from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import mm, cm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import Flowable

OUTPUT = "/home/daytona/workspace/pituitary-study-guide/Pituitary_Study_Guide.pdf"

# ── colour palette ──────────────────────────────────────────────────────────
BLUE_DARK   = colors.HexColor("#1B3A6B")
BLUE_MID    = colors.HexColor("#2E6DB4")
BLUE_LIGHT  = colors.HexColor("#D6E8FA")
BLUE_PALE   = colors.HexColor("#EEF5FB")
TEAL        = colors.HexColor("#0D7C8C")
TEAL_LIGHT  = colors.HexColor("#D0F0F4")
ORANGE      = colors.HexColor("#D95F1A")
ORANGE_LIGHT= colors.HexColor("#FDE8D8")
GREEN       = colors.HexColor("#1A7A4A")
GREEN_LIGHT = colors.HexColor("#D5F0E3")
PURPLE      = colors.HexColor("#6B3A9E")
PURPLE_LIGHT= colors.HexColor("#EAD8FA")
GREY_DARK   = colors.HexColor("#333333")
GREY_MID    = colors.HexColor("#666666")
GREY_LIGHT  = colors.HexColor("#F2F2F2")
WHITE       = colors.white

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

def make_style(name, parent="Normal", **kw):
    s = ParagraphStyle(name, parent=styles[parent], **kw)
    return s

COVER_TITLE  = make_style("CoverTitle",  fontSize=30, textColor=WHITE,
                           alignment=TA_CENTER, leading=36, fontName="Helvetica-Bold")
COVER_SUB    = make_style("CoverSub",    fontSize=14, textColor=BLUE_LIGHT,
                           alignment=TA_CENTER, leading=20, fontName="Helvetica")
COVER_DETAIL = make_style("CoverDetail", fontSize=10, textColor=BLUE_LIGHT,
                           alignment=TA_CENTER, fontName="Helvetica")

H1 = make_style("H1", fontSize=15, textColor=WHITE, fontName="Helvetica-Bold",
                leading=20, spaceAfter=2, spaceBefore=4, alignment=TA_LEFT)
H2 = make_style("H2", fontSize=12, textColor=BLUE_DARK, fontName="Helvetica-Bold",
                leading=16, spaceAfter=3, spaceBefore=8)
H3 = make_style("H3", fontSize=10.5, textColor=TEAL, fontName="Helvetica-Bold",
                leading=14, spaceAfter=2, spaceBefore=5)

BODY  = make_style("Body",  fontSize=9.5, leading=14, textColor=GREY_DARK,
                   spaceAfter=3, alignment=TA_JUSTIFY)
SMALL = make_style("Small", fontSize=8.5, leading=12, textColor=GREY_MID)
BOLD  = make_style("Bold",  fontSize=9.5, leading=14, textColor=GREY_DARK,
                   fontName="Helvetica-Bold")
BULLET = make_style("Bullet", fontSize=9.5, leading=13, textColor=GREY_DARK,
                    leftIndent=14, spaceAfter=2)
CALLOUT = make_style("Callout", fontSize=9.5, leading=14, textColor=BLUE_DARK,
                     leftIndent=10, rightIndent=10, fontName="Helvetica-Oblique")
KEY_BOX = make_style("KeyBox", fontSize=9.5, leading=14, textColor=GREY_DARK,
                     leftIndent=8, rightIndent=8)

# ── helper flowables ─────────────────────────────────────────────────────────

class ColorRect(Flowable):
    """A filled colour rectangle used as a section-header background."""
    def __init__(self, width, height, fill_color, radius=4):
        Flowable.__init__(self)
        self.width  = width
        self.height = height
        self.fill   = fill_color
        self.radius = radius

    def draw(self):
        self.canv.setFillColor(self.fill)
        self.canv.roundRect(0, 0, self.width, self.height,
                            self.radius, stroke=0, fill=1)


def section_header(title, color=BLUE_DARK, width=165*mm):
    """Return a KeepTogether block that looks like a coloured header bar."""
    rect = ColorRect(width, 22, color, radius=4)
    # overlay text
    para = Paragraph(title, H1)
    # We stack rect + para via a 1-cell table trick
    tbl = Table([[para]], colWidths=[width])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",  (0,0), (-1,-1), color),
        ("ROUNDEDCORNERS", [4]),
        ("TOPPADDING",  (0,0), (-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING",(0,0),(-1,-1), 6),
        ("TEXTCOLOR",   (0,0), (-1,-1), WHITE),
    ]))
    return KeepTogether([Spacer(1, 4), tbl, Spacer(1, 4)])


def info_box(text, bg=BLUE_PALE, border=BLUE_MID, width=165*mm):
    tbl = Table([[Paragraph(text, CALLOUT)]], colWidths=[width])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), bg),
        ("BOX",          (0,0),(-1,-1), 1, border),
        ("TOPPADDING",   (0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 8),
        ("LEFTPADDING",  (0,0),(-1,-1), 10),
        ("RIGHTPADDING", (0,0),(-1,-1), 10),
    ]))
    return KeepTogether([tbl, Spacer(1, 6)])


def two_col_table(rows, col_widths, header_row=None, hdr_bg=BLUE_DARK,
                  alt_bg=BLUE_PALE, border=BLUE_MID):
    data = []
    if header_row:
        data.append(header_row)
    data.extend(rows)

    style = [
        ("FONTNAME",      (0,0),  (-1,-1), "Helvetica"),
        ("FONTSIZE",      (0,0),  (-1,-1), 8.5),
        ("LEADING",       (0,0),  (-1,-1), 12),
        ("TOPPADDING",    (0,0),  (-1,-1), 5),
        ("BOTTOMPADDING", (0,0),  (-1,-1), 5),
        ("LEFTPADDING",   (0,0),  (-1,-1), 7),
        ("RIGHTPADDING",  (0,0),  (-1,-1), 7),
        ("ROWBACKGROUNDS",(0,0),  (-1,-1), [WHITE, alt_bg]),
        ("INNERGRID",     (0,0),  (-1,-1), 0.3, colors.HexColor("#BBCFE0")),
        ("BOX",           (0,0),  (-1,-1), 0.8, border),
        ("VALIGN",        (0,0),  (-1,-1), "TOP"),
    ]
    if header_row:
        style += [
            ("BACKGROUND",  (0,0),  (-1,0), hdr_bg),
            ("TEXTCOLOR",   (0,0),  (-1,0), WHITE),
            ("FONTNAME",    (0,0),  (-1,0), "Helvetica-Bold"),
            ("FONTSIZE",    (0,0),  (-1,0), 9),
        ]

    tbl = Table(data, colWidths=col_widths, repeatRows=1 if header_row else 0)
    tbl.setStyle(TableStyle(style))
    return KeepTogether([tbl, Spacer(1, 8)])


def bp(text):
    return Paragraph(f"• {text}", BULLET)

def bold_p(label, text):
    return Paragraph(f"<b>{label}:</b> {text}", BODY)

# ── document ──────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=22*mm, rightMargin=22*mm,
    topMargin=20*mm,  bottomMargin=20*mm,
    title="Pituitary Gland Study Guide",
    author="Orris Medical",
    subject="Endocrine Physiology"
)

W = A4[0] - 44*mm   # usable width

story = []

# ═══════════════════════════════════════════════════════════════════════════════
# COVER PAGE
# ═══════════════════════════════════════════════════════════════════════════════
cover_tbl = Table(
    [[Paragraph("PITUITARY GLAND", COVER_TITLE)],
     [Spacer(1, 6)],
     [Paragraph("Complete Study Guide", COVER_SUB)],
     [Spacer(1, 10)],
     [Paragraph("Hormones · Regulation · Feedback Loops · Clinical Correlates", COVER_DETAIL)],
     [Spacer(1, 4)],
     [Paragraph("Sources: Guyton & Hall · Costanzo Physiology · Ganong's Review · Harrison's", COVER_DETAIL)],
    ],
    colWidths=[W]
)
cover_tbl.setStyle(TableStyle([
    ("BACKGROUND",   (0,0),(-1,-1), BLUE_DARK),
    ("TOPPADDING",   (0,0),(-1,-1), 18),
    ("BOTTOMPADDING",(0,0),(-1,-1), 18),
    ("LEFTPADDING",  (0,0),(-1,-1), 20),
    ("RIGHTPADDING", (0,0),(-1,-1), 20),
    ("ROUNDEDCORNERS", [8]),
]))
story.append(Spacer(1, 40))
story.append(cover_tbl)
story.append(Spacer(1, 20))

# quick overview box
overview_text = (
    "The pituitary gland (hypophysis) is a pea-sized master endocrine gland seated in the "
    "<b>sella turcica</b> of the sphenoid bone, connected to the hypothalamus via the "
    "<b>infundibulum</b>. It integrates neural and hormonal signals to orchestrate growth, "
    "metabolism, reproduction, water balance, and stress responses throughout the body."
)
story.append(info_box(overview_text, bg=BLUE_PALE, border=BLUE_MID))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 1 – ANATOMY & TWO LOBES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("1.  Anatomy & Structural Overview", BLUE_DARK))
story.append(Spacer(1,4))

anatomy_rows = [
    ["Feature", "Anterior Pituitary (Adenohypophysis)", "Posterior Pituitary (Neurohypophysis)"],
    ["Embryological origin", "Rathke's pouch (oral ectoderm)", "Downgrowth of diencephalon (neural tissue)"],
    ["Tissue type", "Glandular epithelium (5 cell types)", "Neural tissue (pituicytes + axon terminals)"],
    ["Hypothalamic link", "Portal blood vessels (endocrine)", "Hypothalamo-hypophyseal axon tract (neural)"],
    ["Hormones", "GH, PRL, TSH, ACTH, FSH, LH", "ADH (vasopressin), Oxytocin"],
    ["Blood supply", "Mostly venous from hypothalamus via portal vessels", "Inferior hypophyseal arteries"],
    ["Size / weight", "~0.5 g males; up to 1.5 g multiparous females", "Smaller component of whole gland"],
]
story.append(two_col_table(
    anatomy_rows[1:], [38*mm, 64*mm, 63*mm],
    header_row=anatomy_rows[0], hdr_bg=BLUE_DARK, alt_bg=BLUE_PALE
))

story.append(Paragraph("Key anatomical points:", H3))
for pt in [
    "The anterior pituitary receives <b>mainly venous blood</b> from the hypothalamus – it is the only organ whose primary supply is portal blood, enabling high concentrations of hypothalamic hormones to reach it without dilution into the systemic circulation.",
    "The posterior pituitary does <b>not synthesise</b> hormones; it stores and releases hormones synthesised in hypothalamic nuclei.",
    "Cutting the pituitary stalk above the gland does <b>not</b> permanently abolish posterior pituitary hormone secretion – the hormone-producing neurons simply discharge from the cut axon ends within the hypothalamus.",
]:
    story.append(bp(pt))

story.append(Spacer(1, 8))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 2 – HYPOTHALAMIC CONTROL
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("2.  Hypothalamic Control of the Pituitary", TEAL))
story.append(Spacer(1,4))

story.append(Paragraph("2a. Posterior Pituitary – Neural Control", H2))
story.append(Paragraph(
    "ADH and oxytocin are synthesised in hypothalamic neuron cell bodies, packaged with "
    "carrier proteins called <b>neurophysins</b>, transported down axons of the "
    "<b>hypothalamo-neurohypophyseal tract</b>, and stored in bulbous nerve terminals "
    "in the posterior lobe. Membrane depolarisation triggers <b>exocytosis</b> directly "
    "into fenestrated capillaries. The relationship is purely neural.",
    BODY))
story.append(Spacer(1,6))

story.append(Paragraph("2b. Anterior Pituitary – Hypophysiotropic Hormones", H2))
story.append(Paragraph(
    "Specialised hypothalamic neurons (in the median eminence) secrete releasing or "
    "inhibiting hormones into the <b>primary capillary plexus</b>. This blood drains "
    "into <b>long and short hypophyseal portal vessels</b> and is delivered at high "
    "concentration to the anterior pituitary cells – the sole targets of these hormones.",
    BODY))
story.append(Spacer(1,4))

hypo_rows = [
    ["Hypothalamic Hormone", "Abbrev.", "Cell body location", "Action on Anterior Pituitary"],
    ["Corticotropin-releasing hormone", "CRH", "Medial paraventricular nucleus", "Stimulates ACTH & β-LPH"],
    ["Thyrotropin-releasing hormone", "TRH", "Medial paraventricular nucleus", "Stimulates TSH & Prolactin"],
    ["Growth hormone-releasing hormone", "GHRH", "Arcuate nucleus", "Stimulates GH"],
    ["Somatostatin (GH-inhibiting hormone)", "GHIH / SRIF", "Periventricular nucleus", "Inhibits GH and TSH"],
    ["Gonadotropin-releasing hormone", "GnRH", "Medial preoptic area", "Stimulates FSH & LH"],
    ["Dopamine (prolactin-inhibiting factor)", "PIF / DA", "Arcuate nucleus", "Inhibits Prolactin (tonic)"],
    ["Prolactin-releasing factor (e.g. TRH)", "PRF", "Various", "Stimulates Prolactin"],
]
story.append(two_col_table(
    hypo_rows[1:], [52*mm, 22*mm, 48*mm, 43*mm],
    header_row=hypo_rows[0], hdr_bg=TEAL, alt_bg=TEAL_LIGHT
))

story.append(info_box(
    "<b>Key point:</b> Prolactin is the <i>only</i> anterior pituitary hormone under "
    "predominant <b>inhibitory</b> hypothalamic control (tonic dopamine suppression). "
    "Cutting the pituitary stalk therefore <i>increases</i> prolactin secretion while "
    "decreasing all other anterior pituitary hormones.",
    bg=ORANGE_LIGHT, border=ORANGE
))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 3 – ANTERIOR PITUITARY HORMONES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("3.  Anterior Pituitary Hormones", BLUE_MID))
story.append(Spacer(1,4))

ap_rows = [
    ["Hormone", "Cell Type", "Staining", "Structure", "Hypothalamic Control", "Key Effects"],
    ["Growth Hormone\n(GH / Somatotropin)",
     "Somatotrophs\n(50% of AP cells)", "Acidophilic",
     "191 aa single-chain polypeptide",
     "GHRH (+)\nSomatostatin (−)\nIGF-1 negative FB",
     "Linear bone growth via IGF-1; protein anabolism; lipolysis; anti-insulin on glucose"],
    ["Prolactin\n(PRL)",
     "Lactotrophs", "Acidophilic",
     "Polypeptide (198 aa)",
     "Dopamine (−) [primary]\nTRH (+)\nSuckling (+)",
     "Initiates & maintains lactation; suppresses GnRH → lactational amenorrhoea"],
    ["TSH\n(Thyrotropin)",
     "Thyrotrophs", "Basophilic",
     "Glycoprotein (α+β subunits)",
     "TRH (+)\nT3/T4 (−)\nSomatostatin (−)",
     "Stimulates T3 & T4 synthesis and secretion; promotes thyroid growth"],
    ["ACTH\n(Corticotropin)",
     "Corticotrophs", "Basophilic",
     "Derived from POMC (39 aa)",
     "CRH (+)\nCortisol (−)\nDiurnal rhythm",
     "Stimulates cortisol, aldosterone, sex hormones from adrenal cortex; adrenocortical growth"],
    ["FSH",
     "Gonadotrophs", "Basophilic",
     "Glycoprotein (α+β subunits)",
     "GnRH (+) pulsatile\nInhibin (−)\nEstradiol (−)",
     "Females: follicle growth, oestrogen. Males: spermatogenesis, Sertoli cell support"],
    ["LH\n(Luteinising Hormone)",
     "Gonadotrophs", "Basophilic",
     "Glycoprotein (α+β subunits)",
     "GnRH (+) pulsatile\nEstradiol + FB (surge)\nTestosterone (−)",
     "Females: ovulation, corpus luteum, progesterone. Males: testosterone (Leydig cells)"],
]
story.append(two_col_table(
    ap_rows[1:],
    [28*mm, 22*mm, 16*mm, 30*mm, 32*mm, 37*mm],
    header_row=ap_rows[0], hdr_bg=BLUE_MID, alt_bg=BLUE_PALE
))

# GH subsection
story.append(KeepTogether([
    Paragraph("Growth Hormone – Detailed Regulation", H3),
    bold_p("Stimulated by", "GHRH, deep sleep (SWS), exercise, fasting, hypoglycaemia, stress, amino acids (arginine)"),
    bold_p("Inhibited by", "Somatostatin, IGF-1 (long-loop feedback), hyperglycaemia, obesity, free fatty acids"),
    bold_p("Pulsatile secretion", "Peak secretion ~1 hour after sleep onset (SWS); multiple smaller pulses during day"),
    bold_p("Mechanism", "Acts on liver to produce IGF-1 (somatomedin-C). Direct effects: lipolysis, protein synthesis. Indirect: IGF-1 drives chondrocyte proliferation at epiphyseal plates"),
    Spacer(1, 4)
]))

# Prolactin subsection
story.append(KeepTogether([
    Paragraph("Prolactin – Unique Features", H3),
    bold_p("Tonic inhibition", "Dopamine from arcuate nucleus travels via portal blood → D2 receptors on lactotrophs → inhibits PRL"),
    bold_p("Suckling reflex", "Tactile signals from nipple → inhibit dopamine release → PRL rises acutely"),
    bold_p("Oestrogen effect", "Increases PRL gene expression and lactotroph proliferation (explains pituitary enlargement in pregnancy)"),
    bold_p("Lactational amenorrhoea", "High PRL inhibits hypothalamic GnRH pulsatility → anovulation"),
    Spacer(1, 4)
]))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 4 – POSTERIOR PITUITARY HORMONES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("4.  Posterior Pituitary Hormones", PURPLE))
story.append(Spacer(1,4))

post_rows = [
    ["Feature", "ADH (Vasopressin)", "Oxytocin"],
    ["Structure", "9 aa nonapeptide: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂", "9 aa nonapeptide: Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH₂"],
    ["Primary synthesis", "Supraoptic nucleus", "Paraventricular nucleus"],
    ["Carrier protein", "Neurophysin II", "Neurophysin I"],
    ["Stimulated by", "↑ plasma osmolality, hypovolaemia, hypotension, pain, nausea, angiotensin II", "Cervical/vaginal distension (Ferguson reflex), suckling, oestrogens"],
    ["Inhibited by", "↓ osmolality, hypervolaemia, alcohol, ANP", "Progesterone, fear"],
    ["Main effects", "↑ water reabsorption in collecting duct (V2/aquaporin-2);\nvasoconstriction at high doses (V1)", "Uterine contraction during labour; milk ejection (myoepithelial cells); social bonding"],
    ["Clinical deficiency", "Diabetes insipidus (polyuria, polydipsia, dilute urine)", "Prolonged/dysfunctional labour; failure of milk let-down"],
    ["Clinical excess", "SIADH – hyponatraemia, concentrated urine", "Rare; uterine hyperstimulation with exogenous use"],
]
story.append(two_col_table(
    post_rows[1:], [38*mm, 64*mm, 63*mm],
    header_row=post_rows[0], hdr_bg=PURPLE, alt_bg=PURPLE_LIGHT
))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 5 – FEEDBACK REGULATION
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("5.  Feedback Regulation of Pituitary Secretion", ORANGE))
story.append(Spacer(1,4))

story.append(Paragraph("Three-Tier Regulatory System", H2))
for tier in [
    ("<b>Tier I – Hypothalamic control:</b>", "Releasing/inhibiting hormones delivered via portal blood. This is the primary driving signal."),
    ("<b>Tier II – Paracrine/autocrine:</b>", "Cytokines and growth factors produced by pituitary cells themselves modulate local secretion."),
    ("<b>Tier III – Circulating hormone feedback:</b>", "Target gland hormones feed back on the hypothalamus and/or anterior pituitary. This is the dominant homeostatic mechanism."),
]:
    story.append(Paragraph(f"{tier[0]} {tier[1]}", BODY))

story.append(Spacer(1, 6))
story.append(Paragraph("Types of Negative Feedback", H2))

fb_rows = [
    ["Loop Type", "Description", "Example"],
    ["Long-loop\n(negative)", "Peripheral hormone feeds back to BOTH hypothalamus and anterior pituitary to inhibit secretion", "Cortisol inhibits CRH (hypothalamus) and ACTH (anterior pituitary)"],
    ["Short-loop\n(negative)", "Anterior pituitary hormone feeds back on hypothalamus to inhibit its releasing hormone", "GH feeds back to suppress GHRH; ACTH suppresses CRH"],
    ["Ultrashort-loop\n(negative)", "Hypothalamic hormone inhibits its own secretion", "GHRH inhibits its own release from arcuate neurons"],
    ["Positive feedback\n(rare)", "Peripheral hormone stimulates MORE secretion – self-amplifying, leads to explosive response", "Rising oestradiol in mid-cycle triggers the preovulatory LH surge → ovulation"],
]
story.append(two_col_table(
    fb_rows[1:], [30*mm, 72*mm, 63*mm],
    header_row=fb_rows[0], hdr_bg=ORANGE, alt_bg=ORANGE_LIGHT
))

story.append(Paragraph("Axis-by-Axis Feedback Summary", H2))
axes = [
    ("HPT Axis  (Hypothalamus → Pituitary → Thyroid)",
     TEAL, TEAL_LIGHT,
     ["TRH (hypothalamus) → TSH (anterior pituitary) → T3/T4 (thyroid)",
      "T3/T4 feeds back (−) on both hypothalamus (↓TRH) and pituitary (↓TSH)",
      "T3 is the biologically active form; T4 is deiodinated to T3 in target tissues",
      "Somatostatin provides additional (−) input to TSH secretion"]),
    ("HPA Axis  (Hypothalamus → Pituitary → Adrenal)",
     colors.HexColor("#8B2020"), colors.HexColor("#FAE0E0"),
     ["CRH (hypothalamus) → ACTH (anterior pituitary) → Cortisol (adrenal cortex)",
      "Cortisol feeds back (−) on both hypothalamus and pituitary",
      "ACTH has a marked diurnal rhythm – peaks 6-8 AM, nadir around midnight",
      "Stress overrides negative feedback: CRH rises acutely despite high cortisol",
      "ACTH derived from POMC precursor; same precursor yields MSH and β-endorphin"]),
    ("HPG Axis  (Hypothalamus → Pituitary → Gonads)",
     GREEN, GREEN_LIGHT,
     ["GnRH (pulsatile!) → FSH & LH → sex steroids + inhibin",
      "Testosterone (males) and oestrogen/progesterone (females) provide (−) long-loop FB",
      "Inhibin B (from Sertoli/granulosa cells) selectively inhibits FSH – NOT LH",
      "Mid-cycle oestradiol surge triggers (+) feedback → LH surge → ovulation",
      "Continuous (non-pulsatile) GnRH PARADOXICALLY suppresses gonadotropins – exploited in GnRH agonist therapy for prostate cancer/endometriosis"]),
    ("GH Axis  (Hypothalamus → Pituitary → Liver)",
     BLUE_MID, BLUE_PALE,
     ["GHRH (+) and Somatostatin (−) regulate GH pulsatile release",
      "GH stimulates IGF-1 production in liver",
      "IGF-1 feeds back (−) on both hypothalamus (↑SS, ↓GHRH) and pituitary (↓GH)",
      "GH itself feeds back (ultrashort/short) to stimulate somatostatin and reduce own secretion",
      "Ghrelin (from stomach) is a potent GH secretagogue acting on pituitary GHS-R"]),
]

for title, hdr_color, row_color, bullets in axes:
    story.append(KeepTogether([
        Paragraph(title, H3),
        *[bp(b) for b in bullets],
        Spacer(1, 5)
    ]))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 6 – RECEPTOR MECHANISMS
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("6.  Receptor & Signal Transduction Mechanisms", BLUE_DARK))
story.append(Spacer(1,4))

rx_rows = [
    ["Hormone", "Receptor Type", "Second Messenger / Pathway", "Key Kinase / Effect"],
    ["GH", "Tyrosine kinase-associated (JAK2)", "JAK-STAT pathway", "STAT5b → IGF-1 gene transcription"],
    ["Prolactin", "Tyrosine kinase-associated (JAK2)", "JAK-STAT pathway (STAT5a/b)", "Milk protein gene transcription"],
    ["TSH", "GPCR (Gs)", "cAMP → PKA", "Thyroid hormone synthesis enzymes"],
    ["ACTH", "GPCR (Gs)", "cAMP → PKA", "StAR protein → steroidogenesis"],
    ["FSH", "GPCR (Gs)", "cAMP → PKA", "Aromatase; inhibin; spermatogenesis genes"],
    ["LH", "GPCR (Gs)", "cAMP → PKA (+IP3/Ca²⁺ at high doses)", "StAR protein → steroidogenesis"],
    ["ADH (V2)", "GPCR (Gs)", "cAMP → PKA", "Aquaporin-2 insertion into collecting duct"],
    ["ADH (V1)", "GPCR (Gq)", "IP3/DAG → PKC → ↑Ca²⁺", "Vascular smooth muscle contraction"],
    ["Oxytocin", "GPCR (Gq)", "IP3/DAG → PKC → ↑Ca²⁺", "Myometrial contraction; milk ejection"],
    ["GnRH", "GPCR (Gq)", "IP3/DAG → PKC → ↑Ca²⁺", "Gonadotropin gene expression & exocytosis"],
    ["CRH", "GPCR (Gs)", "cAMP → PKA", "POMC transcription; ACTH exocytosis"],
    ["GHRH", "GPCR (Gs)", "cAMP → PKA", "GH gene transcription; exocytosis"],
    ["Somatostatin", "GPCR (Gi)", "↓cAMP; ↓Ca²⁺ channels", "Inhibits GH and TSH secretion"],
]
story.append(two_col_table(
    rx_rows[1:], [30*mm, 40*mm, 46*mm, 49*mm],
    header_row=rx_rows[0], hdr_bg=BLUE_DARK, alt_bg=BLUE_PALE
))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 7 – CLINICAL CORRELATES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("7.  Clinical Correlates – Hypo/Hypersecretion", colors.HexColor("#5A3B0A")))
story.append(Spacer(1,4))

clin_rows = [
    ["Hormone", "Hyposecretion (Deficiency)", "Hypersecretion (Excess)"],
    ["GH\n(children)", "Growth hormone deficiency → short stature, hypoglycaemia", "Gigantism (open epiphyses) → excessive linear growth"],
    ["GH\n(adults)", "Reduced muscle mass, ↑ fat, poor QoL", "Acromegaly → enlarged hands/feet/jaw, glucose intolerance, cardiomegaly"],
    ["Prolactin", "Failure of lactation post-partum", "Prolactinoma: galactorrhoea, amenorrhoea, infertility, hypogonadism"],
    ["TSH", "Secondary hypothyroidism (↓TSH → ↓T3/T4)", "Secondary hyperthyroidism (rare TSH-secreting adenoma)"],
    ["ACTH", "Secondary adrenal insufficiency: weakness, hypoglycaemia, hyponatraemia", "Cushing's disease: central obesity, striae, hypertension, hyperglycaemia"],
    ["FSH/LH", "Hypogonadotropic hypogonadism: infertility, ↓sex steroids, amenorrhoea", "Precocious puberty (rare gonadotropin-secreting tumour)"],
    ["ADH", "Diabetes insipidus: polyuria, polydipsia, hypernatraemia, dilute urine", "SIADH: hyponatraemia, concentrated urine, neurological symptoms"],
    ["Oxytocin", "Prolonged labour; impaired milk letdown", "Mainly occurs with exogenous use → uterine hyperstimulation"],
    ["Pan-hypopituitarism", "Loss of ALL anterior pituitary hormones (e.g. Sheehan's syndrome post-partum haemorrhage)", "—"],
]
story.append(two_col_table(
    clin_rows[1:], [28*mm, 67*mm, 70*mm],
    header_row=clin_rows[0], hdr_bg=colors.HexColor("#5A3B0A"), alt_bg=colors.HexColor("#FEF6E8")
))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 8 – QUICK REFERENCE / MNEMONICS
# ═══════════════════════════════════════════════════════════════════════════════
story.append(section_header("8.  Quick Reference & Memory Aids", GREEN))
story.append(Spacer(1,4))

story.append(Paragraph("Anterior Pituitary Hormones – Mnemonic: <b>FLAT PiG</b>", H2))
for item in [
    "<b>F</b>SH – follicle-stimulating hormone",
    "<b>L</b>H – luteinising hormone",
    "<b>A</b>CTH – adrenocorticotrophic hormone",
    "<b>T</b>SH – thyroid-stimulating hormone",
    "<b>P</b>rolactin",
    "<b>i</b> – (in = and)",
    "<b>G</b>H – growth hormone",
]:
    story.append(bp(item))

story.append(Spacer(1, 8))
story.append(Paragraph("Acidophilic vs. Basophilic Cells – Mnemonic: <b>GPA / FLAT</b>", H2))
for item in [
    "<b>Acidophilic:</b> GH (G), Prolactin (P) — remember: 'GraPe' for Growth & Prolactin = Acid",
    "<b>Basophilic:</b> FSH, LH, ACTH, TSH (FLAT) — all the trophic hormones",
]:
    story.append(bp(item))

story.append(Spacer(1, 8))
story.append(Paragraph("Posterior Pituitary – Key Distinction", H2))
story.append(info_box(
    "The posterior pituitary is a <b>storage and release</b> site only. "
    "ADH and oxytocin are synthesised in the <b>hypothalamus</b> "
    "(supraoptic and paraventricular nuclei), transported down axons as "
    "neurophysin complexes, and released by exocytosis on nerve stimulation.",
    bg=PURPLE_LIGHT, border=PURPLE
))

story.append(Paragraph("Feedback Rules Summary", H2))
feedback_summary = [
    ["Rule", "Detail"],
    ["Negative feedback is the norm", "Most axes: high peripheral hormone → inhibits hypothalamus + pituitary → reduces own secretion"],
    ["Prolactin exception", "Unique – predominantly inhibited (NOT stimulated) by hypothalamus via dopamine"],
    ["GnRH must be pulsatile", "Continuous GnRH → receptor downregulation → paradoxical suppression of FSH/LH"],
    ["Positive feedback is rare", "Oestradiol surge mid-cycle → LH surge → ovulation (self-amplifying)"],
    ["Diurnal rhythms", "ACTH/cortisol peak at 6–8 AM. GH peaks in early SWS. Melatonin inhibits GnRH nocturnally"],
    ["Inhibin is FSH-specific", "Inhibin B selectively suppresses FSH; does NOT suppress LH"],
]
story.append(two_col_table(
    feedback_summary[1:], [55*mm, 110*mm],
    header_row=feedback_summary[0], hdr_bg=GREEN, alt_bg=GREEN_LIGHT
))

# ═══════════════════════════════════════════════════════════════════════════════
# REFERENCES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Spacer(1, 6))
story.append(HRFlowable(width=W, thickness=0.5, color=GREY_MID))
story.append(Spacer(1, 4))
story.append(Paragraph("Sources", H2))
for ref in [
    "Guyton AC, Hall JE. <i>Textbook of Medical Physiology</i>, 14th ed.",
    "Costanzo LS. <i>Physiology</i>, 7th ed. Chapter 9: Endocrinology.",
    "Ganong WF. <i>Review of Medical Physiology</i>, 26th ed. Chapter 17.",
    "Ross MH, Pawlina W. <i>Histology: A Text and Atlas</i>, 8th ed. Chapter 21.",
    "Longo DL et al. <i>Harrison's Principles of Internal Medicine</i>, 22nd ed.",
    "Katzung BG. <i>Basic and Clinical Pharmacology</i>, 16th ed. Chapter 37.",
]:
    story.append(Paragraph(f"• {ref}", SMALL))

story.append(Spacer(1, 6))
story.append(Paragraph(
    "Study guide compiled by Orris Medical AI  |  June 2026",
    make_style("Footer", fontSize=8, textColor=GREY_MID, alignment=TA_CENTER)
))

# ── build ─────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF created: {OUTPUT}")