The Menstrual Cycle and Menstrual Disorders - Week 2

Study Notes: The Menstrual Cycle and Menstrual Disorders

  • Source content covers gynecology topics from Week 2: The Menstrual Cycle and Menstrual Disorders, including cycle physiology, amenorrhea, abnormal uterine bleeding (AUB), pelvic pathology, systemic causes, and PMS/PMDD.
  • Emphasis on detailed clinical reasoning: ask precise questions about bleeding (duration, color, clots, pain), follow breadcrumbs to diagnosis, and connect to foundational physiology and pathology.

Core Concepts: Menstrual Cycle Anatomy and Regulation

  • Ovarian cycle components
    • Growing follicle
    • Ovulation
    • Corpus luteum
    • Estrogen (from growing follicles)
    • Progesterone (from corpus luteum)
    • Key local anatomy: granulosa cells reside in ovarian follicles; follicles themselves are in the ovary.
  • Hormones and glands involved
    • Hypothalamus secretes GnRH (Gonadotropin-Releasing Hormone).
    • Pituitary secretes FSH (Follicle Stimulating Hormone) and LH (Luteinising Hormone).
    • Ovary secretes estradiol (E2) and progesterone (P4).
  • Feedback mechanisms (HPO axis)
    • Negative feedback: high estradiol from growing follicles can suppress FSH.
    • Positive feedback: high estradiol triggers LH surge.
    • Progesterone exerts negative feedback on LH/FSH.
    • Central control: Hypothalamus → GnRH → Pituitary → FSH/LH → Ovary → Estradiol/Progesterone → feedback to hypothalamus and pituitary.
  • Clinical markers and cycles
    • Ovulation presence is inferred from luteal phase progesterone and basal body temperature (BBT) patterns.
    • Luteal progesterone levels in a normal ovulatory cycle help confirm ovulation: typically elevated post-ovulation.

The Menstrual Cycle: Phases and Hormonal Milestones

  • Phases (timeline approximate):
    • Follicular or Proliferative Phase (pre-ovulation)
    • Ovulation
    • Luteal or Secretory Phase (post-ovulation)
  • Timeline cues: CD1 (cycle day 1) is the first day of menses; CD14 ~ ovulation window; CD28 end of cycle.
  • Hormonal profile across phases
    • Follicular phase: rising FSH; developing follicles secrete estrogen (estradiol).
    • Ovulation: LH surge drives ovulation; estrogen peaks then progesterone rises.
    • Luteal phase: corpus luteum secretes progesterone (and estrogen); endometrium prepares for possible implantation.
  • Endometrial changes correspond to hormones: proliferative phase (estrogen-driven growth), secretory phase (progesterone-driven secretory transformation).

Quick Reference: Common Questions about the Corpus Luteum and Hormones

  • What is the Corpus Luteum? A yellow body left on the ovary after follicle releases ovum.
  • What hormone does the CL secrete after ovulation? Progesterone.
  • What is GnRH? Gonadotropin-Releasing Hormone; secreted by the hypothalamus.
  • Where do FSH and LH come from? They are secreted by the pituitary in response to GnRH.
  • Where are granulosa cells located? In the ovarian follicles.
  • Where are the follicles located? In the ovary.
  • What hormone do the follicles secrete? Estradiol (a form of estrogen).

Hormone Feedback Details (HPO Axis)

  • Estradiol dynamics
    • Negative feedback on FSH at high levels during certain phases.
    • Positive feedback on LH at high levels, facilitating the LH surge and ovulation.
  • Progesterone dynamics
    • High progesterone exerts negative feedback on LH and FSH.
  • Summary axis labels
    • Hypothalamus: GnRH
    • Pituitary: FSH, LH
    • Ovary: Estradiol, Progesterone
    • Key organs: HPO Axis (Hypothalamic–Pituitary–Ovarian)

Traditional Chinese Medicine (EAM) Framework (Brief)

  • Four divisions of the menstrual cycle described as Blood Phase, Yin Phase, Yang Phase, Qi Phase (as per slide on page 8).
  • Note: This is a traditional medical framing and not the standard Western physiology model.

Adrenal Glands and Steroidogenesis (Overview)

  • Adrenal glands sit on top of kidneys; two parts with distinct products:
    • Adrenal cortex: produces sex hormones (androgens, estrogens), aldosterone, cortisol.
    • Adrenal medulla: produces catecholamines (epinephrine, norepinephrine).
  • Steroidogenesis path (overview)
    • Cholesterol is the precursor to steroid hormones; in the adrenal cortex, cholesterol is converted to pregnenolone.
    • Pregnenolone can be converted into progesterone, DHEA, cortisol, testosterone, and estradiol.
    • Aromatase converts testosterone to estradiol; this occurs in gonads, brain, adipose tissue, placenta, skin, bone, and blood vessels.

Not Bleeding/Bleeding Disorders: Core Diagnostic Categories

  • Amenorrhea: absence of menses.
  • Primary amenorrhea: no menses by age 16 with normal secondary sexual characteristics, or by age 14 without secondary sexual development.
  • Secondary amenorrhea: absence of menses for 3+ months in someone who previously menstruated.
  • Post-OCP amenorrhea: failure to resume ovulation after stopping hormonal contraception (often 6 months threshold).
  • Key diagnostic split: Gonadotrophic vs normogonadotrophic vs hypergonadotrophic etiologies.

Gonadotrophic Amenorrhea: Key Patterns

  • Hypergonadotrophic hypogonadism: high FSH, low estrogen; pituitary releases high FSH/LH but ovaries do not respond (e.g., menopause, premature ovarian failure).
  • Hypogonadotrophic hypogonadism: low FSH/LH, low estrogen; pituitary not releasing enough FSH/LH to stimulate ovarian follicles (e.g., anorexia, hypothalamic amenorrhea, hyperprolactinemia).
  • Normogonadotrophic anovulation: normal FSH/LH but disrupted cycle; often low progesterone with estrogen in the normal range (e.g., PCOS).

Amenorrhea: Primary vs Secondary (Incidence and Basics)

  • Primary Amenorrhea: <1% incidence in general population.
  • Secondary Amenorrhea: 3-4% incidence.
  • Primary amenorrhea differential includes constitutional delay of growth and puberty (CDGP), disorders of sexual development (DSDs), outflow tract obstructions (e.g., imperforate hymen, transverse vaginal septum).
  • Secondary amenorrhea requires evaluation for pregnancy first, then other etiologies.

Constitutional Delay of Growth and Puberty (CDGP)

  • Slower linear growth early in life and during puberty; puberty onset occurs later than average.
  • Catch-up growth possible; adult height may be shorter than target/parents’ height; many cases monitored without intervention.
  • Source references available for CDGP characteristics and natural history.

Disorders of Sexual Development (DSDs): Conceptual Framework

  • Defining sex dimensions
    • Chromosomal sex: XX, XY, or atypical (e.g., X0, XXY).
    • Gonadal sex: testes or ovaries.
    • Phenotypic sex: female or male internal/external genitalia.
  • Intersex: umbrella term for conditions where anatomy does not fit typical definitions of female or male.
  • DSDs and primary amenorrhea: key examples include Turner syndrome (45,X0), Müllerian agenesis, Androgen Insensitivity Syndrome (AIS), Kallmann syndrome.
  • Case highlights and management considerations emphasize thorough assessment and multidisciplinary care.

Turner Syndrome (45,X0)

  • Genetic condition with monosomy or structural alteration of one X chromosome; female phenotype only.
  • Incidence roughly 1 in 2000–5000 live births.
  • Common features: short stature, congenital heart/kidney anomalies, lymphedema, webbed neck; usually hypergonadotrophic hypogonadism and often presents with primary amenorrhea.

Müllerian Agenesis (Müllerian Dysgenesis)

  • Embryologic underdevelopment of Müllerian ducts leading to absent uterus or uterus/vagina anomalies.
  • Incidence ~1 in 4,500–5,000 females; classic presentation is primary amenorrhea with otherwise normal secondary sexual characteristics.

Androgen Insensitivity Syndrome (AIS)

  • Genetic males (XY) with bodies unable to respond to androgens; spectrum from complete to partial AIS.
  • Complete AIS: XY, undescended testes, no uterus, female external genitalia.
  • Partial AIS: variable genitalia with mixed characteristics.
  • Incidence: 2–5 per 100,000.

Kallmann Syndrome (KS)

  • Congenital hypogonadotropic hypogonadism with anosmia (impaired sense of smell).
  • Caused by defects in GnRH neuron development; puberty delayed or absent; adolescence diagnosis common.

Outflow Tract Obstructions in Primary Amenorrhea

  • Transverse vaginal septum: horizontal tissue barrier within vagina.
  • Imperforate hymen: hymenal membrane entirely obstructs vaginal opening.
  • Diagnosis: may be identified on exam or imaging.

Primary Amenorrhea: Differential Diagnosis (DDx) and Workup Considerations

  • Case-based approach: consider constitutional delays, DSDs, outflow tract obstructions, Turner syndrome, Müllerian agenesis, AIS, Kallmann.
  • Early evaluation includes growth/puberty history, physical exam, and targeted labs/imaging.

Secondary Amenorrhea: Broad DDx and Testing (Key Points)

  • Pregnancy must be ruled out first in any amenorrheic patient of reproductive age.
  • Common non-pregnant causes include hypothalamic amenorrhea (FHA), hyperprolactinemia, thyroid disease, PCOS, Premature Ovarian Failure/Insufficiency (POF/POI).
  • Diagnostic flow includes assessment of pituitary hormones (FSH, LH), prolactin, TSH, imaging when indicated, and consideration of gynecologic causes.

Hyperprolactinemia and Prolactinoma

  • Prolactin is a pituitary hormone for milk production; normal range <
    25 \, \text{ng/mL}.
  • Prolactinomas: prolactin > 100 \, \text{ng/mL} suspicious for adenoma; treatment may include dopamine agonists or surgery.
  • Prolactin levels in the range 25–40 ng/mL may be mild elevation; several non-tumor causes exist (stress, pregnancy, hypothyroidism, medications, ectopic sources).
  • Symptoms: galactorrhea, irregular or absent menses, low estrogen symptoms (vaginal dryness, bone density loss), infertility, decreased libido.
  • Other causes include stress, hypothyroidism (TRH stimulates prolactin), various medications (OCPs, antipsychotics, antidepressants, antihypertensives, H2 blockers, opiates, cocaine).

Prolactinoma Details

  • When prolactin > 100 \, \text{ng/mL}: consider pituitary MRI to evaluate for prolactinoma.
  • Large prolactinomas may cause headaches, visual changes, neurological symptoms due to mass effect.

Empty Sella Syndrome (ESS)

  • Radiologic finding where the sella turcica is filled with CSF and pituitary tissue is flattened; may be incidental or cause hypopituitarism if significant.
  • Prolactin elevation can occur in ESS; management depends on clinical context.

Menopause, POI/POF, and FHA

  • Menopause: clinical diagnosis = absence of menses for 12 consecutive months; typical age ~ 51 years (range 40–58).
  • Perimenopause/POI:POF defined as diminished ovarian function before age 40; POI incidence ~1 in 100 by age <40; ~1 in 1000 by age <30.
  • Symptoms: irregular periods to amenorrhea, hot flashes, night sweats, vaginal dryness, sleep disturbance, mood changes. Diagnosis often involves two FSH measurements in menopausal range (> 40 \, \mu{IU/mL}) at least one month apart, with low estrogen.
  • Functional Hypothalamic Amenorrhea (FHA): a common cause of secondary amenorrhea; hypothalamus releases too little GnRH leading to low FSH/LH and estrogen; can be weight loss-related, stress-related, or exercise-related; associated risks include osteopenia/osteoporosis and mental health concerns.
  • Sheehan’s syndrome (postpartum pituitary necrosis): postpartum pituitary failure due to severe blood loss; risk of adrenal crisis; emergency management required.

Normogonadotrophic Hypogonadism and Related Conditions

  • PCOS (Polycystic Ovary Syndrome): common cause of normogonadotrophic hyperandrogenism with ovulatory dysfunction; LH often elevated relative to FSH (LH:FSH ~ 3:1 on Day 3). Features: menstrual dysfunction, hyperandrogenism, polycystic ovaries on imaging; association with obesity, insulin resistance, metabolic syndrome; diagnostic criteria require at least two of three features (ovulatory dysfunction, hyperandrogenism, polycystic ovaries).
  • Cushing Syndrome: hypercortisolism (endogenous or exogenous) can disrupt menstrual cycles; moon face, truncal obesity, purple striae, amenorrhea or oligomenorrhea.
  • Congenital Adrenal Hyperplasia (CAH): enzyme deficiencies leading to excess androgens; variable presentation by age and severity; females may have oligomenorrhea, hirsutism, or ambiguous genitalia at birth depending on severity.
  • Hypothyroidism: can cause ovulatory dysfunction via TRH-mediated prolactin elevation and altered gonadotropin signaling; can be mistaken for PCOS; treat underlying thyroid dysfunction.
  • Adrenal or ovarian tumors can contribute to hyperandrogenism and menstrual irregularities.
  • Outflow tract obstructions (Asherman’s syndrome, cervical stenosis) can cause secondary amenorrhea via mechanical blockage.

Abnormal Uterine Bleeding (AUB): Framework and Terminology

  • AUB includes heavy, irregular, or inappropriate bleeding and is a diagnosis that requires ruling out pathology.
  • PALM-COEIN model (International Federation of Gynecology and Obstetrics) for AUB causes:
    • Structural causes (P): Polyp, Adenomyosis, Leiomyoma, Malignancy
    • Non-structural causes (A, L, E, I, N): Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not otherwise classified
  • Key bleeding terms
    • Menorrhagia: heavy flow and/or long duration (> 7\,\text{days}) with regular cycles (24–35 days); heavy defined as > 80\,\text{mL/month} with features like frequent product changes, large clots.
    • Metrorrhagia: bleeding at irregular intervals.
    • Menometrorrhagia: heavy bleeding with irregular intervals.
    • Oligomenorrhea: intervals > 35 days (infrequent periods).
    • Polymenorrhea: cycles < 21 days.
    • Dysfunctional Uterine Bleeding (DUB): bleeding not due to structural or systemic disease; diagnosis of exclusion.
  • Ovulatory vs Anovulatory bleeding
    • Ovulatory: regular cycles with PMS symptoms; examples include menorrhagia with ovulatory cycles.
    • Anovulatory: irregular or infrequent periods due to lack of ovulation; no progesterone production; leads to unchecked estrogen-driven endometrial proliferation and instability; examples include oligomenorrhea and menometrorrhagia.
  • Ovulation detection and endometrial timing
    • Basal body temperature (BBT) pattern: sustained luteal phase rise indicates ovulation.
    • Luteal progesterone levels: typically >2\text{ to }25\,\text{ng/mL} during the luteal phase in an ovulatory cycle.

Abnormal Uterine Bleeding: Diagnostic Workup and Imaging

  • Pregnancy test first in any AVB case.
  • If pregnancy negative and cycle is irregular with heavy bleeding, evaluate with:
    • Thyroid function (TSH) and prolactin levels.
    • Complete blood count.
    • Transvaginal ultrasound (TVUS) to assess endometrium and uterine structure; consider saline infusion sonohysterography for better cavity visualization.
    • Endometrial biopsy if endometrial pathology is suspected (risk of hyperplasia or cancer in certain populations).
  • Imaging modalities have varying sensitivity and specificity for detecting endometrial pathology:
    • Endometrial biopsy: readily available, low complication rate.
    • Office hysteroscopy with or without saline infusion: direct visualization and targeted biopsy.
    • TVUS: assesses endometrial thickness and uterine/ovarian pathology.
  • Endometrial hyperplasia and cancer
    • Hyperplasia often presents with abnormal uterine bleeding; risk factors include unopposed estrogen exposure (anovulatory cycles, PCOS, perimenopause).
    • Evaluation includes TVUS, endometrial biopsy, D&C, or hysteroscopy; stratified by simple/complex hyperplasia and presence/absence of atypia.
    • Treatments commonly involve progestin therapy or levonorgestrel-releasing intrauterine system (Mirena); atypical hyperplasia may require hysterectomy.
  • Endometrial cancer
    • 90% of cases present with abnormal vaginal bleeding; screening is not routine.

Bleeding in Pregnancy: Key Conditions

  • Normal implantation bleeding can occur early; discuss with obstetric care provider.
  • Ectopic pregnancy: implantation outside the uterus; presents with cramping, shoulder/abdominal pain, possible shock if rupture; risk of rupture and hemorrhage.
  • Gestational trophoblastic disease (GTD) including molar pregnancy: abnormal trophoblastic tissue; often presents with vaginal bleeding and uterine enlargement; molar tissue may resemble a bunch of grapes.
  • Placenta previa: placenta covers the cervical os; risk of bleeding during pregnancy and delivery.
  • Spontaneous abortion (SAb): miscarriage before 20 weeks; symptoms include cramping, bleeding, and tissue passage.
  • Stillbirth: fetal death after 20 weeks; can require delivery.
  • Retained products of conception (RPOC): tissue remaining post-miscarriage or delivery; risk of infection and hemorrhage.

Gynecologic Cancers: Overview and Warning Signs

  • Endometrial cancer: often presents with abnormal uterine bleeding, especially postmenopausal bleeding; no standard screening in general population.
  • Cervical cancer: symptoms may be absent early; abnormal vaginal bleeding (postcoital bleeding, postmenopausal bleeding) may occur as cancer progresses.
  • Importance of recognizing alarm symptoms and seeking timely evaluation.

Abnormal Bleeding: Systemic and Iatrogenic Causes

  • Systemic endocrine causes: hypothyroidism/hyperthyroidism, Cushing disease, hyperprolactinemia, PCOS, adrenal disorders, CAH.
  • Coagulopathies: von Willebrand disease, thrombocytopenia, leukemia-associated bleeding, liver/kidney disease impacts.
  • Iatrogenic/medication causes: anticoagulants (warfarin, direct oral anticoagulants), hormonal therapies (OCPs, estrogen therapy), intrauterine devices (IUDs), SERMs (e.g., tamoxifen), psychotropic drugs causing hyperprolactinemia.

Management: Functional Approaches to Abnormal Bleeding (DUB/AUB-O and AUB-I)

  • DUB/AUB-O (ovulatory):
    • First-line: combined oral contraceptives (OCPs) or cyclic progestin therapy; consider tranexamic acid for heavy menstrual bleeding (Lysteda).
    • Levonorgestrel-releasing intrauterine system (Mirena) as an option for continuous local hormone delivery.
    • NSAIDs (e.g., NSAIDs) can be used to reduce menstrual bleeding and relieve cramps.
  • AUB-I (iatrogenic): manage underlying medications, adjust therapies, or switch to alternatives.
  • For ongoing heavy bleeding unresponsive to medical therapy: endometrial biopsy, hysteroscopy with potential endometrial ablation or hysterectomy may be considered.

PMS and PMDD: Diagnostic Criteria and Treatments

  • Premenstrual Syndrome (PMS): diagnosis based on repeated affective and somatic symptoms in the five days before menses across at least three cycles; symptoms must improve within four days of onset of menses and be absent by day 13 of the cycle; functional impairment must be evident.
    • Common affective symptoms: irritability, anxiety, depression, social withdrawal, anger.
    • Common somatic symptoms: abdominal bloating, breast tenderness, headaches, joint/muscle pain, weight gain.
  • Premenstrual Dysphoric Disorder (PMDD): requires at least five symptoms in the final week before menses, with distress/impairment; at least four core symptoms (one must be an affective symptom like depressed mood, anxiety, irritability, or affective lability).
  • Treatments for PMS/PMDD include: combined oral contraceptives, selective serotonin reuptake inhibitors (SSRIs), anti-psychotics (in severe cases), behavioral therapy, acupuncture and herbal approaches.

Practical Takeaways and Clinical Implications

  • Always assess pregnancy status in any abnormal vaginal bleeding scenario.
  • Distinguish ovulatory vs anovulatory causes by cycle regularity, ovarian function tests (FSH/LH, prolactin, TSH), and endometrial status.
  • In amenorrhea, evaluate for ovarian failure, hypothalamic-pituitary disorders, and anatomical obstructions; tailor workup with imaging and karyotyping as indicated.
  • The PALM-COEIN framework is a practical tool for organizing differential diagnosis of AUB-O, AUB-I, and AUB-E (endometrial pathology) in clinical practice.
  • Endometrial pathology risk increases with age (especially postmenopause and perimenopause) and with unopposed estrogen exposure; endometrial biopsy decisions hinge on risk stratification.
  • Hormonal regulation and feedback loops are central to understanding cycle dynamics and pathologies such as FHA, PCOS, and POI/POF.
  • Patient-centered care: consider psychosocial aspects, mood symptoms, and quality of life when diagnosing PMS/PMDD or managing heavy bleeding.

Notable Equations and Thresholds (LaTeX Formatted)

  • LH:FSH ratio (Day 3) often around \frac{LH}{FSH} \approx 3:1 in PCOS.
  • Prolactin thresholds
    • Normal: ext{Prolactin} < 25\ \text{ng/mL}
    • Mild elevation: 25 \le \text{Prolactin} \le 40\ \text{ng/mL}
    • Suspicious for prolactinoma: \text{Prolactin} > 100\ \text{ng/mL}
  • Ovulatory cycle markers
    • Mid-luteal progesterone thresholds indicating ovulation: \text{Progesterone}_{mid-luteal} \in (2, 25)\ \text{ng/mL}
  • Menstrual blood loss definitions
    • Heavy menstrual bleeding: typically > 80\ \text{mL}\text{/cycle} (often with products changes every 1–2 hours and clots > 1in / 2.54 cm).
  • Endometrial hyperplasia terminology
    • Simple vs complex; with or without atypia; management guided by biopsy results and cancer risk assessment.

Quick Case Prompts (to test your understanding)

  • A 17-year-old with primary amenorrhea, breast development but no menarche. What are your top DDX and initial tests? Consider Turner syndrome, Müllerian agenesis, AIS, and constitutional delay; order karyotype, pelvic ultrasound, and FSH/LH as appropriate.
  • A 32-year-old with irregular cycles and hirsutism. What syndrome is most likely, what tests would you order, and what imaging/criteria would confirm the diagnosis? PCOS suspicion with pelvic ultrasound, LH:FSH ratio evaluation, and assessment of metabolic risk factors.
  • A woman with secondary amenorrhea and galactorrhea. What stepwise workup would you perform? Pregnancy test, prolactin level, MRI to evaluate for prolactinoma if prolactin is elevated, and thyroid testing.

References and Context

  • The material integrates standard gynecology content: menstrual physiology, amenorrhea workup (primary/secondary), AUB taxonomy (PALM-COEIN), pregnancy-related bleeding considerations, endometrial pathology, and PMS/PMDD management.

  • Some slides reference traditional medicine frameworks (EAM) as complementary perspectives; core Western physiology remains the primary model for diagnosis and management in clinical practice.

  • Several clinical pearls highlight the importance of preserving patient safety, recognizing red flags (pregnancy, ectopic bleed, heavy bleeding with hemodynamic instability), and involving multidisciplinary teams when indicated.

  • Quiz and review items are cited as “Quiz 1 Next Week!” for study preparation and self-check.