"""
Anterior Pituitary Hormones - Comprehensive Study Guide PDF
Style: Indu Khurana Textbook of Medical Physiology
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.platypus.flowables import Flowable
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.graphics.shapes import Drawing, Rect, String, Line, Arrow, Polygon
from reportlab.graphics import renderPDF
from reportlab.graphics.shapes import (
    Drawing, Rect, String, Line, Polygon, Group, Path
)
from reportlab.lib.colors import (
    HexColor, white, black, lightblue, lightyellow, lightgreen, lightgrey
)
import io

# ─── COLOR PALETTE ───────────────────────────────────────────────
C_HEADER     = HexColor("#1B3A5C")   # deep navy
C_SUBHDR     = HexColor("#2E6DA4")   # medium blue
C_ACCENT     = HexColor("#E8F4FD")   # very light blue bg
C_GOLD       = HexColor("#F0A500")   # gold for highlights
C_RED        = HexColor("#C0392B")   # red for inhibitors
C_GREEN      = HexColor("#1E8449")   # green for stimulators
C_TABLE_HDR  = HexColor("#1B3A5C")
C_TABLE_ALT  = HexColor("#EBF5FB")
C_TABLE_ALT2 = HexColor("#FDFEFE")
C_BOX_BG     = HexColor("#FEF9E7")   # key statement box
C_BOX_BORDER = HexColor("#F0A500")
C_FLOW_BOX   = HexColor("#D6EAF8")
C_FLOW_ARROW = HexColor("#2E6DA4")
C_CLINICAL   = HexColor("#FDEDEC")
C_CLIN_BDR   = HexColor("#C0392B")
C_MNEM       = HexColor("#E8F8F5")
C_MNEM_BDR   = HexColor("#1E8449")
PAGE_W, PAGE_H = A4

# ─── STYLES ──────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def make_style(name, parent='Normal', **kwargs):
    return ParagraphStyle(name, parent=styles[parent], **kwargs)

ST_TITLE      = make_style('ST_TITLE', 'Title',
                    fontSize=22, textColor=C_HEADER, spaceAfter=4,
                    fontName='Helvetica-Bold', alignment=TA_CENTER)
ST_SUBTITLE   = make_style('ST_SUBTITLE', fontSize=13, textColor=C_SUBHDR,
                    spaceAfter=6, fontName='Helvetica-Bold', alignment=TA_CENTER)
ST_SECTION    = make_style('ST_SECTION', fontSize=14, textColor=white,
                    fontName='Helvetica-Bold', spaceAfter=6, spaceBefore=14,
                    backColor=C_HEADER, leftIndent=-10, rightIndent=-10,
                    borderPadding=(4, 8, 4, 8))
ST_SUBSECTION = make_style('ST_SUBSECTION', fontSize=12, textColor=C_SUBHDR,
                    fontName='Helvetica-Bold', spaceAfter=4, spaceBefore=8,
                    borderPadding=(2, 0, 2, 0))
ST_BODY       = make_style('ST_BODY', fontSize=9.5, leading=14,
                    spaceAfter=4, alignment=TA_JUSTIFY)
ST_BULLET     = make_style('ST_BULLET', fontSize=9.5, leading=13,
                    leftIndent=14, bulletIndent=4, spaceAfter=2,
                    firstLineIndent=0)
ST_KEYBOX     = make_style('ST_KEYBOX', fontSize=9.5, leading=13,
                    textColor=HexColor("#7D6608"), fontName='Helvetica-BoldOblique',
                    leftIndent=8, rightIndent=8)
ST_CLINICAL   = make_style('ST_CLINICAL', fontSize=9.5, leading=13,
                    textColor=HexColor("#7B241C"), fontName='Helvetica',
                    leftIndent=8, rightIndent=8)
ST_MNEM       = make_style('ST_MNEM', fontSize=10, leading=14,
                    textColor=HexColor("#145A32"), fontName='Helvetica-Bold',
                    leftIndent=8, rightIndent=8, alignment=TA_CENTER)
ST_TH         = make_style('ST_TH', fontSize=9, textColor=white,
                    fontName='Helvetica-Bold', alignment=TA_CENTER, leading=12)
ST_TD         = make_style('ST_TD', fontSize=8.5, leading=11,
                    fontName='Helvetica', alignment=TA_LEFT)
ST_TD_C       = make_style('ST_TD_C', fontSize=8.5, leading=11,
                    fontName='Helvetica', alignment=TA_CENTER)
ST_CAPTION    = make_style('ST_CAPTION', fontSize=8, textColor=C_SUBHDR,
                    fontName='Helvetica-Oblique', alignment=TA_CENTER,
                    spaceAfter=6)
ST_VIVA_Q     = make_style('ST_VIVA_Q', fontSize=9.5, textColor=C_HEADER,
                    fontName='Helvetica-Bold', spaceBefore=6, spaceAfter=2)
ST_VIVA_A     = make_style('ST_VIVA_A', fontSize=9.5, leading=13,
                    fontName='Helvetica', leftIndent=12, spaceAfter=4)
ST_PAGENUM    = make_style('ST_PAGENUM', fontSize=8, alignment=TA_CENTER,
                    textColor=C_SUBHDR)

# ─── HELPER FLOWABLES ─────────────────────────────────────────────

def section_heading(text):
    """Blue banner section heading."""
    data = [[Paragraph(f"  {text}", make_style('sh_inner', fontSize=13,
              textColor=white, fontName='Helvetica-Bold', leading=16))]]
    t = Table(data, colWidths=[PAGE_W - 4*cm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), C_HEADER),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING', (0,0), (-1,-1), 10),
    ]))
    return t

def subsection_heading(text):
    return Paragraph(f"<font color='#{C_SUBHDR.hexval()[2:]}' size='11'><b>{text}</b></font>", ST_BODY)

def key_statement(text):
    data = [[Paragraph(f"📌 <b>Key Statement:</b> {text}", ST_KEYBOX)]]
    t = Table(data, colWidths=[PAGE_W - 4*cm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), C_BOX_BG),
        ('BOX', (0,0), (-1,-1), 1.5, C_BOX_BORDER),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING', (0,0), (-1,-1), 10),
        ('RIGHTPADDING', (0,0), (-1,-1), 10),
    ]))
    return t

def clinical_box(lines):
    content = "<b>🏥 Applied / Clinical (Khurana):</b><br/>" + "<br/>".join(f"• {l}" for l in lines)
    data = [[Paragraph(content, ST_CLINICAL)]]
    t = Table(data, colWidths=[PAGE_W - 4*cm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), C_CLINICAL),
        ('BOX', (0,0), (-1,-1), 1.5, C_CLIN_BDR),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING', (0,0), (-1,-1), 10),
        ('RIGHTPADDING', (0,0), (-1,-1), 10),
    ]))
    return t

def mnemonic_box(text):
    data = [[Paragraph(text, ST_MNEM)]]
    t = Table(data, colWidths=[PAGE_W - 4*cm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), C_MNEM),
        ('BOX', (0,0), (-1,-1), 1.5, C_MNEM_BDR),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
    ]))
    return t

def make_table(headers, rows, col_widths=None):
    """Build a styled table with header row."""
    header_cells = [Paragraph(h, ST_TH) for h in headers]
    data = [header_cells]
    for i, row in enumerate(rows):
        cells = [Paragraph(str(c), ST_TD) for c in row]
        data.append(cells)
    if col_widths is None:
        n = len(headers)
        col_widths = [(PAGE_W - 4*cm) / n] * n
    t = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ('BACKGROUND', (0,0), (-1,0), C_TABLE_HDR),
        ('TEXTCOLOR', (0,0), (-1,0), white),
        ('ALIGN', (0,0), (-1,-1), 'LEFT'),
        ('VALIGN', (0,0), (-1,-1), 'MIDDLE'),
        ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
        ('FONTSIZE', (0,0), (-1,-1), 8.5),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('GRID', (0,0), (-1,-1), 0.5, colors.grey),
    ]
    for i in range(1, len(data)):
        bg = C_TABLE_ALT if i % 2 == 0 else C_TABLE_ALT2
        style.append(('BACKGROUND', (0,i), (-1,i), bg))
    t.setStyle(TableStyle(style))
    return t

def hr():
    return HRFlowable(width="100%", thickness=0.5, color=C_SUBHDR, spaceAfter=4, spaceBefore=4)

def sp(h=6):
    return Spacer(1, h)

# ─── FLOWCHART DRAWING HELPERS ─────────────────────────────────────

def flow_box(d, x, y, w, h, text, bg=C_FLOW_BOX, text_color=C_HEADER, font_size=8):
    """Draw a rounded rectangle with text centered."""
    d.add(Rect(x, y, w, h, rx=5, ry=5, fillColor=bg, strokeColor=C_FLOW_ARROW, strokeWidth=1))
    # Multi-line: split on \n
    lines = text.split('\n')
    line_h = font_size + 2
    total_h = len(lines) * line_h
    start_y = y + h/2 + total_h/2 - line_h
    for i, line in enumerate(lines):
        d.add(String(x + w/2, start_y - i*line_h, line,
                     textAnchor='middle', fontSize=font_size,
                     fillColor=text_color, fontName='Helvetica-Bold'))

def flow_text_box(d, x, y, w, h, text, bg=C_FLOW_BOX, text_color=C_HEADER, font_size=8, bold=False):
    fn = 'Helvetica-Bold' if bold else 'Helvetica'
    d.add(Rect(x, y, w, h, rx=4, ry=4, fillColor=bg, strokeColor=C_SUBHDR, strokeWidth=0.8))
    lines = text.split('\n')
    lh = font_size + 2
    ty = y + h/2 + (len(lines)-1)*lh/2
    for i, ln in enumerate(lines):
        d.add(String(x+w/2, ty - i*lh, ln, textAnchor='middle',
                     fontSize=font_size, fillColor=text_color, fontName=fn))

def arrow_down(d, x, y, length=25, label='', color=C_FLOW_ARROW):
    d.add(Line(x, y, x, y-length, strokeColor=color, strokeWidth=1.5))
    # arrowhead
    d.add(Polygon([x, y-length, x-4, y-length+7, x+4, y-length+7],
                  fillColor=color, strokeColor=color))
    if label:
        d.add(String(x+5, y-length/2, label, fontSize=7, fillColor=color,
                     fontName='Helvetica-Bold'))

def arrow_up(d, x, y, length=25, label='', color=C_RED):
    d.add(Line(x, y, x, y+length, strokeColor=color, strokeWidth=1.2,
               strokeDashArray=[3,2]))
    d.add(Polygon([x, y+length, x-4, y+length-7, x+4, y+length-7],
                  fillColor=color, strokeColor=color))
    if label:
        d.add(String(x+5, y+length/2, label, fontSize=7, fillColor=color,
                     fontName='Helvetica-Bold'))

def plus_label(d, x, y):
    d.add(String(x, y, '(+)', fontSize=7.5, fillColor=C_GREEN, fontName='Helvetica-Bold'))

def minus_label(d, x, y):
    d.add(String(x, y, '(−)', fontSize=7.5, fillColor=C_RED, fontName='Helvetica-Bold'))

# ─── FLOWCHART 1: MASTER HPT AXIS ─────────────────────────────────

def draw_master_axis_flowchart():
    """Master flowchart: Hypothalamus → AP hormones → Target glands."""
    W, H = 480, 400
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#F8FBFF"), strokeColor=C_SUBHDR, strokeWidth=0.5))

    # Title
    d.add(String(W/2, H-18, "Hypothalamus – Anterior Pituitary – Target Glands Axis",
                 textAnchor='middle', fontSize=9, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    # Hypothalamus box
    flow_text_box(d, 150, H-55, 180, 28, 'HYPOTHALAMUS', bg=C_HEADER,
                  text_color=white, font_size=9, bold=True)

    # Arrows down from hypothalamus to AP
    d.add(Line(240, H-55, 240, H-90, strokeColor=C_FLOW_ARROW, strokeWidth=1.5))
    d.add(Polygon([240, H-90, 236, H-83, 244, H-83], fillColor=C_FLOW_ARROW, strokeColor=C_FLOW_ARROW))
    d.add(String(245, H-74, 'Hypophysiotropic\nhormones (portal\nblood)', fontSize=6.5,
                 fillColor=C_SUBHDR, fontName='Helvetica-Oblique'))

    # Anterior Pituitary box
    flow_text_box(d, 150, H-118, 180, 28, 'ANTERIOR PITUITARY\n(Adenohypophysis)',
                  bg=HexColor("#2E6DA4"), text_color=white, font_size=8.5, bold=True)

    # 6 hormone boxes fanning out
    hormones = [
        ('GH', 15, HexColor("#D5F5E3")),
        ('TSH', 95, HexColor("#D6EAF8")),
        ('ACTH', 175, HexColor("#FDEDEC")),
        ('PRL', 255, HexColor("#FEF9E7")),
        ('FSH', 335, HexColor("#F4ECF7")),
        ('LH', 405, HexColor("#FDFEFE")),
    ]
    horm_y = H - 185
    for name, hx, bg in hormones:
        flow_text_box(d, hx, horm_y, 55, 22, name, bg=bg, text_color=C_HEADER, font_size=8.5, bold=True)
        # arrow from AP to hormone
        src_x = 240
        dst_x = hx + 27
        d.add(Line(src_x, H-118, dst_x, horm_y+22, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
        d.add(Polygon([dst_x, horm_y+22, dst_x-3, horm_y+28, dst_x+3, horm_y+28],
                      fillColor=C_FLOW_ARROW, strokeColor=C_FLOW_ARROW))

    # Target gland boxes
    targets = [
        ('Liver/\nBone\n(IGF-1)', 15, HexColor("#D5F5E3")),
        ('Thyroid\n(T₃/T₄)', 95, HexColor("#D6EAF8")),
        ('Adrenal\nCortex\n(Cortisol)', 175, HexColor("#FDEDEC")),
        ('Breast\n(Milk)', 255, HexColor("#FEF9E7")),
        ('Ovary/\nTestis', 335, HexColor("#F4ECF7")),
        ('Ovary/\nLeydig\n(Test.)', 405, HexColor("#FDFEFE")),
    ]
    tgt_y = H - 270
    for (name, tx, bg), (_, hx, _) in zip(targets, hormones):
        flow_text_box(d, tx, tgt_y, 55, 34, name, bg=bg, text_color=C_HEADER, font_size=7.5)
        dst_x = tx + 27
        src_x = hx + 27
        d.add(Line(src_x, horm_y, dst_x, tgt_y+34, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
        d.add(Polygon([dst_x, tgt_y+34, dst_x-3, tgt_y+38, dst_x+3, tgt_y+38],
                      fillColor=C_FLOW_ARROW, strokeColor=C_FLOW_ARROW))

    # Neg feedback arrow (long loop)
    d.add(Line(12, tgt_y+17, 12, H-104, strokeColor=C_RED, strokeWidth=1.2, strokeDashArray=[4,2]))
    d.add(Polygon([12, H-104, 8, H-110, 16, H-110], fillColor=C_RED, strokeColor=C_RED))
    d.add(String(2, H-168, '(−)\nNeg.\nFeedback\n(Long\nLoop)',
                 fontSize=6.5, fillColor=C_RED, fontName='Helvetica-Bold'))

    # Legend
    leg_y = 18
    d.add(Line(W-150, leg_y+4, W-130, leg_y+4, strokeColor=C_FLOW_ARROW, strokeWidth=1.5))
    d.add(String(W-125, leg_y, 'Stimulation', fontSize=7, fillColor=C_FLOW_ARROW))
    d.add(Line(W-150, leg_y-10, W-130, leg_y-10, strokeColor=C_RED, strokeWidth=1.2, strokeDashArray=[3,2]))
    d.add(String(W-125, leg_y-14, 'Inhibition', fontSize=7, fillColor=C_RED))

    return d

# ─── FLOWCHART 2: GH REGULATION ───────────────────────────────────

def draw_gh_regulation():
    W, H = 420, 310
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#F8FBFF"), strokeColor=C_SUBHDR, strokeWidth=0.5))
    d.add(String(W/2, H-14, "Fig. VIII.2-4: Control of Growth Hormone Secretion (Indu Khurana)",
                 textAnchor='middle', fontSize=8, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    # Stimulators column
    stims = ['Hypoglycaemia', 'Exercise/Stress', 'Slow-wave Sleep', 'Ghrelin (stomach)', 'Amino acids (Arg)']
    inhib = ['Hyperglycaemia', 'Somatostatin (GRIH)', 'IGF-1 (neg. feedback)', 'Glucocorticoids', 'Obesity/FFA']

    x_stim, x_inhib, x_hyp = 20, 270, 145
    box_w, box_h = 110, 18

    for i, s in enumerate(stims):
        yy = H - 50 - i*22
        flow_text_box(d, x_stim, yy, box_w, box_h, s, bg=HexColor("#D5F5E3"),
                      text_color=C_GREEN, font_size=7.5)
        d.add(Line(x_stim+box_w, yy+9, x_hyp, H-90, strokeColor=C_GREEN, strokeWidth=0.7))
        d.add(String(x_stim+box_w+2, yy+9, '+', fontSize=8, fillColor=C_GREEN, fontName='Helvetica-Bold'))

    for i, s in enumerate(inhib):
        yy = H - 50 - i*22
        flow_text_box(d, x_inhib, yy, box_w, box_h, s, bg=HexColor("#FDEDEC"),
                      text_color=C_RED, font_size=7.5)
        d.add(Line(x_inhib, yy+9, x_hyp+100, H-90, strokeColor=C_RED, strokeWidth=0.7,
                   strokeDashArray=[2,2]))
        d.add(String(x_inhib-12, yy+9, '−', fontSize=9, fillColor=C_RED, fontName='Helvetica-Bold'))

    # Hypothalamus
    flow_text_box(d, x_hyp, H-105, 100, 28, 'HYPOTHALAMUS\n(GHRH / GRIH)',
                  bg=C_HEADER, text_color=white, font_size=8.5, bold=True)

    # Arrows down
    arrow_down(d, x_hyp+50, H-105, 28)
    d.add(String(x_hyp+54, H-120, 'GHRH (+)\nGRIH (−)', fontSize=7, fillColor=C_SUBHDR))

    # Anterior pituitary
    flow_text_box(d, x_hyp, H-162, 100, 28, 'ANTERIOR PITUITARY\n(Somatotropes)',
                  bg=HexColor("#2E6DA4"), text_color=white, font_size=8, bold=True)

    arrow_down(d, x_hyp+50, H-162, 22)
    d.add(String(x_hyp+54, H-175, 'GH', fontSize=8, fillColor=C_SUBHDR, fontName='Helvetica-Bold'))

    # GH box
    flow_text_box(d, x_hyp, H-212, 100, 28, 'GROWTH\nHORMONE (GH)',
                  bg=HexColor("#D6EAF8"), text_color=C_HEADER, font_size=8.5, bold=True)

    # Branch: Direct and indirect
    d.add(Line(x_hyp+50, H-212, x_hyp-30, H-240, strokeColor=C_FLOW_ARROW, strokeWidth=1))
    d.add(Line(x_hyp+50, H-212, x_hyp+130, H-240, strokeColor=C_FLOW_ARROW, strokeWidth=1))

    flow_text_box(d, x_hyp-80, H-268, 90, 28, 'Direct Actions\n(Anti-insulin\nDiabetogenic)',
                  bg=HexColor("#FEF9E7"), text_color=HexColor("#7D6608"), font_size=7.5)
    flow_text_box(d, x_hyp+90, H-268, 90, 28, 'Via IGF-1\n(Liver → Bone\nGrowth)',
                  bg=HexColor("#D5F5E3"), text_color=C_GREEN, font_size=7.5)

    # Feedback arrow IGF-1 → hypothalamus
    d.add(Line(x_hyp+135, H-240, x_hyp+170, H-180, strokeColor=C_RED, strokeWidth=1,
               strokeDashArray=[3,2]))
    d.add(Line(x_hyp+170, H-180, x_hyp+160, H-90, strokeColor=C_RED, strokeWidth=1,
               strokeDashArray=[3,2]))
    d.add(Polygon([x_hyp+160, H-90, x_hyp+155, H-97, x_hyp+165, H-97],
                  fillColor=C_RED, strokeColor=C_RED))
    d.add(String(x_hyp+172, H-150, '(−)\nIGF-1\nfeedback', fontSize=6.5,
                 fillColor=C_RED, fontName='Helvetica-Bold'))

    return d

# ─── FLOWCHART 3: FEEDBACK LOOPS ──────────────────────────────────

def draw_feedback_loops():
    W, H = 460, 320
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#FDFEFE"), strokeColor=C_SUBHDR, strokeWidth=0.5))
    d.add(String(W/2, H-14, "Fig. VIII.1-2: Feedback Loop Types in Hypothalamic-Pituitary Axis",
                 textAnchor='middle', fontSize=8.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    # Left: Negative feedback (3 types)
    section_x = 20
    d.add(String(section_x+50, H-30, 'NEGATIVE FEEDBACK', textAnchor='middle',
                 fontSize=8, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    bx, bw, bh = section_x, 90, 22
    levels = [
        (H-52,  'HYPOTHALAMUS', C_HEADER, white),
        (H-100, 'ANTERIOR PITUITARY', HexColor("#2E6DA4"), white),
        (H-148, 'TARGET GLAND', HexColor("#1E8449"), white),
        (H-196, 'TARGET HORMONE', C_GOLD, C_HEADER),
    ]
    for yy, label, bg, tc in levels:
        flow_text_box(d, bx, yy, bw, bh, label, bg=bg, text_color=tc, font_size=7.5, bold=True)

    for i in range(3):
        y_top = levels[i][0]
        y_bot = levels[i+1][0] + bh
        cx = bx + bw/2
        d.add(Line(cx, y_top, cx, y_bot, strokeColor=C_FLOW_ARROW, strokeWidth=1.2))
        d.add(Polygon([cx, y_bot, cx-3, y_bot+5, cx+3, y_bot+5],
                      fillColor=C_FLOW_ARROW, strokeColor=C_FLOW_ARROW))
        d.add(String(cx+5, (y_top+y_bot)//2, '(+)', fontSize=7, fillColor=C_GREEN,
                     fontName='Helvetica-Bold'))

    # Long loop arrow (hormone back to hypothalamus + pituitary)
    long_x = bx + bw + 8
    d.add(Line(long_x-8, levels[3][0]+11, long_x+15, levels[3][0]+11, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[3,2]))
    d.add(Line(long_x+15, levels[3][0]+11, long_x+15, levels[0][0]+11, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[3,2]))
    d.add(Polygon([long_x+15, levels[0][0]+11, long_x+10, levels[0][0]+17, long_x+20, levels[0][0]+17],
                  fillColor=C_RED, strokeColor=C_RED))
    d.add(String(long_x+17, H-150, 'LONG\nLOOP\n(−)', fontSize=6.5, fillColor=C_RED, fontName='Helvetica-Bold'))

    # Short loop (pituitary back to hypothalamus)
    short_x = bx - 18
    d.add(Line(bx, levels[1][0]+11, short_x, levels[1][0]+11, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[2,2]))
    d.add(Line(short_x, levels[1][0]+11, short_x, levels[0][0]+11, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[2,2]))
    d.add(Polygon([short_x, levels[0][0]+11, short_x-4, levels[0][0]+6, short_x+4, levels[0][0]+6],
                  fillColor=C_RED, strokeColor=C_RED))
    d.add(String(short_x-38, H-80, 'SHORT\nLOOP\n(−)', fontSize=6.5, fillColor=C_RED, fontName='Helvetica-Bold'))

    # Ultra short (hypothalamus back to itself)
    us_x = bx - 38
    d.add(Line(bx, levels[0][0]+18, us_x, levels[0][0]+18, strokeColor=HexColor("#8E44AD"), strokeWidth=1, strokeDashArray=[2,2]))
    d.add(Line(us_x, levels[0][0]+18, us_x, levels[0][0]+8, strokeColor=HexColor("#8E44AD"), strokeWidth=1, strokeDashArray=[2,2]))
    d.add(Polygon([us_x, levels[0][0]+8, us_x-3, levels[0][0]+14, us_x+3, levels[0][0]+14],
                  fillColor=HexColor("#8E44AD"), strokeColor=HexColor("#8E44AD")))
    d.add(String(us_x-2, levels[0][0]-6, 'Ultra-\nshort', fontSize=6, fillColor=HexColor("#8E44AD"), fontName='Helvetica-Bold'))

    # Legend
    ly = 30
    d.add(String(20, ly+16, 'Legend:', fontSize=7.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))
    d.add(Line(20, ly+5, 50, ly+5, strokeColor=C_FLOW_ARROW, strokeWidth=1.5))
    d.add(String(55, ly+1, 'Stimulation (+)', fontSize=7, fillColor=C_FLOW_ARROW))
    d.add(Line(20, ly-8, 50, ly-8, strokeColor=C_RED, strokeWidth=1.2, strokeDashArray=[3,2]))
    d.add(String(55, ly-12, 'Inhibition (−) — Negative Feedback', fontSize=7, fillColor=C_RED))

    # Right panel: Key statements
    rx = 240
    d.add(Rect(rx, 20, 200, H-40, rx=6, ry=6, fillColor=C_BOX_BG, strokeColor=C_BOX_BORDER, strokeWidth=1))
    d.add(String(rx+100, H-35, 'Types of Feedback', textAnchor='middle',
                 fontSize=8.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    entries = [
        ('LONG LOOP (−)', C_RED,
         'Target hormone feeds back to\nhypothalamus AND pituitary.\nMost common type.\nE.g., Cortisol inhibits CRH + ACTH'),
        ('SHORT LOOP (−)', HexColor("#E74C3C"),
         'Anterior pituitary hormone\nfeeds back to inhibit\nhypothalamic releasing hormone.\nE.g., GH inhibits GHRH'),
        ('ULTRA-SHORT LOOP (−)', HexColor("#8E44AD"),
         'Hypothalamic hormone inhibits\nits own secretion.\nE.g., GHRH inhibits GHRH'),
        ('POSITIVE FEEDBACK (+)', C_GREEN,
         'Hormone stimulates more of\nits own secretion.\nRARE. Example: Oestrogen\nLH surge before ovulation'),
    ]
    ey = H - 60
    for title, color, desc in entries:
        d.add(String(rx+10, ey, title, fontSize=7.5, fillColor=color, fontName='Helvetica-Bold'))
        ey -= 12
        for ln in desc.split('\n'):
            d.add(String(rx+15, ey, ln, fontSize=6.8, fillColor=C_HEADER))
            ey -= 10
        ey -= 6

    return d

# ─── FLOWCHART 4: ACTH / HPA AXIS ─────────────────────────────────

def draw_hpa_axis():
    W, H = 380, 290
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#FDFBF5"), strokeColor=C_SUBHDR, strokeWidth=0.5))
    d.add(String(W/2, H-14, "HPA Axis: Regulation of ACTH Secretion",
                 textAnchor='middle', fontSize=8.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    cx = W//2

    # Stress box
    flow_text_box(d, cx-65, H-48, 130, 22, 'STRESS / Cytokines / Hypoglycaemia',
                  bg=HexColor("#FDEDEC"), text_color=C_RED, font_size=7.5, bold=True)

    arrow_down(d, cx, H-48, 22, label='')
    d.add(String(cx+5, H-62, '(+)', fontSize=7.5, fillColor=C_GREEN, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-60, H-95, 120, 22, 'HYPOTHALAMUS\nCRH + AVP (synergy)',
                  bg=C_HEADER, text_color=white, font_size=8, bold=True)

    arrow_down(d, cx, H-95, 22)
    d.add(String(cx+5, H-110, 'CRH(+)\nAVP(+)', fontSize=7, fillColor=C_GREEN, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-60, H-142, 120, 22, 'ANTERIOR PITUITARY\n(Corticotropes)',
                  bg=HexColor("#2E6DA4"), text_color=white, font_size=8, bold=True)

    arrow_down(d, cx, H-142, 22)
    d.add(String(cx+5, H-156, 'ACTH', fontSize=8, fillColor=C_SUBHDR, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-60, H-189, 120, 22, 'ADRENAL CORTEX\n(Zona Fasciculata)',
                  bg=HexColor("#D5F5E3"), text_color=C_GREEN, font_size=8, bold=True)

    arrow_down(d, cx, H-189, 22)
    d.add(String(cx+5, H-203, 'CORTISOL', fontSize=8, fillColor=C_SUBHDR, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-60, H-236, 120, 22, 'TARGET TISSUES\n(Metabolic effects)',
                  bg=C_GOLD, text_color=C_HEADER, font_size=8, bold=True)

    # Negative feedback arrow (cortisol back)
    fb_x = cx + 75
    d.add(Line(cx+60, H-225, fb_x, H-225, strokeColor=C_RED, strokeWidth=1.2, strokeDashArray=[3,2]))
    d.add(Line(fb_x, H-225, fb_x, H-80, strokeColor=C_RED, strokeWidth=1.2, strokeDashArray=[3,2]))
    d.add(Polygon([fb_x, H-80, fb_x-4, H-87, fb_x+4, H-87], fillColor=C_RED, strokeColor=C_RED))
    d.add(String(fb_x+3, H-155, '(−)\nNegative\nFeedback\n(Cortisol)', fontSize=6.5,
                 fillColor=C_RED, fontName='Helvetica-Bold'))

    # Diurnal rhythm note
    d.add(Rect(10, 10, 155, 40, rx=4, ry=4, fillColor=C_BOX_BG, strokeColor=C_BOX_BORDER, strokeWidth=0.8))
    d.add(String(14, 38, '⏰ Diurnal Rhythm of ACTH:', fontSize=7.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))
    d.add(String(14, 26, 'Peak: 6–8 AM (early morning)', fontSize=7, fillColor=C_HEADER))
    d.add(String(14, 14, 'Trough: ~Midnight', fontSize=7, fillColor=C_HEADER))

    # POMC note
    d.add(Rect(W-165, 10, 155, 40, rx=4, ry=4, fillColor=C_CLINICAL, strokeColor=C_CLIN_BDR, strokeWidth=0.8))
    d.add(String(W-161, 38, 'POMC → ACTH + β-LPH', fontSize=7.5, fillColor=C_RED, fontName='Helvetica-Bold'))
    d.add(String(W-161, 26, 'β-LPH → β-Endorphin', fontSize=7, fillColor=C_RED))
    d.add(String(W-161, 14, 'ACTH → MSH (pigmentation)', fontSize=7, fillColor=C_RED))

    return d

# ─── FLOWCHART 5: PROLACTIN REGULATION ───────────────────────────

def draw_prolactin_regulation():
    W, H = 400, 260
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#FFF8F8"), strokeColor=C_SUBHDR, strokeWidth=0.5))
    d.add(String(W/2, H-14, "Regulation of Prolactin Secretion",
                 textAnchor='middle', fontSize=8.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    cx = 200

    # Suckling reflex
    flow_text_box(d, cx-80, H-46, 80, 22, 'SUCKLING\nREFLEX',
                  bg=HexColor("#FFF3E0"), text_color=HexColor("#E65100"), font_size=8, bold=True)
    flow_text_box(d, cx+10, H-46, 80, 22, 'STRESS /\nOESTROGEN',
                  bg=HexColor("#F3E5F5"), text_color=HexColor("#6A1B9A"), font_size=8)

    # Arrows to hypothalamus
    d.add(Line(cx-40, H-46, cx-15, H-78, strokeColor=C_FLOW_ARROW, strokeWidth=1))
    d.add(Line(cx+50, H-46, cx+15, H-78, strokeColor=C_FLOW_ARROW, strokeWidth=1))

    flow_text_box(d, cx-60, H-98, 120, 22, 'HYPOTHALAMUS\n↓ Dopamine (PIH)',
                  bg=C_HEADER, text_color=white, font_size=8, bold=True)

    arrow_down(d, cx, H-98, 22)
    d.add(String(cx+5, H-114, 'PIH ↓  PRH ↑', fontSize=7.5, fillColor=C_SUBHDR))

    flow_text_box(d, cx-60, H-145, 120, 22, 'ANTERIOR PITUITARY\n(Lactotropes)',
                  bg=HexColor("#2E6DA4"), text_color=white, font_size=8, bold=True)

    arrow_down(d, cx, H-145, 22)
    d.add(String(cx+5, H-160, 'PROLACTIN ↑', fontSize=8, fillColor=C_SUBHDR, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-60, H-192, 120, 22, 'MAMMARY GLANDS\n→ Milk Synthesis',
                  bg=HexColor("#D5F5E3"), text_color=C_GREEN, font_size=8, bold=True)

    # Dopamine inhibition arrow (from hypothalamus directly suppressing)
    inh_x = cx - 90
    d.add(Rect(inh_x-60, H-135, 55, 28, rx=4, ry=4, fillColor=HexColor("#FDEDEC"),
               strokeColor=C_RED, strokeWidth=1))
    d.add(String(inh_x-32, H-114, 'DOPAMINE', fontSize=7.5, textAnchor='middle',
                 fillColor=C_RED, fontName='Helvetica-Bold'))
    d.add(String(inh_x-32, H-126, '(PIH)', fontSize=7.5, textAnchor='middle', fillColor=C_RED))
    d.add(Line(inh_x-5, H-121, cx-60, H-133, strokeColor=C_RED, strokeWidth=1.2,
               strokeDashArray=[3,2]))
    d.add(String(inh_x+5, H-118, '(−)', fontSize=8, fillColor=C_RED, fontName='Helvetica-Bold'))

    # Key note
    d.add(Rect(10, 10, 180, 28, rx=4, ry=4, fillColor=C_BOX_BG, strokeColor=C_BOX_BORDER))
    d.add(String(14, 28, '⭐ Unique: ONLY anterior pituitary', fontSize=7, fillColor=C_HEADER, fontName='Helvetica-Bold'))
    d.add(String(14, 17, 'hormone under DOMINANT inhibitory\ncontrol (Dopamine/PIH)', fontSize=7, fillColor=C_HEADER))

    # Amenorrhoea note
    d.add(Rect(W-180, 10, 170, 28, rx=4, ry=4, fillColor=C_CLINICAL, strokeColor=C_CLIN_BDR))
    d.add(String(W-176, 28, '↑ PRL → inhibits GnRH', fontSize=7, fillColor=C_RED, fontName='Helvetica-Bold'))
    d.add(String(W-176, 17, '→ Lactational Amenorrhoea\n(physiological contraception)', fontSize=7, fillColor=C_RED))

    return d

# ─── FLOWCHART 6: GNRH / GONADOTROPINS ───────────────────────────

def draw_gonadotropins():
    W, H = 460, 280
    d = Drawing(W, H)
    d.add(Rect(0, 0, W, H, fillColor=HexColor("#F9F4FF"), strokeColor=C_SUBHDR, strokeWidth=0.5))
    d.add(String(W/2, H-14, "Regulation of FSH and LH (Gonadotropins)",
                 textAnchor='middle', fontSize=8.5, fillColor=C_HEADER, fontName='Helvetica-Bold'))

    cx = W//2
    flow_text_box(d, cx-65, H-48, 130, 22, 'HYPOTHALAMUS\n(GnRH — PULSATILE)',
                  bg=C_HEADER, text_color=white, font_size=8.5, bold=True)

    arrow_down(d, cx, H-48, 22)
    d.add(String(cx+5, H-63, 'GnRH (+)', fontSize=7.5, fillColor=C_GREEN, fontName='Helvetica-Bold'))

    flow_text_box(d, cx-65, H-95, 130, 22, 'ANTERIOR PITUITARY\n(Gonadotropes)',
                  bg=HexColor("#2E6DA4"), text_color=white, font_size=8.5, bold=True)

    # Two arrows - LH and FSH
    lh_x, fsh_x = cx - 60, cx + 30
    d.add(Line(cx, H-95, lh_x+25, H-125, strokeColor=C_FLOW_ARROW, strokeWidth=1))
    d.add(Line(cx, H-95, fsh_x+25, H-125, strokeColor=C_FLOW_ARROW, strokeWidth=1))

    flow_text_box(d, lh_x-15, H-147, 80, 22, 'LH', bg=HexColor("#FDEDEC"),
                  text_color=C_RED, font_size=10, bold=True)
    flow_text_box(d, fsh_x, H-147, 80, 22, 'FSH', bg=HexColor("#D6EAF8"),
                  text_color=C_SUBHDR, font_size=10, bold=True)

    # LH targets
    d.add(Line(lh_x+25, H-147, lh_x-5, H-178, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
    d.add(Line(lh_x+25, H-147, lh_x+55, H-178, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
    flow_text_box(d, lh_x-45, H-205, 75, 28, 'OVULATION\n(LH Surge)\nCorpus Luteum',
                  bg=HexColor("#FCF3CF"), text_color=HexColor("#9A7D0A"), font_size=7)
    flow_text_box(d, lh_x+20, H-205, 75, 28, 'LEYDIG CELLS\n→ Testosterone',
                  bg=HexColor("#D5F5E3"), text_color=C_GREEN, font_size=7)

    # FSH targets
    d.add(Line(fsh_x+40, H-147, fsh_x+10, H-178, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
    d.add(Line(fsh_x+40, H-147, fsh_x+70, H-178, strokeColor=C_FLOW_ARROW, strokeWidth=0.8))
    flow_text_box(d, fsh_x-20, H-205, 75, 28, 'FOLLICULAR\nDev. + Oestrogen\n(Aromatase)',
                  bg=HexColor("#F4ECF7"), text_color=HexColor("#6C3483"), font_size=7)
    flow_text_box(d, fsh_x+60, H-205, 75, 28, 'SERTOLI CELLS\n→ Sperm.\n+ Inhibin',
                  bg=HexColor("#D6EAF8"), text_color=C_SUBHDR, font_size=7)

    # Negative feedback
    fb_x = W - 30
    d.add(Line(W-60, H-191, fb_x, H-191, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[3,2]))
    d.add(Line(fb_x, H-191, fb_x, H-33, strokeColor=C_RED, strokeWidth=1, strokeDashArray=[3,2]))
    d.add(Polygon([fb_x, H-33, fb_x-4, H-40, fb_x+4, H-40], fillColor=C_RED, strokeColor=C_RED))
    d.add(String(fb_x-28, H-110, '(−)\nSex\nSteroids\nInhibin\n(FSH only)', fontSize=6.5,
                 fillColor=C_RED, fontName='Helvetica-Bold'))

    # Positive feedback box
    d.add(Rect(8, H-220, 130, 36, rx=4, ry=4, fillColor=HexColor("#E8F8F5"),
               strokeColor=C_GREEN, strokeWidth=1.2))
    d.add(String(12, H-192, '⭐ EXCEPTION — Positive Feedback:', fontSize=7, fillColor=C_GREEN, fontName='Helvetica-Bold'))
    d.add(String(12, H-202, 'High sustained Oestrogen →', fontSize=7, fillColor=C_HEADER))
    d.add(String(12, H-212, '(+) feedback → LH SURGE → Ovulation', fontSize=7, fillColor=C_HEADER))

    # Pulsatile note
    d.add(Rect(8, H-260, 130, 34, rx=4, ry=4, fillColor=C_BOX_BG,
               strokeColor=C_BOX_BORDER, strokeWidth=1))
    d.add(String(12, H-232, '⭐ GnRH must be PULSATILE:', fontSize=7, fillColor=C_HEADER, fontName='Helvetica-Bold'))
    d.add(String(12, H-242, 'Continuous GnRH → receptor', fontSize=7, fillColor=C_HEADER))
    d.add(String(12, H-252, 'downregulation → ↓ FSH/LH', fontSize=7, fillColor=C_HEADER))

    return d


# ─── FLOWCHART WRAPPER ────────────────────────────────────────────
class DrawingFlowable(Flowable):
    def __init__(self, drawing, caption=''):
        self.drawing = drawing
        self.caption_text = caption
        self._width = drawing.width
        self._height = drawing.height + (14 if caption else 0)

    def wrap(self, availWidth, availHeight):
        return self._width, self._height

    def draw(self):
        self.drawing.drawOn(self.canv, 0, 14 if self.caption_text else 0)
        if self.caption_text:
            self.canv.setFont('Helvetica-Oblique', 7.5)
            self.canv.setFillColor(C_SUBHDR)
            self.canv.drawCentredString(self._width/2, 2, self.caption_text)


# ─── HEADER / FOOTER ─────────────────────────────────────────────
def on_page(canvas, doc):
    canvas.saveState()
    w, h = A4
    # Header bar
    canvas.setFillColor(C_HEADER)
    canvas.rect(0, h-28, w, 28, fill=1, stroke=0)
    canvas.setFont('Helvetica-Bold', 10)
    canvas.setFillColor(white)
    canvas.drawCentredString(w/2, h-18, "ANTERIOR PITUITARY HORMONES — COMPREHENSIVE STUDY GUIDE")
    canvas.setFont('Helvetica', 8)
    canvas.drawRightString(w-20, h-18, "Indu Khurana Style")
    # Footer
    canvas.setFillColor(C_SUBHDR)
    canvas.rect(0, 0, w, 18, fill=1, stroke=0)
    canvas.setFont('Helvetica', 7.5)
    canvas.setFillColor(white)
    canvas.drawCentredString(w/2, 5, f"Page {doc.page}  |  Based on Indu Khurana — Textbook of Medical Physiology  |  Section VIII.2")
    canvas.restoreState()


# ─── BUILD PDF ────────────────────────────────────────────────────
def build_pdf(path):
    doc = SimpleDocTemplate(
        path,
        pagesize=A4,
        leftMargin=1.8*cm, rightMargin=1.8*cm,
        topMargin=1.5*cm, bottomMargin=1.5*cm,
        title="Anterior Pituitary Hormones Study Guide",
        author="Medical Study Guide — Indu Khurana Style",
        subject="Endocrinology — Anterior Pituitary"
    )

    story = []
    W = PAGE_W - 3.6*cm  # usable width

    # ── COVER ──────────────────────────────────────────────────────
    story.append(Spacer(1, 0.8*cm))
    story.append(Paragraph("ANTERIOR PITUITARY HORMONES", ST_TITLE))
    story.append(Paragraph("Their Actions and Regulation", ST_SUBTITLE))
    story.append(Paragraph("A Comprehensive 10-Mark Study Guide", make_style('cov3',
        fontSize=11, textColor=C_GOLD, fontName='Helvetica-BoldOblique', alignment=TA_CENTER)))
    story.append(Spacer(1, 0.3*cm))

    cover_data = [[
        Paragraph("<b>Reference:</b> Indu Khurana — <i>Textbook of Medical Physiology</i><br/>"
                  "Section VIII.2: Endocrinal Functions of Hypothalamus &amp; Pituitary Gland", ST_BODY),
        Paragraph("<b>Also covers:</b> Ganong's Review of Medical Physiology 26E,<br/>"
                  "Costanzo Physiology 7E, Harrison's Principles of Internal Medicine 22E", ST_BODY)
    ]]
    ct = Table(cover_data, colWidths=[W*0.5, W*0.5])
    ct.setStyle(TableStyle([
        ('BOX', (0,0), (-1,-1), 1, C_SUBHDR),
        ('INNERGRID', (0,0), (-1,-1), 0.5, colors.lightgrey),
        ('BACKGROUND', (0,0), (-1,-1), C_ACCENT),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
    ]))
    story.append(ct)
    story.append(sp(8))
    story.append(mnemonic_box("🧠  MNEMONIC  —  \"FLAT PG\"   |   FSH · LH · ACTH · TSH · Prolactin · GH"))
    story.append(sp(8))

    # Master flowchart
    story.append(DrawingFlowable(draw_master_axis_flowchart(),
        "Fig. VIII.2-3: Hypothalamus – Anterior Pituitary – Target Glands (Master Axis)"))
    story.append(sp(10))

    # ── CELL TYPES TABLE ──────────────────────────────────────────
    story.append(section_heading("A.  CELL TYPES OF THE ANTERIOR PITUITARY"))
    story.append(sp(4))
    ct_headers = ["Cell Type", "Hormone Secreted", "Approx. %", "Tissue-Specific\nTranscription Factor"]
    ct_rows = [
        ["Somatotropes", "Growth Hormone (GH)", "~50%", "Pit-1, Prop-1"],
        ["Corticotropes", "ACTH + β-LPH (from POMC)", "~20%", "T-Pit"],
        ["Lactotropes", "Prolactin (PRL)", "~15–20%", "Pit-1, Prop-1"],
        ["Thyrotropes", "TSH", "~5%", "Pit-1, Prop-1, TEF"],
        ["Gonadotropes", "FSH + LH", "~10%", "SF-1, DAX-1"],
    ]
    story.append(make_table(ct_headers, ct_rows,
        [W*0.22, W*0.32, W*0.14, W*0.32]))
    story.append(sp(6))

    # ── HYPOTHALAMIC HORMONES TABLE ──────────────────────────────
    story.append(section_heading("B.  HYPOTHALAMIC (HYPOPHYSIOTROPIC) HORMONES"))
    story.append(sp(4))
    hh_headers = ["Hypothalamic Hormone", "Abbrev.", "Effect", "Anterior Pituitary Hormone"]
    hh_rows = [
        ["Corticotropin-releasing hormone", "CRH", "↑ Stimulates", "ACTH + β-LPH"],
        ["Thyrotropin-releasing hormone", "TRH", "↑ Stimulates", "TSH (also PRL)"],
        ["Gonadotropin-releasing hormone", "GnRH", "↑ Stimulates", "LH + FSH"],
        ["GH-releasing hormone", "GHRH", "↑ Stimulates", "GH"],
        ["GH release-inhibiting hormone (Somatostatin)", "GRIH", "↓ Inhibits", "GH (also TSH)"],
        ["Prolactin-inhibiting hormone (= Dopamine)", "PIH", "↓ Inhibits", "Prolactin"],
        ["Prolactin-releasing hormone", "PRH (TRH/VIP)", "↑ Stimulates", "Prolactin"],
    ]
    story.append(make_table(hh_headers, hh_rows,
        [W*0.37, W*0.12, W*0.16, W*0.35]))
    story.append(key_statement(
        "Anterior pituitary secretion is controlled by chemical agents (hypophysiotropic hormones) "
        "carried in portal hypophyseal vessels from hypothalamus to pituitary. "
        "The predominant hypothalamic effect is STIMULATORY — except for Prolactin where it is INHIBITORY."))
    story.append(sp(6))

    # ── PAGE BREAK ───────────────────────────────────────────────
    story.append(PageBreak())

    # ─── 1. GROWTH HORMONE ────────────────────────────────────────
    story.append(section_heading("I.  GROWTH HORMONE (GH) / SOMATOTROPIN"))
    story.append(sp(4))

    gh_basic = [
        ["Chemical Nature", "Polypeptide — 191 amino acids, single chain"],
        ["Secreted by", "Somatotropes (most abundant cell, ~50%)"],
        ["Plasma Half-life", "~20 minutes"],
        ["Receptor type", "Cell-surface receptor → JAK-STAT pathway"],
        ["Secretion pattern", "Pulsatile; major pulse during Stage III–IV NREM (slow-wave) sleep"],
    ]
    bt = Table([[Paragraph(r[0], make_style('bk', fontSize=8.5, fontName='Helvetica-Bold', textColor=C_HEADER)),
                 Paragraph(r[1], ST_TD)] for r in gh_basic],
               colWidths=[W*0.28, W*0.72])
    bt.setStyle(TableStyle([
        ('GRID', (0,0), (-1,-1), 0.4, colors.lightgrey),
        ('BACKGROUND', (0,0), (0,-1), C_ACCENT),
        ('TOPPADDING', (0,0), (-1,-1), 3),
        ('BOTTOMPADDING', (0,0), (-1,-1), 3),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
    ]))
    story.append(bt)
    story.append(sp(6))

    story.append(subsection_heading("A. Actions of Growth Hormone:"))
    story.append(sp(3))

    gh_actions_headers = ["System", "Direct (Anti-insulin / Diabetogenic)", "Indirect (via IGF-1)"]
    gh_actions_rows = [
        ["Protein", "↑ Amino acid uptake, ↑ Protein synthesis (anabolic)", "↑ Cell proliferation, organ growth"],
        ["Carbohydrate", "↓ Glucose uptake by cells → ↑ Blood glucose (DIABETOGENIC)", "—"],
        ["Fat", "↑ Lipolysis → ↑ Free fatty acids in blood", "—"],
        ["Bone/Cartilage", "—", "↑ Chondrogenesis at epiphyseal plates → Linear growth"],
        ["Mineral", "Retains Na⁺, K⁺, Ca²⁺, Cl⁻, Phosphate", "↑ Intestinal Ca²⁺ absorption"],
        ["Organ", "—", "Visceromegaly (liver, spleen, kidney)"],
    ]
    story.append(make_table(gh_actions_headers, gh_actions_rows,
        [W*0.15, W*0.47, W*0.38]))
    story.append(sp(4))
    story.append(key_statement(
        '"GH has both INSULIN-LIKE (anabolic, via IGF-1) and ANTI-INSULIN (diabetogenic, direct) effects." — Indu Khurana'))
    story.append(sp(6))

    story.append(subsection_heading("B. Regulation of GH Secretion:"))
    story.append(sp(3))
    story.append(DrawingFlowable(draw_gh_regulation(),
        "Fig. VIII.2-4: Control of Growth Hormone Secretion (Khurana)"))
    story.append(sp(4))

    reg_headers = ["Stimulators of GH ↑", "Inhibitors of GH ↓"]
    reg_rows = [
        ["GHRH (hypothalamus) — main stimulator", "Somatostatin / GRIH (hypothalamus) — main inhibitor"],
        ["Ghrelin (from stomach)", "IGF-1 / Somatomedins (negative feedback)"],
        ["Hypoglycaemia (↓ blood glucose)", "Hyperglycaemia (↑ blood glucose)"],
        ["Exercise, physical stress", "Obesity / elevated free fatty acids"],
        ["Slow-wave NREM sleep (Stages III–IV)", "Glucocorticoids (chronic excess)"],
        ["Amino acids (arginine, leucine)", "Hypothyroidism"],
        ["Oestrogen, testosterone", "GH itself (short-loop feedback)"],
        ["Starvation / protein deficiency", "REM sleep"],
    ]
    rt = make_table(reg_headers, reg_rows, [W*0.5, W*0.5])
    story.append(rt)
    story.append(sp(4))
    story.append(clinical_box([
        "Excess GH BEFORE puberty (epiphyses open) → GIGANTISM — tall stature",
        "Excess GH AFTER puberty (epiphyses fused) → ACROMEGALY — coarse facial features, prognathism, large hands/feet",
        "GH deficiency in childhood → PITUITARY DWARFISM — proportionate short stature, normal intelligence",
        "GH excess causes SECONDARY DIABETES MELLITUS (diabetogenic effect)",
    ]))
    story.append(sp(8))

    # ─── 2. TSH ───────────────────────────────────────────────────
    story.append(section_heading("II.  THYROID-STIMULATING HORMONE (TSH) / THYROTROPIN"))
    story.append(sp(4))
    story.append(Paragraph(
        "<b>Chemical Nature:</b> Glycoprotein — shared <b>α-subunit</b> (with FSH, LH, hCG) + unique <b>β-subunit</b> "
        "(determines biological activity). 211 amino acids. Secreted by <b>Thyrotropes</b>.", ST_BODY))
    story.append(sp(4))

    tsh_actions = [
        ["1", "Stimulates ALL steps of thyroid hormone synthesis: iodine uptake, iodination, coupling, release of T₃ and T₄"],
        ["2", "Causes HYPERTROPHY and HYPERPLASIA of thyroid follicular cells"],
        ["3", "Increases VASCULARITY of thyroid gland"],
        ["4", "Increases overall THYROID GLAND WEIGHT (goitrogenic effect with chronic excess)"],
        ["5", "Activates adenylyl cyclase (cAMP) in thyroid cells"],
    ]
    at = Table([[Paragraph(r[0], make_style('num', fontSize=9, fontName='Helvetica-Bold',
                                             textColor=white, alignment=TA_CENTER)),
                 Paragraph(r[1], ST_TD)] for r in tsh_actions],
               colWidths=[W*0.06, W*0.94])
    at.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (0,-1), C_SUBHDR),
        ('GRID', (0,0), (-1,-1), 0.4, colors.lightgrey),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
        ('VALIGN', (0,0), (-1,-1), 'MIDDLE'),
    ]))
    story.append(at)
    story.append(sp(4))

    tsh_reg_headers = ["Stimulators of TSH ↑", "Inhibitors of TSH ↓"]
    tsh_reg_rows = [
        ["TRH (from hypothalamus) — main", "T₃/T₄ — main (negative long-loop feedback)"],
        ["Cold exposure (reflex via hypothalamus)", "Somatostatin"],
        ["Low thyroid hormone levels", "Dopamine"],
        ["", "Glucocorticoids"],
    ]
    story.append(make_table(tsh_reg_headers, tsh_reg_rows, [W*0.5, W*0.5]))
    story.append(sp(4))
    story.append(key_statement(
        '"T₃ (more potent) and T₄ exert negative feedback at BOTH the hypothalamic (↓TRH) and '
        'pituitary (↓TSH) levels — long-loop negative feedback." — Indu Khurana'))
    story.append(sp(8))

    # ─── PAGE BREAK ──────────────────────────────────────────────
    story.append(PageBreak())

    # ─── 3. ACTH ─────────────────────────────────────────────────
    story.append(section_heading("III.  ADRENOCORTICOTROPIC HORMONE (ACTH) / CORTICOTROPIN"))
    story.append(sp(4))
    story.append(Paragraph(
        "<b>Chemical Nature:</b> Polypeptide — <b>39 amino acids</b>. Secreted by <b>Corticotropes</b>. "
        "Derived from large precursor <b>POMC (Pro-opiomelanocortin)</b> — 266 amino acids.", ST_BODY))
    story.append(sp(4))

    story.append(subsection_heading("A. POMC Processing — Khurana Key Diagram:"))
    story.append(sp(3))

    pomc_data = [
        [Paragraph("<b>POMC</b>\n(266 AA)", make_style('pc', fontSize=9, alignment=TA_CENTER, fontName='Helvetica-Bold')),
         Paragraph("→", make_style('arr', fontSize=14, alignment=TA_CENTER)),
         Paragraph("<b>ACTH (1–39)</b>\n↓ MSH + CLIP", make_style('pc2', fontSize=8.5, alignment=TA_CENTER, fontName='Helvetica-Bold', textColor=C_RED)),
         Paragraph("+", make_style('plus', fontSize=12, alignment=TA_CENTER)),
         Paragraph("<b>β-Lipotropin (β-LPH)</b>\n↓ γ-LPH + β-Endorphin", make_style('pc3', fontSize=8.5, alignment=TA_CENTER, fontName='Helvetica-Bold', textColor=C_SUBHDR))],
    ]
    pt = Table(pomc_data, colWidths=[W*0.18, W*0.06, W*0.26, W*0.06, W*0.44])
    pt.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (0,0), C_ACCENT),
        ('BACKGROUND', (2,0), (2,0), HexColor("#FDEDEC")),
        ('BACKGROUND', (4,0), (4,0), HexColor("#D6EAF8")),
        ('BOX', (0,0), (-1,-1), 1, C_SUBHDR),
        ('VALIGN', (0,0), (-1,-1), 'MIDDLE'),
        ('TOPPADDING', (0,0), (-1,-1), 8),
        ('BOTTOMPADDING', (0,0), (-1,-1), 8),
        ('LEFTPADDING', (0,0), (-1,-1), 5),
    ]))
    story.append(pt)
    story.append(sp(4))
    story.append(key_statement(
        '"ACTH, MSH, β-LPH and β-endorphin are ALL derived from the same precursor molecule POMC. '
        'This explains why Addison\'s disease (↑ACTH) causes skin hyperpigmentation (MSH-like effect)."'))
    story.append(sp(4))

    story.append(subsection_heading("B. Actions of ACTH:"))
    story.append(sp(3))
    acth_rows = [
        ["Adrenal cortex (main)", "Stimulates synthesis & secretion of GLUCOCORTICOIDS (cortisol) — main action"],
        ["Adrenal cortex", "Stimulates MINERALOCORTICOIDS (aldosterone) — minor/permissive role"],
        ["Adrenal cortex", "Stimulates ADRENAL ANDROGENS (DHEA, androstenedione)"],
        ["Adrenal cortex (trophic)", "Maintains ADRENAL CORTEX SIZE & vascularity (adrenal atrophy without ACTH)"],
        ["Melanocytes", "High ACTH stimulates melanocytes → SKIN PIGMENTATION (MSH-like)"],
        ["Adipose tissue", "Promotes LIPOLYSIS (extra-adrenal action)"],
    ]
    story.append(make_table(["Target", "Action of ACTH"], acth_rows, [W*0.25, W*0.75]))
    story.append(sp(4))

    story.append(subsection_heading("C. Regulation of ACTH (HPA Axis):"))
    story.append(sp(3))
    story.append(DrawingFlowable(draw_hpa_axis(), "HPA Axis: CRH → ACTH → Cortisol (with negative feedback)"))
    story.append(sp(4))
    story.append(clinical_box([
        "ACTH shows DIURNAL RHYTHM — Peak: 6–8 AM | Trough: ~Midnight",
        "Prolonged exogenous glucocorticoids → ↓ ACTH → Adrenal cortex ATROPHY",
        "Cushing's syndrome (excess cortisol): moon face, central obesity, purple striae, hypertension",
        "Addison's disease (cortisol deficiency): ↑ ACTH → skin hyperpigmentation (MSH effect), hypotension",
        "Nelson's syndrome: Post-adrenalectomy → loss of cortisol feedback → massive ↑ ACTH → hyperpigmentation",
    ]))
    story.append(sp(8))

    # ─── PAGE BREAK ──────────────────────────────────────────────
    story.append(PageBreak())

    # ─── 4. PROLACTIN ─────────────────────────────────────────────
    story.append(section_heading("IV.  PROLACTIN (PRL)"))
    story.append(sp(4))
    story.append(Paragraph(
        "<b>Chemical Nature:</b> Polypeptide — <b>198 amino acids</b>. Structurally similar to GH. "
        "Secreted by <b>Lactotropes</b>. Plasma half-life ~20 min.", ST_BODY))
    story.append(sp(4))

    prl_rows = [
        ["1. Lactation (main)", "Initiates and maintains milk synthesis (casein, lactalbumin) in mammary alveolar cells"],
        ["2. Mammary gland growth", "Promotes lobulo-alveolar development (synergistic with oestrogen + progesterone)"],
        ["3. Inhibits GnRH", "↑ PRL → suppresses GnRH → ↓ LH/FSH → suppresses ovulation → LACTATIONAL AMENORRHOEA"],
        ["4. Immunomodulation", "Immunostimulatory role; PRL receptors on lymphocytes"],
        ["5. Luteotrophic", "Maintains corpus luteum in some species (less important in humans)"],
    ]
    story.append(make_table(["Action", "Details"], prl_rows, [W*0.25, W*0.75]))
    story.append(sp(4))
    story.append(key_statement(
        '"PROLACTIN is the ONLY anterior pituitary hormone whose predominant hypothalamic control is '
        'INHIBITORY (via dopamine/PIH). Dopamine tonically suppresses prolactin secretion." — Indu Khurana'))
    story.append(sp(4))
    story.append(DrawingFlowable(draw_prolactin_regulation(), "Regulation of Prolactin Secretion (Suckling Reflex → ↓ Dopamine → ↑ PRL)"))
    story.append(sp(4))

    prl_reg_headers = ["Stimulators of PRL ↑", "Inhibitors of PRL ↓"]
    prl_reg_rows = [
        ["Suckling reflex — most potent physiological", "Dopamine / PIH — main (tonic inhibition)"],
        ["TRH (from hypothalamus)", "—"],
        ["Oestrogen", "—"],
        ["VIP (vasoactive intestinal peptide)", "—"],
        ["Stress (physical/emotional)", "—"],
        ["Hypothyroidism (↑TRH → ↑PRL)", "—"],
        ["Antipsychotics (block dopamine D2)", "—"],
    ]
    story.append(make_table(prl_reg_headers, prl_reg_rows, [W*0.5, W*0.5]))
    story.append(sp(4))
    story.append(clinical_box([
        "Hyperprolactinaemia → GALACTORRHOEA + AMENORRHOEA (in women); ↓ libido + erectile dysfunction (in men)",
        "Most common cause: PROLACTINOMA (most common secreting pituitary adenoma)",
        "Other causes: antipsychotics (chlorpromazine, haloperidol), metoclopramide, hypothyroidism, renal failure",
        "Treatment: DOPAMINE AGONISTS — Bromocriptine, Cabergoline (↓ PRL, shrink adenoma)",
    ]))
    story.append(sp(8))

    # ─── PAGE BREAK ──────────────────────────────────────────────
    story.append(PageBreak())

    # ─── 5. FSH AND LH ───────────────────────────────────────────
    story.append(section_heading("V.  GONADOTROPINS: FSH & LH"))
    story.append(sp(4))
    story.append(Paragraph(
        "<b>Chemical Nature:</b> Both are <b>glycoproteins</b> with a SHARED <b>α-subunit</b> "
        "(same as TSH and hCG) + unique <b>β-subunit</b> (confers biological specificity). "
        "Secreted by <b>Gonadotropes</b>.", ST_BODY))
    story.append(sp(4))

    story.append(subsection_heading("A. Actions of FSH and LH:"))
    story.append(sp(3))
    gon_headers = ["", "FSH", "LH"]
    gon_rows = [
        ["TARGET (Females)", "Granulosa cells of ovarian follicle", "Theca cells + corpus luteum"],
        ["ACTION (Females)", "Stimulates follicular development; ↑ aromatase → oestrogen synthesis", "LH surge triggers OVULATION; maintains corpus luteum → progesterone"],
        ["TARGET (Males)", "Sertoli cells (seminiferous tubules)", "Leydig cells (interstitial)"],
        ["ACTION (Males)", "Spermatogenesis (with testosterone); produces INHIBIN + ABP", "Testosterone synthesis (Leydig cells)"],
        ["Receptor", "FSH-R (Gs → ↑ cAMP)", "LH-R (Gs → ↑ cAMP → ↑ steroidogenesis)"],
    ]
    story.append(make_table(gon_headers, gon_rows, [W*0.18, W*0.41, W*0.41]))
    story.append(sp(4))

    story.append(subsection_heading("B. Regulation of FSH and LH:"))
    story.append(sp(3))
    story.append(DrawingFlowable(draw_gonadotropins(), "Regulation of Gonadotropins — FSH, LH and Negative/Positive Feedback"))
    story.append(sp(4))

    gon_reg_headers = ["Stimulators ↑", "Inhibitors ↓"]
    gon_reg_rows = [
        ["GnRH — pulsatile (main stimulator for both)", "Sex steroids: testosterone, oestrogen, progesterone"],
        ["Activins (from gonads)", "INHIBIN — selectively inhibits FSH only (not LH)"],
        ["Oestrogen: HIGH sustained level → (+) feedback → LH SURGE", "Continuous (non-pulsatile) GnRH → receptor downregulation → ↓ LH/FSH"],
        ["Kisspeptin → stimulates GnRH neurons", ""],
    ]
    story.append(make_table(gon_reg_headers, gon_reg_rows, [W*0.5, W*0.5]))
    story.append(sp(4))
    story.append(key_statement(
        '"GnRH must be secreted in a PULSATILE manner. Continuous GnRH causes paradoxical '
        'DOWNREGULATION of GnRH receptors → suppression of LH and FSH — this is exploited clinically '
        '(GnRH analogues for prostate cancer, endometriosis, precocious puberty)." — Indu Khurana'))
    story.append(sp(4))
    story.append(key_statement(
        '"INHIBIN (secreted by Sertoli cells in males and granulosa cells in females) SELECTIVELY '
        'INHIBITS FSH secretion without affecting LH — used as a marker of testicular/ovarian function."'))
    story.append(sp(8))

    # ─── PAGE BREAK ──────────────────────────────────────────────
    story.append(PageBreak())

    # ─── FEEDBACK LOOPS ──────────────────────────────────────────
    story.append(section_heading("VI.  FEEDBACK REGULATION — TYPES (Khurana Fig. VIII.1-2)"))
    story.append(sp(4))
    story.append(DrawingFlowable(draw_feedback_loops(), "Types of Feedback: Long-loop, Short-loop, Ultrashort-loop, and Positive feedback"))
    story.append(sp(6))

    fb_headers = ["Type", "Pathway", "Example"]
    fb_rows = [
        ["Long-loop (−)", "Target gland hormone → inhibits BOTH Hypothalamus + Anterior Pituitary",
         "Cortisol inhibits CRH (hypothalamus) + ACTH (pituitary)"],
        ["Short-loop (−)", "Anterior pituitary hormone → inhibits Hypothalamus",
         "GH inhibits GHRH secretion"],
        ["Ultrashort-loop (−)", "Hypothalamic hormone → inhibits its OWN secretion",
         "GHRH inhibits GHRH secretion"],
        ["Positive feedback (+)", "Target hormone stimulates more release (RARE)",
         "High sustained oestrogen → (+) → LH surge → ovulation"],
    ]
    story.append(make_table(fb_headers, fb_rows, [W*0.22, W*0.42, W*0.36]))
    story.append(sp(8))

    # ─── MASTER SUMMARY TABLE ────────────────────────────────────
    story.append(section_heading("VII.  MASTER SUMMARY TABLE (Khurana Table VIII.2-1 Style)"))
    story.append(sp(4))
    ms_headers = ["Hormone", "Cell/Nature", "Hypothalamic\nControl", "Main Actions", "Feedback\nInhibition", "Disorder\n(Excess / Deficiency)"]
    ms_rows = [
        ["GH\n(Somatotropin)", "Somatotrope\n191 AA polypeptide",
         "GHRH (+)\nGRIH (−)", "Linear growth (via IGF-1)\nLipolysis\n↑ Blood glucose\nProtein anabolism",
         "IGF-1 (long)\nGH (short)", "Excess: Gigantism /\nAcromegaly\nDeficiency: Dwarfism"],
        ["TSH\n(Thyrotropin)", "Thyrotrope\nGlycoprotein α+β",
         "TRH (+)\nSomatostatin (−)", "↑ T₃/T₄ synthesis\nThyroid hypertrophy\n↑ Vascularity",
         "T₃/T₄ (long)", "Excess: Hyperthyroidism\nDeficiency: Hypothyroidism"],
        ["ACTH\n(Corticotropin)", "Corticotrope\n39 AA from POMC",
         "CRH + AVP (+)\nCortisol (−)", "↑ Cortisol (main)\n↑ Adrenal androgens\nTrophic to adrenal\nSkin pigmentation",
         "Cortisol (long)", "Excess: Cushing's\nDeficiency: Addison's"],
        ["Prolactin\n(PRL)", "Lactotrope\n198 AA polypeptide",
         "Dopamine/PIH (−)\nTRH/PRH (+)", "Lactation (milk\nsynthesis)\nMammary growth\n↓ GnRH (amenorrhoea)",
         "Dopamine (not\ntarget hormone)", "Excess: Prolactinoma\n→ Galactorrhoea\n+ Amenorrhoea"],
        ["FSH", "Gonadotrope\nGlycoprotein α+β",
         "GnRH (+)\nInhibin (−)", "Folliculogenesis\nSpermatogenesis\nOestrogen (aromatase)",
         "Inhibin (specific)\nOestrogen", "Excess: —\nDeficiency:\nHypogonadism"],
        ["LH", "Gonadotrope\nGlycoprotein α+β",
         "GnRH (+)\nSex steroids (−)", "LH surge → Ovulation\nCorpus luteum\nTestosterone\n(Leydig cells)",
         "Testosterone\nOestrogen\nProgesterone", "Excess: PCOS\nDeficiency:\nHypogonadism"],
    ]
    story.append(make_table(ms_headers, ms_rows, [W*0.10, W*0.15, W*0.16, W*0.22, W*0.16, W*0.21]))
    story.append(sp(8))

    # ─── α-SUBUNIT TABLE ─────────────────────────────────────────
    story.append(section_heading("VIII.  GLYCOPROTEIN HORMONES — SHARED α-SUBUNIT"))
    story.append(sp(4))
    story.append(Paragraph(
        "TSH, FSH, LH, and hCG all share an <b>identical α-subunit</b>. "
        "Specificity is determined by their unique <b>β-subunit</b>. "
        "This is why hCG can mimic TSH/LH in certain tumours (e.g., hydatidiform mole).", ST_BODY))
    story.append(sp(4))
    alph_headers = ["Hormone", "Shared α-subunit", "Unique β-subunit", "Source", "Clinical relevance"]
    alph_rows = [
        ["TSH", "Yes ✓", "β-TSH", "Anterior pituitary (Thyrotropes)", "Stimulates thyroid"],
        ["FSH", "Yes ✓", "β-FSH", "Anterior pituitary (Gonadotropes)", "Folliculogenesis"],
        ["LH", "Yes ✓", "β-LH", "Anterior pituitary (Gonadotropes)", "Ovulation / Testosterone"],
        ["hCG", "Yes ✓", "β-hCG (unique, long half-life)", "Placental trophoblast", "Pregnancy test; can cross-react with TSH/LH receptors"],
    ]
    story.append(make_table(alph_headers, alph_rows, [W*0.10, W*0.14, W*0.18, W*0.26, W*0.32]))
    story.append(sp(8))

    # ─── PAGE BREAK ──────────────────────────────────────────────
    story.append(PageBreak())

    # ─── CLINICAL CORRELATIONS ───────────────────────────────────
    story.append(section_heading("IX.  IMPORTANT CLINICAL CORRELATIONS (Khurana Applied Boxes)"))
    story.append(sp(4))
    cc_headers = ["Condition", "Hormone Involved", "Mechanism", "Key Features"]
    cc_rows = [
        ["Gigantism", "↑ GH (pre-pubertal)", "↑ IGF-1 → linear bone growth (open epiphyses)", "Abnormally tall stature, large organs"],
        ["Acromegaly", "↑ GH (post-pubertal)", "↑ IGF-1 → periosteal bone growth (fused epiphyses)", "Coarse features, prognathism, spade hands, glucose intolerance"],
        ["Pituitary dwarfism", "↓ GH (childhood)", "↓ IGF-1 → ↓ linear bone growth", "Proportionate short stature, normal intelligence"],
        ["Cushing's disease", "↑ ACTH (pituitary adenoma)", "↑ CRH → ↑ ACTH → ↑ Cortisol", "Moon face, buffalo hump, purple striae, hypertension"],
        ["Addison's disease", "↓ Cortisol → ↑↑ ACTH", "Loss of adrenal tissue → ↑ MSH from POMC", "Hyperpigmentation, hypotension, hyponatraemia"],
        ["Nelson's syndrome", "↑↑ ACTH post-adrenalectomy", "No cortisol feedback → ACTH-secreting tumour", "Severe hyperpigmentation, visual field defects"],
        ["Prolactinoma", "↑ PRL", "Dopamine deficiency / tumour → ↑ PRL", "Galactorrhoea + amenorrhoea; treat with cabergoline"],
        ["Lactational amenorrhoea", "↑ PRL (physiological)", "↑ PRL → ↓ GnRH → ↓ LH/FSH → ↓ ovulation", "Post-partum contraception during breastfeeding"],
        ["Sheehan's syndrome", "All AP hormones ↓", "Post-partum pituitary infarction (hypotension)", "Panhypopituitarism, failure of lactation"],
    ]
    story.append(make_table(cc_headers, cc_rows, [W*0.18, W*0.17, W*0.32, W*0.33]))
    story.append(sp(8))

    # ─── VIVA QUESTIONS ──────────────────────────────────────────
    story.append(section_heading("X.  VIVA QUESTIONS (Khurana Self-Assessment Style)"))
    story.append(sp(4))

    vivas = [
        ("Q1. What are the hormones of the anterior pituitary?",
         "Six hormones: GH, TSH, ACTH (+ β-LPH from POMC), Prolactin, FSH, and LH."),
        ("Q2. Which anterior pituitary hormone is under predominantly INHIBITORY hypothalamic control?",
         "PROLACTIN — inhibited by dopamine (PIH). All others are predominantly stimulated."),
        ("Q3. Name the precursor of ACTH. What other hormones are derived from it?",
         "POMC (Pro-opiomelanocortin) → ACTH, β-LPH (which gives β-endorphin, γ-LPH), MSH, and CLIP."),
        ("Q4. Why does Addison's disease cause skin hyperpigmentation?",
         "↓ Cortisol → loss of negative feedback → ↑↑ ACTH production (from POMC). ACTH has MSH-like activity → stimulates melanocytes → hyperpigmentation."),
        ("Q5. Distinguish between gigantism and acromegaly.",
         "GIGANTISM: Excess GH before epiphyseal fusion (pre-pubertal) → tall stature. ACROMEGALY: Excess GH after epiphyseal fusion (post-pubertal) → coarse facial features, enlarged hands/feet, no increase in height."),
        ("Q6. Why does continuous GnRH suppress LH and FSH?",
         "Continuous (non-pulsatile) GnRH causes DOWNREGULATION (desensitisation) of GnRH receptors on gonadotropes → paradoxical suppression of LH/FSH. Clinical use: GnRH agonists for prostate cancer, endometriosis."),
        ("Q7. What is the role of inhibin?",
         "Inhibin (secreted by Sertoli cells in males, granulosa cells in females) SELECTIVELY inhibits FSH without affecting LH. Used as a marker of testicular/ovarian reserve."),
        ("Q8. Name the shared subunit among TSH, FSH, LH, and hCG.",
         "All share an identical α-subunit. Biological specificity is due to their UNIQUE β-subunit."),
        ("Q9. What causes lactational amenorrhoea?",
         "Suckling → afferent impulses → hypothalamus → ↓ Dopamine (PIH) + ↑ PRH → ↑ Prolactin → PRL inhibits GnRH → ↓ LH/FSH → suppressed ovulation (amenorrhoea)."),
        ("Q10. Describe the diurnal rhythm of ACTH.",
         "ACTH shows a circadian rhythm: PEAK at 6–8 AM (early morning), progressively falls during the day, TROUGH at midnight. Corresponds to cortisol rhythm. Disrupted in Cushing's syndrome."),
    ]

    for q, a in vivas:
        story.append(KeepTogether([
            Paragraph(q, ST_VIVA_Q),
            Paragraph(f"<b>Ans:</b> {a}", ST_VIVA_A),
            sp(2),
        ]))
    story.append(sp(8))

    # ─── QUICK REFERENCE CARD ────────────────────────────────────
    story.append(section_heading("XI.  QUICK REFERENCE — 10 KEY EXAM POINTS"))
    story.append(sp(4))
    key_points = [
        "The anterior pituitary secretes 6 hormones: GH, TSH, ACTH (+β-LPH), Prolactin, FSH, LH from 5 cell types.",
        "PROLACTIN is the ONLY AP hormone under DOMINANT INHIBITORY hypothalamic control (dopamine/PIH).",
        "ACTH is derived from POMC — explains MSH-like pigmentation in Addison's disease.",
        "GnRH must be PULSATILE — continuous GnRH → receptor downregulation → ↓ LH/FSH (clinical use).",
        "GH peaks during SLOW-WAVE (NREM Stages III–IV) sleep — most important physiological secretory pulse.",
        "ACTH shows diurnal rhythm — PEAK at 6–8 AM, TROUGH at midnight.",
        "The α-SUBUNIT is shared by TSH, FSH, LH, and hCG — specificity comes from the unique β-subunit.",
        "Three feedback loop types: LONG-LOOP (most common), SHORT-LOOP, and ULTRASHORT-LOOP.",
        "INHIBIN selectively inhibits FSH ONLY (not LH) — secreted by Sertoli/granulosa cells.",
        "Positive feedback (RARE) — High sustained oestrogen → (+) → LH surge → ovulation.",
    ]
    qr_data = [[
        Paragraph(f"<b>{i+1}.</b>  {pt}", ST_BODY)
    ] for i, pt in enumerate(key_points)]
    qr_table = Table(qr_data, colWidths=[W])
    qr_table.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), C_ACCENT),
        ('ROWBACKGROUNDS', (0,0), (-1,-1), [C_ACCENT, C_TABLE_ALT2]),
        ('BOX', (0,0), (-1,-1), 1, C_SUBHDR),
        ('LINEBELOW', (0,0), (-1,-2), 0.3, colors.lightgrey),
        ('TOPPADDING', (0,0), (-1,-1), 5),
        ('BOTTOMPADDING', (0,0), (-1,-1), 5),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
    ]))
    story.append(qr_table)
    story.append(sp(8))

    # Footer note
    story.append(hr())
    story.append(Paragraph(
        "<i>Based on: Indu Khurana — Textbook of Medical Physiology &amp; Concise Textbook of Physiology, "
        "Section VIII.2. Supplemented by Ganong's Review of Medical Physiology 26E, "
        "Costanzo Physiology 7E, and Harrison's Principles of Internal Medicine 22E.</i>",
        make_style('ref', fontSize=7.5, textColor=colors.grey, alignment=TA_CENTER)))

    doc.build(story, onFirstPage=on_page, onLaterPages=on_page)
    print(f"PDF generated: {path}")


if __name__ == '__main__':
    build_pdf('/tmp/workspace/pituitary-study-guide/Anterior_Pituitary_Study_Guide.pdf')

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/pituitary-study-guide/generate_pdf.py'