg at night\nCAH / adrenal hyperandrogenism",
         "Cushing side effects (long-term), osteoporosis, immunosuppression",
         "Active infections; use minimum effective dose"],
    ]

    drug_col_w = [col_w*0.14, col_w*0.19, col_w*0.22, col_w*0.25, col_w*0.20]
    drug_table_data = [drug_headers]
    for d in drugs:
        drug_table_data.append([Paragraph(txt, s['tbl_cell_bold'] if i == 0 else s['tbl_cell'])
                                 for i, txt in enumerate(d)])

    drug_table = Table(drug_table_data, colWidths=drug_col_w, repeatRows=1)
    row_bg = [colors.HexColor("#E8F5E9"), colors.white]
    drug_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_GREEN),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('FONTSIZE', (0,0), (-1,0), 8),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), row_bg),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 4),
        ('RIGHTPADDING', (0,0), (-1,-1), 4),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        # Highlight flutamide row (row 6) in red
        ('BACKGROUND', (0,6), (-1,6), colors.HexColor("#FFCDD2")),
        # Highlight spironolactone (row 1) lightly
        ('BACKGROUND', (0,1), (-1,1), colors.HexColor("#C8E6C9")),
    ]))
    story.append(drug_table)
    story.append(Spacer(1, 8))

    # Management of specific manifestations
    story.append(Paragraph("C. Management of Specific Cutaneous Manifestations", s['subsection']))
    story.append(Spacer(1, 3))

    # Hirsutism management
    story.append(Paragraph("1. Hirsutism", s['subsubsection']))

    hirs_mgmt = [
        Paragraph("<b>Physical / Cosmetic Methods (temporary):</b>", s['body']),
        Paragraph("• Shaving, threading, waxing, depilatory creams (fast; not permanent)", s['bullet']),
        Paragraph("<b>Eflornithine 13.9% cream:</b> Topical ornithine decarboxylase inhibitor; applied twice daily on face; slows growth (not permanent); improvement in 6–8 weeks", s['bullet']),
        Spacer(1, 3),
        Paragraph("<b>Laser Hair Removal:</b>", s['body']),
        Paragraph("• Mechanism: Selective photothermolysis — targets melanin in pigmented hair follicles", s['bullet']),
        Paragraph("• Devices: 755-nm Alexandrite | 800-nm Diode | 1064-nm Nd:YAG (preferred for dark skin) | Intense Pulsed Light (IPL)", s['bullet']),
        Paragraph("• Requires 3–6 treatment cycles; not effective for light/white/grey hair", s['bullet']),
        Paragraph("• Adverse effects: Post-inflammatory hyperpigmentation (PIH), folliculitis, HSV reactivation, paradoxical hypertrichosis (rare)", s['bullet']),
        Spacer(1, 3),
        Paragraph("<b>Electrolysis:</b>", s['body']),
        Paragraph("• Only truly permanent hair removal method", s['bullet']),
        Paragraph("• Types: Galvanic (chemical), thermolysis (heat), blend", s['bullet']),
        Paragraph("• Disadvantages: Time-consuming, painful, risk of scarring and follicular hyperpigmentation; regrowth ~40%", s['bullet']),
        Spacer(1, 3),
        Paragraph("<b>Systemic Therapy:</b>", s['body']),
        Paragraph("• Spironolactone 100–200 mg/day (first-line for idiopathic hirsutism / PCOS)", s['bullet']),
        Paragraph("• OCP with drospirenone or CPA", s['bullet']),
        Paragraph("• Finasteride / Dutasteride", s['bullet']),
        Paragraph("• Metformin (PCOS with insulin resistance)", s['bullet']),
    ]
    story.append(coloured_box(hirs_mgmt, BOX_GREEN, GREEN_DARK))
    story.append(Spacer(1, 4))

    story.append(Paragraph("2. Hormonal Acne", s['subsubsection']))
    acne_mgmt = [
        Paragraph("• OCP (drospirenone- or CPA-containing preferred)", s['bullet']),
        Paragraph("• Spironolactone 50–150 mg/day", s['bullet']),
        Paragraph("• Cyproterone acetate-containing OCP (Diane-35)", s['bullet']),
        Paragraph("• Clascoterone 1% cream (topical AR antagonist — FDA approved)", s['bullet']),
        Paragraph("• Plus standard topical therapy: Retinoids + Benzoyl peroxide ± Topical antibiotics", s['bullet']),
        Paragraph("• Oral isotretinoin for severe nodulo-cystic disease", s['bullet']),
    ]
    story.append(coloured_box(acne_mgmt, BOX_ORANGE, ORANGE))
    story.append(Spacer(1, 4))

    story.append(Paragraph("3. Androgenetic Alopecia (AGA)", s['subsubsection']))
    aga_mgmt_data = [
        [Paragraph("WOMEN", s['tbl_hdr']), Paragraph("MEN", s['tbl_hdr'])],
        [ec("Topical minoxidil 2–5% (first-line)"), ec("Topical minoxidil 5% (first-line)")],
        [ec("Spironolactone (systemic or topical)"), ec("Finasteride 1 mg/day")],
        [ec("OCP with antiandrogenic progestin"), ec("Dutasteride 0.5 mg/day")],
        [ec("Finasteride (post-menopausal; limited evidence)"), ec("Hair transplantation (FUE/FUT)")],
        [ec("Low-level laser therapy (LLLT)"), ec("Low-level laser therapy (LLLT)")],
        [ec("Platelet-rich plasma (PRP) injections"), ec("Platelet-rich plasma (PRP) injections")],
    ]
    aga_mgmt_table = Table(aga_mgmt_data, colWidths=[col_w*0.5, col_w*0.5], repeatRows=1)
    aga_mgmt_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), GREEN_DARK),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#E8F5E9"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
    ]))
    story.append(aga_mgmt_table)
    story.append(Spacer(1, 5))

    # Disease-specific management
    story.append(Paragraph("D. Management by Underlying Aetiology", s['subsection']))

    disease_data = [
        [Paragraph("CONDITION", s['tbl_hdr']), Paragraph("SPECIFIC MANAGEMENT", s['tbl_hdr'])],
        [ec("PCOS", bold=True),
         ec("1. Lifestyle modification + weight loss (5–10% wt loss restores cycles)\n"
            "2. Metformin (insulin resistance, menstrual regulation)\n"
            "3. OCP (cycle regulation, cutaneous hyperandrogenism)\n"
            "4. Spironolactone (cutaneous features)\n"
            "5. Clomiphene citrate (if fertility desired)\n"
            "6. Bariatric surgery (severe obesity)")],
        [ec("Non-Classic CAH\n(21-OH deficiency)", bold=True),
         ec("1. Low-dose glucocorticoids: Dexamethasone 0.25–0.5 mg/night or prednisolone 5–7.5 mg/day (suppress ACTH)\n"
            "2. OCP + antiandrogen therapy as alternative or adjunct\n"
            "3. Antenatal dexamethasone (homozygous female fetuses → prevent virilisation)\n"
            "4. CYP21 genotyping to confirm; genetic counselling")],
        [ec("Adrenal / Ovarian\nTumour", bold=True),
         ec("Surgical resection (curative).\nSertoli-Leydig, granulosa-theca, hilus cell tumours: low metastatic potential; surgery adequate")],
        [ec("Cushing Syndrome", bold=True),
         ec("Treat primary cause:\n• Pituitary adenoma → Transsphenoidal surgery\n• Adrenal adenoma → Adrenalectomy\n• Ectopic ACTH → Resect primary + ketoconazole/metyrapone")],
        [ec("Hyperprolactinaemia", bold=True),
         ec("Dopamine agonists: Cabergoline (first-line) or Bromocriptine\nIf prolactinoma: cabergoline often shrinks tumour; surgery if resistant")],
        [ec("Hypothyroidism", bold=True),
         ec("Thyroxine replacement → SHBG normalises → free androgen levels fall")],
        [ec("Acromegaly", bold=True),
         ec("Transsphenoidal surgery + Somatostatin analogues (octreotide, lanreotide) + Pegvisomant (GH antagonist)")],
        [ec("Drug-induced", bold=True),
         ec("Withdraw causative agent if possible")],
        [ec("Idiopathic Hirsutism", bold=True),
         ec("Spironolactone (first-line) or OCP. Laser hair removal / electrolysis. Eflornithine cream.")],
    ]
    disease_colw = [col_w*0.21, col_w*0.79]
    disease_table = Table(disease_data, colWidths=disease_colw, repeatRows=1)
    disease_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), TBL_HDR_NAVY),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#E8EAF6"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 5),
        ('BOTTOMPADDING', (0,0), (-1,-1), 5),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        ('BACKGROUND', (0,1), (-1,1), colors.HexColor("#DCEDC8")),
        ('BACKGROUND', (0,2), (-1,2), colors.HexColor("#E8EAF6")),
        ('BACKGROUND', (0,3), (-1,3), colors.HexColor("#FFEBEE")),
    ]))
    story.append(disease_table)
    story.append(Spacer(1, 8))

    # ── KEY EXAM POINTS ───────────────────────────────────────────────────────
    story.append(section_header("7. HIGH-YIELD EXAM POINTS", s['section'], AMBER))
    story.append(Spacer(1, 5))

    exam_points = [
        ("<b>SAHA syndrome</b> = Seborrhoea + Acne + Hirsutism + Androgenetic Alopecia; 4 subtypes (idiopathic, ovarian, adrenal, hyperprolactinaemic); 17.7% of PCOS patients"),
        ("<b>HAIR-AN syndrome</b> = Hyperandrogenism + Insulin Resistance + Acanthosis Nigricans"),
        ("<b>mFG score</b>: ≤8 normal | 8–14 mild hirsutism | ≥15 moderate-severe hirsutism"),
        ("<b>DHT</b> is the most potent intracellular androgen; produced by 5α-reductase from testosterone"),
        ("<b>SHBG reduction</b> (obesity, insulin resistance, progestins) → ↑ free androgens → cutaneous features"),
        ("<b>Free testosterone</b> is the most sensitive biochemical marker of hyperandrogenism"),
        ("<b>Testosterone >200 ng/dL</b> → suspect androgen-secreting tumour → urgent CT/MRI"),
        ("<b>17-OHP >10 ng/mL</b> post-ACTH stimulation → NCAH (21-hydroxylase deficiency, CYP21A2 mutation)"),
        ("<b>Idiopathic hirsutism</b> = normal androgens + regular cycles + increased local 5α-reductase activity"),
        ("<b>Abrupt rapid onset of hirsutism</b> = red flag for malignancy"),
        ("<b>Finasteride</b> is CONTRAINDICATED in women of childbearing age (feminisation of male fetus)"),
        ("<b>Flutamide</b> — avoid due to fatal hepatotoxicity"),
        ("<b>Bicalutamide</b> — hepatotoxicity at ≥50 mg/day; safe at 25 mg/day"),
        ("<b>Laser hair removal</b>: works via selective photothermolysis; Nd:YAG 1064 nm preferred for dark skin; NOT effective for light/white/grey hair"),
        ("<b>Eflornithine</b> — topical ornithine decarboxylase inhibitor; slows facial hair growth; not permanent"),
        ("<b>Electrolysis</b> — only truly PERMANENT hair removal; regrowth rate ~40%"),
        ("<b>PCOS treatment</b>: weight loss first-line (obese); metformin; OCP; spironolactone; clomiphene if fertility desired"),
        ("<b>NCAH treatment</b>: low-dose glucocorticoids (dexamethasone 0.25–0.5 mg/night) to suppress ACTH"),
        ("<b>Spironolactone</b> — first-line antiandrogen in dermatology; monitor potassium; contraindicated in pregnancy"),
        ("<b>Acanthosis nigricans</b> in hyperandrogenism = marker of insulin resistance, NOT a direct androgen effect"),
    ]

    exam_box_rows = [Paragraph("★ KEY POINTS FOR EXAM", ParagraphStyle('kph', fontName='Helvetica-Bold', fontSize=11, textColor=AMBER))]
    for i, pt in enumerate(exam_points, 1):
        exam_box_rows.append(Paragraph(f"<b>{i}.</b> {pt}", s['exam_point']))
    story.append(coloured_box(exam_box_rows, BOX_YELLOW, AMBER))
    story.append(Spacer(1, 8))

    # ── QUICK REFERENCE TABLE ─────────────────────────────────────────────────
    story.append(section_header("8. QUICK REFERENCE: ANTIANDROGENS IN DERMATOLOGY", s['section'], DARK_NAVY))
    story.append(Spacer(1, 5))

    qr_headers = [
        Paragraph("DRUG", s['tbl_hdr']),
        Paragraph("MECHANISM", s['tbl_hdr']),
        Paragraph("MAIN USES", s['tbl_hdr']),
        Paragraph("KEY CAUTION", s['tbl_hdr']),
    ]
    qr_drugs = [
        ["Spironolactone", "AR antagonist + 5α-RI + ↓ synthesis", "Hirsutism, acne, AGA ♀", "Hyperkalaemia; CONTRAINDICATED in pregnancy"],
        ["Cyproterone acetate", "AR antagonist + progestin", "Hirsutism, acne, AGA ♀", "Hepatotoxicity (high dose)"],
        ["Finasteride", "5α-RI (Type 1+2)", "AGA ♂; hirsutism", "TERATOGENIC — contraindicated in pregnancy"],
        ["Dutasteride", "5α-RI dual (Type 1+2)", "AGA ♂; hirsutism", "Same as finasteride"],
        ["Flutamide ⚠", "AR antagonist", "Hirsutism (rarely)", "FATAL HEPATOTOXICITY — rarely used"],
        ["Bicalutamide", "Non-steroidal AR antagonist", "Hirsutism (PCOS/idiopathic)", "Hepatotoxicity ≥50 mg/day"],
        ["OCP", "↑ SHBG; ↓ LH; antiandrogenic progestins", "Hirsutism, acne, AGA ♀", "Thromboembolism; smoking + age >35"],
        ["Metformin", "Insulin sensitiser (indirect)", "PCOS", "Renal failure; GI side effects"],
        ["Clascoterone 1%", "Topical AR antagonist", "Acne (FDA approved)", "Local irritation"],
        ["Eflornithine 13.9%", "Topical ODC inhibitor", "Facial hirsutism (slows growth)", "Local irritation; not permanent"],
    ]
    qr_data = [qr_headers]
    for d in qr_drugs:
        qr_data.append([Paragraph(d[0], s['tbl_cell_bold'])] + [Paragraph(x, s['tbl_cell']) for x in d[1:]])

    qr_colw = [col_w*0.17, col_w*0.22, col_w*0.22, col_w*0.39]
    qr_table = Table(qr_data, colWidths=qr_colw, repeatRows=1)
    qr_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), DARK_NAVY),
        ('TEXTCOLOR', (0,0), (-1,0), colors.white),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0,1), (-1,-1), [colors.HexColor("#EEF2FF"), colors.white]),
        ('GRID', (0,0), (-1,-1), 0.4, colors.HexColor("#BDBDBD")),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'TOP'),
        ('BACKGROUND', (0,5), (-1,5), colors.HexColor("#FFCDD2")),  # flutamide
    ]))
    story.append(qr_table)
    story.append(Spacer(1, 6))

    # Footer note
    story.append(HRFlowable(width=col_w, thickness=1, color=ROYAL_BLUE))
    story.append(Spacer(1, 3))
    story.append(Paragraph(
        "<b>References:</b> Fitzpatrick's Dermatology 9th Ed (Vol. 1–2) | Andrews' Diseases of the Skin, Clinical Dermatology 13th Ed | "
        "Dermatology 2-Volume Set 5th Ed | Harrison's Principles of Internal Medicine 22nd Ed (2025)",
        ParagraphStyle('ref', fontName='Helvetica-Oblique', fontSize=8, textColor=colors.HexColor("#616161"),
                       alignment=TA_CENTER, leading=11)))

    # Build
    doc.build(story, onFirstPage=add_page_decorations, onLaterPages=add_page_decorations)
    print(f"PDF generated: {output_path}")


if __name__ == "__main__":
    build_pdf("/tmp/workspace/cutaneous-hyperandrogenism/Cutaneous_Hyperandrogenism_MD_Derm_Notes.pdf")

Running Command

cd /tmp/workspace/cutaneous-hyperandrogenism && python generate_pdf.py 2>&1

Running Command

ls -lh /tmp/workspace/cutaneous-hyperandrogenism/

Your colourful PDF is ready for download:

Cutaneous Hyperandrogenism MD Derm Notes

PDF Document · PDF

What's inside the PDF (38 KB, A4, fully formatted):

Section	Content
Title Page	Dark navy banner with full title and source citations
1. Definition	SAHA syndrome and HAIR-AN syndrome in coloured highlight boxes
2. Etiology	Full colour-coded table — Ovarian / Adrenal / Pituitary / Idiopathic / Drug-induced / Pregnancy causes
3. Pathogenesis	Key hormones table, 5α-reductase and SHBG mechanism boxes, mechanisms of each cutaneous manifestation
4. Clinical Features	Hirsutism (mFG scoring table), hormonal acne, seborrhoea, AGA, virilisation red-flag box, SAHA, HAIR-AN, PCOS features
5. Approach	History, examination, first-line + second-line investigations, red-flag lab values, diagnostic algorithm flow
6. Management	Full antiandrogen pharmacotherapy table (11 drugs), hirsutism (laser/electrolysis/eflornithine/systemic), acne, AGA, disease-specific management (PCOS, NCAH, tumour, Cushing, prolactinoma)
7. High-Yield Exam Points	20 numbered exam-ready key facts in an amber highlighted box
8. Quick Reference Table	All antiandrogens at a glance — mechanism, uses, key cautions
Header + Footer	Every page has a navy header and blue footer with page number

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