Y2S2 P1 Reproductive Pathology

Primary Amenorrhea

• Failure to menstruate by age 16 with normal secondary sexual characteristics or by age 14 with no signs of sexual maturation.

Causes of Primary Amenorrhea

• Hypothalamic

  • Low body weight
  • Stress
  • Severe diet restriction (anorexia) or heavy exercise
  • Kallmann’s syndrome

• Pituitary

  • Tumor

• Ovarian

  • Polycystic Ovarian Syndrome (PCOS) with normal LH/FSH levels
  • Turner’s syndrome

• Uterine

  • Gonadal dysgenesis
  • Imperforate hymen
  • Mullerian agenesis
  • Inter - vaginal septum
  • Androgen insensitivity

• Systemic

  • Constitutional delay
  • Hyper or hypothyroidism

Secondary Amenorrhea

• Absence of three menstrual cycles if normally regular or 6 months if normally oligomenorrhea.

Causes of Secondary Amenorrhea

• Hypothalamic

  • Low body weight
  • Stress
  • Severe diet restriction or heavy exercise

• Pituitary

  • Tumor or infarction (usually during labor)

• Ovarian

  • PCOS with normal LH/FSH levels
  • Early menopause with high FSH/LH levels

• Uterine

  • Pregnancy
  • Physical obstruction
  • Iatrogenic

• Systemic

  • Breastfeeding
  • Hyperthyroidism
  • Cushing’s

Polycystic Ovarian Syndrome (PCOS)

• Diagnosis requires two out of three of the following characteristics:
  • Hyperandrogenism features
  • Oligo or Anovulation
  • Polycystic ovaries on ultrasound

PCOS Pathophysiology

• Not fully understood but associated with the following:

  • Insulin resistance

  • Hyperglycemia

  • Increased storage of glucose as adipose tissue

  • Truncal obesity

  • High LH

  • Hyperandrogenism

  • Hirsutism

  • Oily skin

  • Acne

  • Low FSH

  • Oligo or anovulation

  • Infertility

PCOS Management

• Diet and lifestyle
• COCP to control the menstrual cycle and hyperandrogenism

Menorrhagia

• Uterine

  • Infection
  • Polyps
  • Adenomyosis
  • Leiomyoma/Fibroid
  • Malignancy

• Systemic

  • Iatrogenic
  • Coagulopathy
  • Endocrine (hypothyroidism)

Pelvic Pain in Females

• Ovarian

  • Cyst
  • Malignancy
  • Torsion

• Tubal

  • Pelvic inflammatory disease
  • Ectopic pregnancy

• Uterine

  • Fibroid
  • Malignancy
  • Endometriosis
  • Adenomyosis

• Other

  • Appendicitis
  • Diverticulitis
  • IBD
  • Renal stones
  • UTI/Pyelonephritis

Ectopic Pregnancy

• Implantation and maturation of a fertilized embryo outside of the uterine cavity.
• Occurs in 1% of pregnancies.
• 97% arise in the fallopian tube.
• Can rupture and cause massive internal haemorrhage, a medical emergency.

Ectopic Pregnancy Presentation

• Classic triad of:
  • Constant abdominal pain
  • Known pregnancy or features of pregnancy:
    • Amenorrhoea
    • Breast tenderness
    • Nausea and vomiting
  • Bleeding

Ruptured Ectopic Pregnancy

• Shock
• Urge to defecate

Menopause

• The final menstrual period in a woman who has not had a hysterectomy.
• Average age is 51.5 years.

Perimenopause

• From the onset of cycle irregularity through until 12 months after the FMP.

Menopause Transition

• From onset of cycle irregularity to FMP.
• More anovulatory cycles
• Irregular menses
• Lighter or heavier menses
• Symptoms of estrogen insufficiency or excess (if more follicles are being recruited)

Premature Ovarian Insufficiency (POI)

• Cessation of ovarian function before 40 years of age.

Causes of POI

• Idiopathic (most common)

• Physical insults

  • Ionising radiation
  • Chemotherapy
  • Viral infection
  • Smoking
  • Surgery

• Genetic

  • Fragile X
  • Turner’s

• Enzyme/gonadotropin defects

• Immune disturbances

Consequences of Menopause

• Loss of cyclical estrogen production leads to:
  • Vasomotor symptoms:
    • Hot flushes
    • Night sweats
  • Formication (crawling sensation on skin)
  • Muscle/joint pains
  • Anxiety/depression/irritability
  • Fatigue
  • Sleep disturbance
  • Lessened memory/concentration
  • Low libido
  • Vaginal dryness and urogenital symptoms

Long Term Consequences of Menopause

• Osteoporosis
• Risk of CVD/Metabolic syndrome

Delayed or Absent Puberty

• Absence of secondary sexual characteristics at age 13 in girls and 16 in boys.

Causes of Delayed or Absent Puberty

• Nonpathologic/Transient (“late bloomer”)

• Hypogonadotropic hypogonadism/Secondary failure

  • Low LH and FSH.
  • Deficiency in pulsatile GnRH, FSH or LH secretion.
  • Due to issues with the hypothalamus or pituitary stalk.
    • Congenital: Kallmann syndrome
    • Acquired: CNS tumors or congenital malformations
    • Functional: Anorexia nervosa, intense exercise, IBD, coeliac

• Hypergonadotropic hypogonadism/Primary failure

  • High LH and FSH
  • Direct gonadal dysfunction.
    • Klinefelter syndrome
    • Turner’s syndrome

Kallmann's Syndrome

• Congenital GnRH deficiency due to failure of GnRH neurons to migrate into the hypothalamus.
• Triad of:
  • GnRH deficiency
  • Absent puberty
  • Small testes
  • Hyposmia/Anosmia
  • Hypoplasia of the olfactory lobes
• 4x more common in males than females.

Kallmann's Syndrome Treatment

• Gonadotropin therapy
  • HCG
  • FSH
• Testosterone replacement for virilisation after 5 years.

Androgen Deficiency in Men

• Androgens support virilisation.

Symptoms of Androgen Deficiency

• General

  • Decreased sense of wellbeing
  • Tiredness
  • Poor stamina
  • Poor concentration
  • Depression
  • Irritability

• Sexual

  • Decreased libido
  • Decreased ejaculate volume
  • Erectile failure

• Organ Specific

  • Decreased muscle mass and strength
  • Osteoporosis and fracture
  • Increased fat mass
  • CVD and metabolic

Treatment of Androgen Deficiency

• Testosterone

Male Infertility

• Defined as the absence of conception after 1 year of regular, unprotected intercourse around the time of ovulation.

Primary Amenorrhea

• Failure to menstruate by age 16 with normal secondary sexual characteristics or age 14 with no signs of sexual maturation
• Causes can be classified based on location of the issue
  • Hypothalamic Level: Low body weight, stress, severe diet restriction, heavy exercise, Kallmann's Syndrome
  • Pituitary Level: Tumor
  • Ovarian Level: PCOS, Turner's Syndrome
  • Uterine Level: Gonadal Dysgenesis (Imperforate hymen, Mullerian agenesis, Inter-vaginal septum), Androgen Insensitivity
  • Systemic: Constitutional delay, hyper or hypothyroidism

Secondary Amenorrhea

• Absence of three menstrual cycles (if normally regular) or six months (if normally oligomenorrhea)
• Causes can be classified based on location of the issue
  • Hypothalamic Level: Low body weight, stress, severe diet restriction, heavy exercise
  • Pituitary Level: Tumor or infarction
  • Ovarian Level: PCOS or early menopause
  • Uterine Level: Pregnancy, physical obstruction, iatrogenic
  • Systemic: Breastfeeding, hyperthyroidism, Cushing's

Polycystic Ovarian Syndrome (PCOS)

• Diagnostic criteria: two out of three
  • Features of hyperandrogenism
  • Oligo or Anovulation
  • Polycystic ovaries on ultrasound
• Associated with: Insulin resistance, high LH, low FSH
• Management: Lifestyle changes, COCP

Menorrhagia

• Excessive menstrual bleeding
• Causes can be classified as:
  • Uterine: Infection, polyps, adenomyosis, leiomyoma/fibroids, malignancy
  • Systemic: Iatrogenic, coagulopathy, endocrine (hypothyroidism)

Pelvic Pain in Females

• Classified by location:
  • Ovarian: Cyst, malignancy, torsion
  • Tubal: Pelvic inflammatory disease, ectopic pregnancy
  • Uterine: Fibroid, malignancy, endometriosis, adenomyosis
  • Other: Appendicitis, diverticulitis, IBD, renal stones, UTI/pyelonephritis

Ectopic Pregnancy

• Implantation and maturation of a fertilized embryo outside of the uterine cavity
• Occurs in 1% of pregnancies
• 97% occur in the fallopian tube
• Can cause massive internal haemorrhage
• Classic Triad of Symptoms:
  • Constant abdominal pain
  • Known pregnancy (but not always) or features of pregnancy
  • Bleeding (but not always)
• If the ectopic has ruptured: Shock, urge to defecate
• ANY FEMALE OF REPRODUCTIVE AGE WITH ABDO PAIN SHOULD GET A PREGNANCY TEST

Menopause

• The final menstrual period in a woman who has not had a hysterectomy (average age 51.5 years)
• Perimenopause: From onset of cycle irregularity through until 12 months after the FMP
• Menopause transition: From onset of cycle irregularity to FMP
• Consequences: Vasomotor symptoms, formication, muscle/joint pains, anxiety/depression/irritability, fatigue, sleep disturbance, lowered memory/concentration, low libido, vaginal dryness and urogenital symptoms

Premature Ovarian Insufficiency

• Cessation of ovarian function before 40 years of age
• Idiopathic: Most common
• Physical insults: Ionizing radiation, chemotherapy, viral infection, smoking, surgery
• Genetic: Fragile X or Turner's Syndrome
• Other: Enzyme/gonadotropin defects, immune disturbances

Consequences of Menopause

• Loss of cyclical oestrogen production leads to: Vasomotor symptoms, formication, muscle/joint pains, anxiety/depression/irritability, fatigue, sleep disturbance, lessened memory/concentration, low libido, vaginal dryness and urogenital symptoms
• Overall diminished wellbeing

Long Term Consequences of Menopause

• Osteoporosis: Ageing, Vitamin D deficiency, menopausal oestrogen decline
• Risk of CVD/Metabolic syndrome: Altered energy metabolism, "Menopausal Metabolic Syndrome"

Delayed or Absent Puberty

• Absence of secondary sexual characteristics at age 13 in girls and 16 in boys
• Nonpathologic/Transient: “Late bloomer”
• Hypogonadotropic hypogonadism/Secondary Failure: Low LH and FSH, deficiency in pulsatile GnRH, FSH or LH secretion (congenital, acquired, functional)
• Hypergonadotropic hypogonadism/Primary failure: High LH and FSH, direct gonadal dysfunction (Klinefelter syndrome, Turner's syndrome)

Kallmann's Syndrome

• Congenital GnRH deficiency
• Triad of: GnRH deficiency, Hyposmia/Anosmia , Hypoplasia of the olfactory lobes
• 4x more common in males than females
• Treatment: Gonadotropin therapy (HCG, FSH), testosterone after 5 years

Androgen Deficiency in Men

• Androgens are responsible for establishing and maintaining virilisation
• Symptoms: Decreased sense of wellbeing, tiredness, poor stamina, poor concentration, depression, irritability, decreased libido, decreased ejaculate volume, erectile failure, decreased muscle mass and strength, osteoporosis, increased fat mass
• Treatment: Testosterone

Male Infertility

• Infertility is defined as the absence of conception after 1 year of regular, unprotected intercourse around the time of ovulation.

Primary Amenorrhoea

• Failure to menstruate: by age 16 with normal secondary sexual characteristics OR by age 14 with no signs of puberty
• Hypothalamic Level: Low body weight, stress, severe diet restriction (anorexia)/heavy exercise, Kallmann’s syndrome
• Pituitary Level: Tumour
• Ovarian Level: PCOS (with normal LH/FSH levels), Turner’s syndrome
• Uterine Level: Gonadal Dysgenesis (Imperforate hymen, Mullerian agenesis, Inter-vaginal septum), Androgen insensitivity
• Systemic: Constitutional delay (late bloomer), hyper or hypothyroidism

Secondary Amenorrhoea

• Absence of three menstrual cycles (if normally regular) OR 6 months (if normally irregular)
• Hypothalamic Level: Low body weight, stress, severe diet restriction/heavy exercise
• Pituitary Level: Tumour or infarction (usually during labour)
• Ovarian Level: PCOS (normal LH/FSH levels) or early menopause (high FSH/LH)
• Uterine Level: Pregnancy, physical obstruction, iatrogenic
• Systemic: Breastfeeding, hyperthyroidism, Cushing’s

Polycystic Ovarian Syndrome (PCOS)

• Requires 2 of the following for diagnosis: Features of hyperandrogenism, Oligo or Anovulation, Polycystic ovaries on ultrasound
• Pathophysiology: Insulin resistance → hyperglycemia → increased glucose storage as adipose tissue → truncal obesity
• Pathophysiology: High LH → Hyperandrogenism → hirsutism, oily skin, acne
• Pathophysiology: Low FSH → oligo or anovulation → infertility
• Management: Diet and lifestyle changes (weight loss improves menstrual cycle regularity and lowers diabetes risk), COCP to control menstrual cycle and hyperandrogenism

Menorrhagia

• Uterine Causes: Infection, Polyps, Adenomyosis, Leiomyoma/Fibroid, Malignancy
• Systemic Causes: Iatrogenic, Coagulopathy, Endocrine (hypothyroidism)

Pelvic Pain in Females

• Ovarian: Cyst, Malignancy, Torsion
• Tubal: Pelvic inflammatory disease, Ectopic pregnancy
• Uterine: Fibroid, Malignancy, Endometriosis, Adenomyosis
• Other: Appendicitis, Diverticulitis, IBD, Renal stones, UTI/Pyelonephritis

Ectopic Pregnancy

• Implantation of a fertilised embryo outside the uterine cavity
• Occurs in 1% of pregnancies, 97% in fallopian tube, can rupture and cause massive internal haemorrhage
• Classic Triad: Constant abdominal pain, known pregnancy or pregnancy features (amenorrhoea, breast tenderness, nausea/vomiting), bleeding
• Ruptured Ectopic: Shock (pale, cold, lightheadedness), urge to defecate
• Any female of reproductive age with abdominal pain should get a pregnancy test

Menopause

• Final menstrual period (FMP) in woman without a hysterectomy (average age 51.5 years)
• Perimenopause: Onset of cycle irregularity through 12 months after FMP
• Menopause transition: Onset of cycle irregularity until FMP
• Menopause Symptoms: More anovulatory cycles, Irregular menses, Lighter/heavier menses, Symptoms of oestrogen insufficiency/excess
• Vasomotor Symptoms: Hot flushes, night sweats
• Other Symptoms: Formication, Muscle/joint pains, Anxiety/depression/irritability, Fatigue, Sleep disturbance, Lessened memory/concentration, Low libido, Vaginal dryness and urogenital symptoms

Premature Ovarian Insufficiency (before 40 years old)

• Idiopathic: Most common
• Physical Insults: Ionising radiation, Chemotherapy, Viral infection, Smoking, Surgery
• Genetic: Fragile X, Turner’s Syndrome
• Enzyme/Gonadotropin Defects:
• Immune Disturbances:

Consequences of Menopause

• Vasomotor Symptoms: Reduced thermoneutral zone, Hot flushes caused by warming, stress, food
• Osteoporosis: Ageing, Vitamin D deficiency/reduced calcium absorption, Menopausal oestrogen decline
• Increased Risk of CVD: Altered energy metabolism, Increased abdominal/intra-abdominal adiposity, “Menopausal Metabolic Syndrome”
• "Menopausal Metabolic Syndrome": Dyslipidemia, Insulin resistance, Increased blood pressure, Chronic inflammation

Delayed or Absent Puberty

• Late Bloomer: Nonpathologic/Transient
• Hypogonadotropic Hypogonadism: Low LH and FSH, Deficient GnRH, FSH, or LH secretion
• Hypergonadotropic Hypogonadism: High LH and FSH, direct gonadal dysfunction (usually due to dysgenesis)

Kallmann’s Syndrome

• Congenital GnRH deficiency due to failure of GnRH neurons to migrate into the hypothalamus
• Triad: GnRH deficiency → absent puberty → small testes, Hyposmia/Anosmia, Hypoplasia of the olfactory lobes
• Treatment: Gonadotropin therapy (HCG, FSH), Testosterone after 5 years for virilisation

Androgen Deficiency In Men

• Symptoms: Decreased sense of wellbeing, Tiredness, poor stamina, poor concentration, Depression, irritability, Decreased libido, Decreased ejaculate volume, Erectile failure, Decreased muscle mass and strength, Osteoporosis and fracture, Increased fat mass, CVD and metabolic
• Treatment: Testosterone replacement therapy

Male Infertility

• The absence of conception after 1 year of regular, unprotected intercourse around the time of ovulation.