Hormonal Regulation of the Female Reproductive System, the Menstrual Cycle, and the Gynecologic Examination

PART I: NEUROENDOCRINOLOGY — HORMONAL REGULATION

The HPO Axis: The Big Picture

FIGURE 7-3: Hypothalamic secretory products control the endocrine function of the ovaries, thyroid, and adrenal glands — Berek & Novak's Gynecology

1. The Hypothalamus

• Periventricular (adjacent to the 3rd ventricle)
• Medial (primarily cell bodies)
• Lateral (primarily axonal)

Major Hypothalamic Secretory Products:

Feedback Loops:

• Long-loop: Circulating sex steroids (estrogen, androgens) feed back onto hypothalamic steroid receptors
• Short-loop: Pituitary hormones feed back to the hypothalamus
• Ultrashort-loop: Hypothalamic secretions feed back onto the hypothalamus itself

2. GnRH — The Master Regulator

FIGURE 7-4: GnRH is a decapeptide — Berek & Novak's Gynecology

• Must be secreted in a pulsatile fashion to be effective — continuous infusion leads to gonadotroph downregulation (decreased surface GnRH receptors) and suppression of LH/FSH
• Intermittent exposure upregulates ("autoprimes") GnRH receptors on pituitary gonadotrophs
• Half-life is only 2–4 minutes (rapid proteolytic cleavage)
• The GnRH gene produces a 92-amino-acid precursor that also encodes GnRH-Associated Peptide (GAP) — a prolactin inhibitor and gonadotropin stimulator

• Follicular phase: frequent, small-amplitude pulses
• Late follicular phase: increased frequency and amplitude
• Luteal phase: progressive lengthening of pulse intervals; higher amplitude but declining over 2 weeks
• Decreasing GnRH pulse frequency → ↓ LH but ↑ FSH (important for late-luteal FSH rise)

3. Anterior Pituitary — Gonadotropins (LH and FSH)

• Recruits a cohort of primordial follicles
• Stimulates granulosa cell proliferation and aromatase activity
• Drives estrogen synthesis in growing follicles
• Suppressed by rising estradiol and inhibin B

• Acts on theca cells to produce androgens (substrate for estrogen synthesis via two-cell theory)
• LH surge (triggered by high estradiol levels) → ovulation 24–36 hours later
• Maintains corpus luteum and drives progesterone production

• Prolactin: Secreted by lactotrophs; elevated prolactin suppresses GnRH pulsatility and causes anovulation. Regulated by dopamine (inhibitory) from the hypothalamus
• GH: Secreted in pulses during sleep; plays a role in ovarian function and follicular responsiveness
• ACTH: Controls adrenal glucocorticoids; diurnal variation with AM peak

4. Posterior Pituitary

• 9-amino-acid peptide produced by the paraventricular nucleus
• Functions: (1) stimulates uterine contractions during parturition, (2) triggers milk letdown (lactiferious duct myoepithelial contraction) via nipple stimulation → thoracic nerves → spinal cord → hypothalamus

• Controls water reabsorption; also linked (in animal models) to sexual activity, learning, temperature regulation, and maternal behavior
• Receptor variants linked to autistic spectrum disorders and altruistic behavior

PART II: THE MENSTRUAL CYCLE

Normal Menstrual Cycle — Overview

• Ovarian cycle: Follicular phase + Luteal phase
• Uterine cycle: Proliferative phase + Secretory phase

• Cycle length: 21–35 days
• Duration of flow: 2–6 days
• Average blood loss: 20–60 mL
• Follicular phase: 10–14 days (source of most cycle-length variability)
• Luteal phase: consistently ~14 days

FIGURE 7-9: Cyclic changes in hormone levels and endometrial histology over a 28-day cycle — Berek & Novak's Gynecology

Sequential Hormonal Events of the Menstrual Cycle

Cyclic Changes of the Endometrium

• Proliferative phase (corresponds to follicular phase): Estrogen drives glandular and stromal proliferation
• Secretory phase (corresponds to luteal phase): Progesterone transforms endometrium into a receptive state for implantation — glands become tortuous, stromal edema, glycogen accumulates
• Menstruation: Withdrawal of estrogen and progesterone → endometrial shedding

Ovarian Follicular Development (Folliculogenesis)

• Theca cells (LH-driven) → androgens (androstenedione, testosterone)
• Granulosa cells (FSH-driven) → aromatize androgens → estradiol

Luteal Phase

PART III: THE GYNECOLOGIC EXAMINATION (per Berek & Novak)

Approach to the Patient

• Non-judgmental communication regarding sexual practices, gender identity, and orientation
• Empathy, attentive listening, and rapport are foundational skills
• Confidentiality is essential for honest disclosure
• Inform the patient of findings immediately after the examination (with patient clothed)

A. History

1. Chief complaint and history of present illness
2. Menstrual history: cycle length, duration, flow, last menstrual period (LMP), menarche
3. Obstetric history: gravida, para, complications
4. Medical and surgical history
5. Medications (including OTC and complementary/alternative)
6. Family history
7. Social history: tobacco, alcohol, recreational drugs, sexual activity, STI exposure, occupation

Technique for present illness (Table 1-5): Use open-ended then directed questions; avoid leading questions; establish negative symptoms to confirm or exclude diagnoses; assess psychosocial response to illness.

B. Physical Examination

1. General/Abdominal Examination

• Palpate all four quadrants systematically (e.g., clockwise from right upper quadrant)
• Assess for organomegaly (liver, spleen) — auscultate before palpation if organomegaly suspected
• Evaluate for mass effect, omental involvement ("omental cake" in ovarian cancer)
• Assess for rebound tenderness (peritoneal irritation) if acute pain is present

2. Inspection of External Genitalia

• Inspect labia majora, labia minora, clitoris, urethral meatus, introitus, and perineum
• Note skin lesions, pigmentation, edema, atrophy
• Ask patient to bear down (Valsalva): assess for cystocele (anterior wall bulge) or rectocele/enterocele (posterior wall bulge)

3. Speculum Examination (Vagina and Cervix)

• Inspection always precedes palpation
• Warm with tap water; do not lubricate if obtaining Pap smear or cultures
• Insert with blades oblique → rotate to horizontal → open blades to expose cervix

• Presence of blood or discharge (culture for gonorrhea, chlamydia; wet prep for trichomonas, BV, candida)
• Mucosal characteristics: color, lesions, vascularity
• Lesion types: inflammatory, neoplastic, vascular, pigmented (Chadwick sign in pregnancy), endometriotic
• Structural abnormalities (congenital and acquired)

• Unusual bleeding from the os → evaluate for neoplasia
• Mucopurulent discharge → cervicitis
• Polyps (surface or endocervical)
• Carcinoma: may mimic inflammation → biopsy for any suspicious lesion

4. Bimanual Pelvic Examination (Table 1-6)

1. Uterus: Evaluate position, size, shape, symmetry, consistency, tenderness, and mobility; note any masses
2. Cervix: Assess position, consistency, tenderness, and cervical motion tenderness (CMT) — rebound tenderness
3. Adnexa (bilateral):
   • Vaginal fingers in lateral fornix + abdominal hand on ipsilateral lower quadrant
   • A normal fallopian tube is not palpable
   • Normal ovary (~4 × 2 × 3 cm): sensitive, firm, freely movable — often not palpable
   • Any adnexal mass: characterize by location, size, consistency, tenderness, mobility

5. Rectovaginal-Abdominal Examination

• Index finger in vagina + middle finger in rectum + abdominal hand
• Allows higher pelvic exploration (beyond the cul-de-sac limit)
• Used to assess: posterior uterine wall, uterosacral ligaments, posterior cul-de-sac, rectum

6. Rectal Examination

• Inspect perianal/pilonidal/perineal region: color, fissures, fistulae, hemorrhoids
• Ask patient to strain — reveals hidden internal hemorrhoids, polyps, or rectal prolapse
• Palpate with lubricated index finger:
  • Note rectal tone, masses, tenderness
  • Assess posterior cervix and uterus
  • Stool on gloved finger: test for occult blood

Special Populations:

• Adolescents: Pelvic exam not routinely required for healthy teens requesting OCP before initiating intercourse
• Patients with intact hymen: Use rectal-abdominal (rather than bimanual vaginal) technique
• Slender, elderly, or adolescent patients: Single-finger vaginal technique preferred

Summary: Key Teaching Points

Part I — Hormonal Regulation

• The HPO axis (hypothalamus → pituitary → ovary → uterus)
• Hypothalamic anatomy and nuclei (arcuate, supraoptic, paraventricular)
• GnRH: decapeptide structure, pulsatile secretion rules, downregulation vs. upregulation, feedback loops (long/short/ultrashort)
• Anterior pituitary: FSH, LH, prolactin, GH, ACTH roles
• Posterior pituitary: oxytocin (parturition, milk letdown) and vasopressin

Part II — Menstrual Cycle

• Normal parameters (21–35 days, 2–6 days flow, 20–60 mL blood loss)
• 8-step sequential hormonal events from follicular through luteal phase
• Endometrial changes (proliferative vs. secretory phases)
• Folliculogenesis table: 5 stages with sizes, features, and gonadotropin dependence
• Two-cell theory of estrogen synthesis
• Corpus luteum lifespan and luteolysis

Part III — Gynecologic Examination

• Patient-centered approach: communication, confidentiality, cultural sensitivity
• Complete history components (menstrual, obstetric, medical, surgical, social)
• Abdominal exam: systematic palpation, rebound tenderness
• Speculum exam: technique, vaginal and cervical inspection checklist
• Bimanual exam: uterus, cervix (CMT), adnexa assessment
• Rectovaginal exam and rectal exam technique
• Special considerations for adolescents and patients with intact hymen