Pathophysiology and Pharmacological Management of Menstrual and Ovarian Disorders

Comprehensive practice flashcards covering the pathophysiology, clinical presentations, epidemiology, diagnostic criteria, and pharmacological management of menorrhagia, primary and secondary dysmenorrhea, PMS, PMDD, PMOS (PCOS), and endometriosis.

What occurs at the time of menstruation?

Menorrhagia & Dysmenorrhea

When does menorrhagia & dysmenorrhea occur?

Time of mensturation

What starts during luteal phase?

PMS & PDD

When does PMS & PDD occur?

Luteal phase

What has heavy menstrual blood loss and prolonged menstrual bleeding?

Menorrhagia

What are signs of menorrhagia?

Heavy/prolonged menstrual flow

What can Menorrhagia lead to?

Anemia & hypovolemia

What hematological causes can cause menorrhagia?

von Willebrand’s disease, Thrombocytopenia purpura, Hepatic Cirrhosis

What uterine causes can cause menorrhagia?

Fibroids, adenomyosis, polyps, cancer

What Endocrine causes can cause menorrhagia?

Hypothyroidism

What drugs are used for menorrhagia drug therapy?

NSAIDs, combined oral contraceptive, Levonorgestrel IUD, GnRH agonists

What drug class inhibits cyclooxygenase enzyme?

NSAIDs

What is the drug therapy for CHC?

3 week pill, 1 week pill free

What hormones does CHC inhibit?

FSH & LH

What does progesterone induce?

Cell differentiation

What drug has the MOA of causes sustained inhibition of endometrial proliferation, resulting in endometrial atrophy, thus reducing bleeding due to a decrease in shed endometrial lining?

Levonorgestrel Intrauterine device

What drug has the synthetic analog of the amino acid lysine and acts as a plasmin blocker?

Tranexamic acid

What prevents plasmin from binding to fibrin?

Tranexamic acid

What drug binds to GnRH receptors on gonadotrophs in the anterior pituitary?

GnRH Receptor Agonists

What happens in the late phase?

FSH & LH shut down

What is described as Crampy pelvic pain occurring with the onset or just prior to menstruation?

Dysmenorrhea

How long does Dysmenorrhea last?

1-3 days

Which Dysmenorrhea is described as Pain in the setting of normal pelvic anatomy and physiology?

Primary

Which Dysmenorrhea is described as some pelvic pathology?

Secondary

What does Low estrogen & progesterone levels due to regressing corpus luteum?

Influx of inflammatory cells & shedding uterine line

What is generated from membrane of sloughed off cells?

Prostaglandins & Leukotrienes

What does the release of prostaglandins result in?

Uterine smooth muscle contraction

What does the release Leukotrienes results in?

nociceptive nerve endings

What leads to secondary Dysmenorrhea

Cervical stenosis, Endometriosis, Pelvic infection

What drugs are used for dysmenorrhea drug therapy?

NSAIDs, Combined hormonal contraceptives, Depot medroxyprogesterone, IUD

What drug has the MOA of Inhibiting the proliferation of endometrial tissue, which reduces the production of prostaglandins & leukotrienes, thus less pain?

Combined oral Contraceptive

What drug has the MOA of Endometrial atrophy and inhibition of generation of prostaglandins & leukotrienes, thus less pain?

Levonorgestrel-releasing IUD & Depot MPA

What are some signs of PMS?

Breast tenderness, Abdominal bloating, Headache, Weight gain

What are some affective symptoms of PMS?

Depression, irritability, anxiety

What are some symptoms of PMDD?

Irritability, anger, depressed mood

When does PMDD not occur?

Before menarche, during pregnancy or after menopause

What is used to manage PMS?

Supportive therapy, lifestyle changes

What are some drugs used to help with PMS, PMDD?

NSAIDs, Antidepressants, Spironolactone, ovulation suppression

What type of cells have FSH receptors?

Granulosa cells

What promotes estradiol synthesis by increasing aromatase activity in granulosa cells, causing follicle maturation?

FSH

What cells have LH receptors?

Theca cells

What promotes androstenedione synthesis?

LH

What has High free or bound testosterone, High androstenedione, Acne, male pattern baldness, Hirsutism

Polyendocrine Metabolic Ovarian Syndrome

What are some signs of PMOS?

High levels of testosterone, loss of FSH LH cyclization, no LH peak

What can cause PMOS?

Increased levels or activity of CYP17, Insulin resistance and hyperinsulinemia, Obesity

What happens when LH is increased?

Increased testerone

What are signs of Hyperandrogenism?

Acne, Hirsutism, Baldness

What are signs of accumulation of follicles?

polycystic appearance of ovaries and oligo- or amenorrhea

What does Reduced FSH lead to?

Reduced estrogen

What happens if there is no corpus luteum?

Lack of progesterone

What lifestyle management should be done to manage PMOS?

Weight loss, exercise, and a balanced diet.

What is Presence of endometrial tissue outside the uterus in the peritoneum?

Endometriosis

What is the Retrograde flow of menstrual fluid and endometrial tissue through fallopian tubes into peritoneal cavity?

Retrograde Flow Theory

What is the Residual embryonic cells of the Wolffian or Mullerian ducts persist and develop into endometrial tissue that respond to estrogen?

Coelomic Metaplasia Theory

What does endometrial tissue respond to?

Cyclic estrogen

What pathophysiological mechanisms cause fatigue, lightheadedness, orthostasis, tachycardia, and pallor in patients with menorrhagia?

Fatigue and lightheadedness are caused by anemia resulting from blood loss; orthostasis, tachycardia, and pallor are caused by hypovolemia resulting from blood loss.

What hematological conditions are listed as causes of menorrhagia, and by what mechanisms?

1. von Willebrand's disease: deficiency of factor VII leading to impaired platelet adhesion; 2. Thrombocytopenia purpura: decreased number of platelets; 3. Hepatic Cirrhosis: impaired synthesis of coagulation factors.

What uterine and endocrine conditions serve as etiologies for menorrhagia?

Uterine causes include fibroids, adenomyosis, polyps, and cancer; endocrine causes include hypothyroidism, which is a rare cause.

Which uterine pathology and anatomical classifications are depicted in this diagram?

Uterine fibroids (leiomyomas), classified by anatomical location as pedunculated, intramural, subserosal, or submucosal.

What uterine condition is illustrated in the right panel, characterized by endometrial tissue extending into the uterine wall?

Adenomyosis.

What quantitative reduction in menstrual blood loss is achieved with NSAIDs in menorrhagia, and which specific agents are used?

NSAIDs achieve a $20\%\text{ to }50\%$ reduction in blood loss in $75\%$ of treated women. Specific agents used include mefenamic acid, ibuprofen, and naproxen.

What is the mechanism of action of NSAIDs in reducing menstrual bleeding in menorrhagia?

NSAIDs inhibit the cyclooxygenase (COX) enzyme, leading to a reduction in uterine prostaglandins, which subsequently reduces uterine inflammation and uterine contractions, resulting in reduced bleeding.

What is the efficacy and typical administration regimen of combined hormonal contraceptives (CHCs) in menorrhagia?

CHCs produce a $40\%\text{ to }50\%$ reduction in menstrual blood loss and are administered as $3\text{ weeks}$ of active pill administration followed by a $1\text{ pill-free week}$.

How do estrogen and progesterone in combined hormonal contraceptives act to reduce menstrual bleeding?

Estrogen inhibits FSH and LH release via feedback mechanism to inhibit follicle development and estrogen synthesis by follicles; progesterone induces cell differentiation. Together, they inhibit endometrial tissue proliferation and reduce prostaglandins, leading to reduced bleeding.

What are the hormonal content, daily release rate, and efficacy of the levonorgestrel-releasing intrauterine device (IUD) in menorrhagia?

The levonorgestrel IUD contains $52\text{ mg}$ of levonorgestrel, releases $20\,\mu\text{g}$ daily, and achieves a $79\%\text{ to }97\%$ reduction in menstrual blood loss.

What is the mechanism of action of the levonorgestrel-releasing IUD in treating menorrhagia?

It causes sustained inhibition of endometrial proliferation, resulting in endometrial atrophy and reducing bleeding due to a decrease in the amount of shed endometrial lining.

What contraceptive and menorrhagia therapy device is shown in this image?

A levonorgestrel-releasing intrauterine device (IUD).

Why are GnRH receptor agonists less preferred for the management of menorrhagia?

They are less preferred because of their high cost, adverse side effects, and parenteral route of administration.

Explain the early versus late phase mechanisms of action of GnRH receptor agonists in anterior pituitary gonadotrophs.

In the early phase, initial binding stimulates GnRH receptors to cause hypersecretion of FSH and LH. In the late phase, continuous stimulation causes GnRH receptor down-regulation and internalization, leading to a complete shutdown of FSH and LH release, which shuts down menstruation and reduces bleeding.

What is tranexamic acid, and what is its specific molecular mechanism of action in menorrhagia?

Tranexamic acid is an antifibrinolytic drug and synthetic analog of the amino acid lysine that acts as a plasmin blocker. It reversibly binds to lysine-binding sites on plasminogen and plasmin, preventing plasmin from binding to fibrin and degrading it to soluble products, thereby facilitating clotting and reducing bleeding.

According to this diagram, at what enzymatic step does tranexamic acid act to prevent the degradation of fibrin?

It blocks the activation of plasminogen into active plasmin (and plasmin's interaction with fibrin), preventing the cleavage of fibrin into fibrin degradation products.

What is dysmenorrhea, and what is the typical duration of symptoms?

Dysmenorrhea is crampy pelvic pain occurring with the onset or just prior to menstruation, with symptoms typically lasting $1\text{--}3\text{ days}$.

What distinguishes primary dysmenorrhea from secondary dysmenorrhea?

Primary dysmenorrhea is crampy pelvic pain in the setting of normal pelvic anatomy and physiology, whereas secondary dysmenorrhea is associated with an underlying pelvic pathology.

What is the reported epidemiology of dysmenorrhea among women?

Dysmenorrhea affects between $16\%\text{--}90\%$ of women.

What is the initiating hormonal event in the pathogenesis of primary dysmenorrhea?

Low estrogen and progesterone levels resulting from the regressing corpus luteum.

How do prostaglandins contribute to pain in primary dysmenorrhea?

Prostaglandins (especially PGE2 and PGF2$\alpha$) generated from the membranes of sloughed-off endometrial cells cause uterine smooth muscle contraction and uterine ischemia (blood vessel constriction due to uterine contraction), leading to pain.

What role do leukotrienes play in the pathogenesis of primary dysmenorrhea?

Leukotrienes (especially LTC4) generated from the cell membranes of sloughed-off cells stimulate nociceptive nerve endings, leading to pain.

What structural and inflammatory conditions cause secondary dysmenorrhea?

Cervical stenosis, endometriosis, pelvic infections, pelvic congestion syndrome, uterine or cervical polyps, uterine fibroids, genital tract outflow obstructions, and pelvic adhesions.

Which pharmacologic options are utilized in the management of dysmenorrhea?

NSAIDs (naproxen and ibuprofen), combined hormonal contraceptives, depot medroxyprogesterone (Depot MPA), and levonorgestrel-releasing IUD.

How do combined oral contraceptives and depot MPA/levonorgestrel IUD alleviate pain in dysmenorrhea?

Combined oral contraceptives inhibit the proliferation of endometrial tissue, reducing the production of prostaglandins and leukotrienes. Depot MPA and levonorgestrel IUD cause endometrial atrophy and inhibit the generation of prostaglandins and leukotrienes.

Which enzyme pathway is inhibited by Aspirin and NSAIDs according to this arachidonic acid cascade?

The cyclooxygenase (COX) enzyme, preventing the conversion of arachidonic acid (AA) into cyclo-endoperoxides.

What is the prevalence of mild PMS, moderate PMS, and PMDD among women across the premenstrual syndrome spectrum?

Mild PMS affects $75\%\text{--}85\%$ of women, moderate PMS affects $5\%\text{--}10\%$ of women, and PMDD affects $3\%\text{--}5\%$ of women.

What are the somatic symptoms of PMS, and which one is the most prevalent?

Breast tenderness, abdominal bloating (most common, occurring in $90\%$ of cases), headache, swelling of extremities, and weight gain.

What affective symptoms characterize premenstrual syndrome (PMS)?

Depression, angry outbursts, irritability, anxiety, social withdrawal, decreased concentration, sleep disturbance, and appetite change/food cravings.

What are the four diagnostic criteria for premenstrual syndrome (PMS) described by Yonkers (2018)?

1) Physical and or emotional symptoms; 2) Symptoms are present during luteal phase and abate as menstruation begins; 3) A symptom-free week; 4) Symptoms are associated with significant impairment during luteal phase.

How many cyclic patterns of PMS symptoms exist, and which patterns do most women experience?

There are four different patterns of PMS symptoms; most women experience patterns 1 or 2.

What are the core symptom and timing criteria required for a diagnosis of PMDD?

Symptoms must be present in the final week before onset of menses, start to improve within a few days after onset of menses, and become minimal or absent in the week postmenses. The patient must have at least $5$ total symptoms out of $11$, with at least $1$ symptom being a core affective symptom (marked affective lability, irritability/anger, depressed mood/hopelessness, or anxiety/tension).

What are the four core affective symptoms of PMDD (items 1 through 4)?

1. Marked affective lability (e.g., mood swings, feeling suddenly sad or tearful, or increased sensitivity to rejection); 2. Marked irritability or anger or increased interpersonal conflicts; 3. Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts; 4. Marked anxiety, tension, feelings of being 'keyed up,' or 'on edge.'

What non-core symptoms make up items 5 through 11 in the PMDD diagnostic criteria?

5. Decreased interest in usual activities; 6. Subjective difficulty in concentration; 7. Lethargy, easy fatigability, or marked lack of energy; 8. Marked change in appetite, overeating, or specific food cravings; 9. Hypersomnia or insomnia; 10. A sense of being overwhelmed or out of control; 11. Physical symptoms such as breast tenderness/swelling, joint/muscle pain, bloating, or weight gain.

What is the 'PMDD Hazard Zone' defined on this menstrual cycle timeline?

The interval occurring during the week before the onset of menses and extending a few days after menses onset, during which PMDD symptoms manifest and peak.

Under what physiological states does PMDD never occur, demonstrating the imperative role of estrogen and progesterone?

PMDD never occurs before menarche, during pregnancy, or after menopause.

How does allopregnanolone (ALLO) contribute to the pathogenesis of PMDD?

Allopregnanolone, a progesterone metabolite, binds to GABA receptors, which in turn interferes with the function of neurons containing the serotonin neurotransmitter.

Which two sequential enzymes convert progesterone into allopregnanolone in the pathway depicted here?

$5\alpha\text{-reductase type I}$ (converting progesterone to $5\alpha\text{-dihydroprogesterone}$) and $3\alpha\text{-hydroxysteroid dehydrogenase}$ (converting $5\alpha\text{-dihydroprogesterone}$ to allopregnanolone).

What effect does estrogen exert on serotonin in PMDD pathogenesis?

Estrogen interferes with the synthesis, metabolism, and autoreceptor-mediated release of serotonin.

What nutritional supplements and specific daily dosages are recommended for non-pharmacological PMS management?

Magnesium sulfate $360\text{ mg/d}$, Calcium $1200\text{ mg/d}$, Vitamin E $400\text{ IU/d}$, and Vitamin B6 $100\text{ mg/d}$.

Which specific pharmacological agents are indicated for bloating and mastalgia in PMS/PMDD?

Spironolactone is used for bloating, and bromocriptine is used for mastalgia.

Which psychotropic drugs and ovulation suppression agents are used in drug therapy for PMS and PMDD?

Antidepressants: SSRIs and buspirone; Ovulation suppression: Combined hormonal contraceptives and GnRH agonists (e.g., Lupron).

What receptors and biosynthetic roles characterize granulosa cells versus theca cells in ovarian follicles?

Granulosa cells possess FSH receptors; FSH promotes estradiol synthesis by increasing aromatase activity, causing follicle maturation. Theca cells possess LH receptors; LH promotes androstenedione synthesis.