Female Repro L3: Disorders of menstruation Flashcards
1
Q
Development of Puberty
A
- Hypothalamus plays a vital role in physiology of normal menstruation
- – Integrates neuronal and endocrine function
- – Regulates bodily processes (such as appetite, osmoregulation, secondary sexual development and reproductive function)
- – Release of kisspeptin/GPR54 ligand/receptor pair
- Hyperplasia of zona reticularis of the adrenal gland occurs at age 6 (adrenarche)
- – Increased secretion of dehydroepiandrosterone sulfate (DHEAS)
- – DHEAS is aromatized to estrone
- Increasing levels of estrone initiates breast development (thelarche) – first sign of puberty
- Adrenarche also stimulates pubic hair development, acne and body ordor (DHEAS)
- Pulsatile release of GnRH begins at 8 years (gonadarche)
- – Increased frequency and amplitude first occur at night
- Maintained throughout the day as the H-P-O axis matures
- – Half-life of GnRH is 4-6 mins.
- Levels of estradiol are too low to exert
- feedback control initially
- Growth spurt
- Menarche occurs at age 10-15 (mean 12.2yr)
2
Q
Turner’s syndrome
A
- Congenital lymphedema (large dilated lymphovascular spaces)
– Fetal edema
– Nuchal skin folds (cystic hygroma)
– Edema of hand and feet at birth
- Broad chest, wide-spaced nipples
- Low posterior hairline
- Low set ears
- Cubitus valgus
- Short stature (usually ≤ 1.5 m, 5ft)
- Intelligence is usually normal (Average IQ 90)
- Decreased motor skills, incoordination
- Cardiac abnormalities
- – Bicuspid aortic valve
- – Coarctation (Preductal)
- – Aortic stenosis
- – Mitral valve prolapse
- Renal anomalies
- – Horse-shoe kidney
- – Double renal pelvis
- Primary hypothyroidism
GYNECOLOGICAL FEATURES
- Sexual infantilism
- Poor breast development
- Primary amenorrhea (Secondary amenorrhea in mosaic state)
- Streak ovaries (no ovarian follicles)
- Elevation in gonadotropin production from 12 years
- – FSH ≥ 50 mIU/mL
- – LH ≥ 90 mIU/mL
- Diagnosis is by demonstration of abnormal karyotype
- High risk of germ cell cancer if Y chromosome is present
3
Q
KALLMAN SYNDROME
A
Rare congenital disorder
– Incidence: 1 in 100,000 to 1 in 70,000
– M: F = 5 : 1
Pathophysiology
– Congenital Gonadotropin-releasing hormone (GnRH) secreting neuron
deficiency
– GnRH secreting neurons in the hypothalamus originate in the olfactory bulb
– Migrate along the olfactory tract into the mediobasal hypothalamus and the arcuate nucleus
– Normal GnRH pulse frequency and amplitude, as well as intact hypophyseal portal system essential for normal menstruation and ovulation
Genetics:
- Most cases are sporadic
- Inherited as X-linked condition, autosomal dominant or autosomal recessive disorder
Associated mutations
- Kallman-1 (Kal-1) gene – Xp22.3 region of X chromosome
- – X-linked
- – Failure of migration of GnRH neurons from olfactory placode to developing hypothalamus
- Loss-of-function mutation of Fibroblast growth factor-1 receptor (FGFR-1 or Kal-2) gene
- G-protein coupled receptor-54 (GPR-54) gene located on chromosome 19p13.3
- GNRH-1 gene – produces a preprohormone that is processed to GnRH
- Loss-of-function mutation of GnRH receptors
Sx
- No obvious genital abnormality in newborn females at birth
- Possible associated congenital abnormalities:
- – Midline defects
- – Unilateral renal agenesis
- – Syndactyly or other skeletal abnormalities
- – Hyposmia or anosmia (lack of sense of smell in infancy)
- At puberty,
- – Failure to undergo sexual maturation
- – No clear-cut growth spurt
- – Primary amenorrhea
- Normal pubertal development in adult-onset form
- Kallman’s syndrome when associated with anosmia
- Arm span exceeds height by 5 cm or more
Investigations
- Prepubertal serum concentration of estrogen (<20 pg/mL or 73 pmol/L)
- Low serum LH and FSH (<4-5 IU/L)
- Otherwise normal pituitary function
- Normal appearance of hypothalamus and pituitary region on MRI
4
Q
MULLERIAN DYSGENESIS
A
- Also called Mayer-Rokitansky-Kϋster -Hauser (MRKH) syndrome
- Second most common cause of primary amenorrhea (Incidence 1: 4500 females)
- A syndrome of congenital malformation of the genital tract
- – Primary amenorrhea in a well developed post-pubertal female
- – Normal external female genitalia
- – Congenital aplasia of the uterus and upper 2/3 of the vagina
- – Normal 46, XX karyotype
- – Normal functioning ovaries are present bilaterally
- Etiology is due to failure of development and canalization of the uterus and cervix
5
Q
Mullerian dysgenesis: Classification
A
Isolated type 1
- Genital manifestation
- Congenital absence of the uterus and vagina (CAUV)
Type 2
- Genital, renal, vertebral ± auditory and cardiac defects
- MURCS association
Diagnosis
- Imaging studies (ultrasound, CT or MRI)
- laparoscopy
6
Q
AIS
A
- X-linked recessive disorder
- A cause of sexual ambiguity and primary amenorrhea
- Incidence: Not clearly known
- The zygote has normal male (46,XY) karyotype
- Fetal testes produce antimullerian hormone (AMH) and testosterone
- AMH inhibits the development of derivatives of the mullerian ducts
**Pathophysiology **
- A loss-of-function mutation in the androgen receptor (AR) gene
- AR gene is localized to the long arm of the X chromosome (Xq11-13)
- 5 alpha-reductase-induced conversion of testosterone to dihydrotestosterone (DHT) is normal
- No response of primitive cloaca to DHT due to AR deficiency or defects
- Female external genitalia form by default
- At puberty, the testes secrete testosterone in normal male range
- Failure of androgen-dependent changes
- Breast development results from peripheral
- aromatization of testosterone to estrone
- A phenotypic female
- Vagina ends in a blind pouch
- The testes could be localized in the abdominal cavity, inguinal canal or hernia sacs
- Risk of gonadoblastoma is increased due to high ambient intraabdominal temperature
7
Q
5 ALPHA-REDUCTASE DEFICIENCY
A
- AR disorder in genetic males (XY female)
5 α-Reductase (5 α -R) enzymes
- Membrane-bound steroid reductase (SRD5A) enzymes
- Two isoenzymes of 5 α -R are localized to different genes
- SRD5A1:chromosome5
- SRD5A2:chromosome2p23
Pathophysiology
- SRD5A2 deficiency results in lack of local production of DHT in external male genitalia
- At birth, external genitalia may appear feminine or ambiguous
- Sustained increase in testosterone secretion occurs during puberty
- Testosterone-dependentprocessessuchasmuscle mass and deepening of the voice develop
- High testosterone levels induce more SRD5A1 activity
- Compensatory SRD5A1 activity results in male pattern hair growth and worsens sexual ambiguity
8
Q
CONGENITAL ADRENAL HYPERPLASIA: 21-HYDROXLASE DEFICIENCY
A
GENETICS
- A pair of CYP21A genes occur in humans
- – A non-functional pseudogene (CYP21A1 or CYP21P)
- – The active gene (CYP21A2 or CYP21)
- Both genes are located on chromosome 6p21.3 within the major histocompartibility region
- Pseudogene lacks 8 bases (codons 110-112) – Confers a stop codon and lack of protein activity
Sx
Salt-losing form (classic form): no enzyme activity
- – Large deletions
- – Intron 2 mutation that affects splicing
- – No aldosterone or corticosteroid secretion
Simple virilizing form: low enzyme activity (1-2%)
- – Point mutation with nonconservative amino acid substitution (e.g. Ile172Asp)
- – Sufficient aldosterone and glucocorticoid production
Nonclassic form (20-60% of enzyme activity)
- – conservative amino acid substitution (e.g. Val281Leu)
NEONATAL PERIOD/INFANCY
- Ambiguous genitalia
- Uterus, fallopian tubes and vagina are present
- Dangerous salt-losing syndrome and electrolyte derangements
- Dehydration and hypotension are common
- Death results from wasting and vomiting
- Differentials
- – Congenital pyloric stenosis
- – Cryptochiadism
CHILDHOOD (Early puberty)
- Excessive growth of body hairs
- More rapid growth: Short stature in adulthood due to premature closure of epiphysis of long bones
ADULTHOOD
- Primary amenorrhea
- Menstrual irregularity
- Hirsutism
9
Q
Secondary amenorrhea: Etiology
A
- PHYSIOLOGIC
- HYPOTHALAMIC DEFECTS
- PITUITARY CAUSES
- OVARIAN FACTORS
- IATROGENIC CAUSES
- ANATOMIC DEFECTS: Asherman syndrome
10
Q
PCOS
A
Defined by the presence of two (2) out of the following three (3) criteria*
o Oligo- and or anovulation
o Hyperandrogenism (clinical and or biochemical)
o Polycystic ovaries (PCO)
– 12 or more follicles in each ovary measuring 2-9 mm in diameter
– Increase in ovarian volume (>10 cm3)
o Exclude other etiologies of hyperandrogenism
**Pathophysiology **
- Appears to be multifactorial and polygenic
- Evidence of genetic basis for PCOS
- Familial clustering
- 50% of first degree relatives (autosomal dominant)
- Polymorphisms in insulin receptor (INSR) gene on chromosome 11p15.5
- Several factors affect expression of the syndrome
- Hyperinsulinemia thought to be the key etiologic factor: Decreased synthesis of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein-1 (IGFBP-1)
- Low levels of SHBG and IGFBP-1 lead to an increase in free androgen index, estrogen, and IGF-1
- IGF-1 stimulates ovarian IGF receptors leading to theca cell and stromal hyperplasia
- LH-induced androgen production by theca cells increases
- Hirsutism results from chronic hyperandrogenism
- Hyperandrogenism inhibits granulosa cells aromatase enzyme activity
- Selection of the dominant follicle is disrupted due to arrest of follicular development
- Progesterone secretion decreases due to impaired follicular maturation
- Chronic anovulation leads to amenorrhea
- Peripheral conversion of ovarian and adrenal androgens to estrone continues
- High endogenous estrogen leads to endometrial hyperplasia with breakthrough bleeding
- High cumulative estrogen levels (free estradiol and estrone) exert a “positive feedback” effect on the hypothalamus
- Results in elevated LH and reduced FSH levels, and an LH to FSH ratio >2
- Chronic anovulation and elevated LH levels are thought to adversely affect fertility.
11
Q
Health Consequences of PCOS
A
- Diabetes mellitus T2
- Hypertension and ischemic heart disease
- Dyslipidemias
- Endometrial cancer
- Breast cancer
- Ovarian cancer
12
Q
Investigation of Hyperprolactinemia
A
- Mild, transient elevation
- – Stress (chest wall trauma or surgery)
- – Physical examination (chest or breast)
- Mild, sustained rise (<1500 mIU/L): Hypothyroidism
- Moderate elevation (1500-4000 mIU/L) – Microadenoma
- – PCOS
- – Craniopharyngioma
- Marked elevation (5000-8000+ mIU/L) – Macroadenoma
- Serum prolactin assay
- – An excellent tumor marker for prolactinoma
- – Higher serum levels correlate with larger tumor size on MRI scan
- – Moderate elevation (2000-3000 mIU/L) with a large tumor suggest a non-functional “disconnection” tumor
13
Q
PREMATURE OVARIAN FAILURE (POF)
A
Accelerated atresia of ovarian follicles before the age of 40
Etiology
- – Chromosomal aberrations (Turner’s mosaic states)
- – Autoimmune polyglandular failure syndrome
- – Metabolic problems (galactosemia)
- – Viral infections (mumps oophoritis)
- – Iatrogenic (chemotherapy, radiation treatment)
- LH and FSH levels are elevated – FSH usually > 40 IU/L
- Ovarian follicles are absent in biopsy specimens
14
Q
ASHERMAN’S SYNDROME
A
- Occurs in a setting of endometritis after curettage
- Amenorrhea caused by failure to regenerate the endometrium and intrauterine adhesion
- Progressively decreasing menstrual bleed that culminates in amenorrhea is typical presentation
- No withdrawal bleed following progesterone challenge test or sequential estrogen and progesterone treatment
15
Q
Investigation of Amenorrhea
A
- Exclude pregnancy (even in cases of primary amenorrhea with normal secondary sex development)
- Thyroid function test (TSH, T4, T3)
- Serum prolactin levels: – Normal < 400 mIU/L
- Hysterosalpingogram (HSG)
- Serum testosterone assay and free androgen index (FAI)
- – Serum testosterone (T) level - 0.5-3.5 nmol/L
- – Free androgen index - <5
- 24-hour urinary free cortisol
- – Normal <400nmol/24 hours
- – Cushing’s syndrome >700nmol/24 hours
- Serum gonadotropins
- – ↑FSH ↑LH: Premature ovarian failure
- – ↓FSH ↑LH: PCOS
- – ↓ FSH ↓LH: Sheehan syndrome
- – FSH >40IU/L: Irreversible ovarian failure or menopause
- Karyotype: indicated in
- – Primary amenorrhea
- – Premature ovarian failure before 25 years
- Bone mineral density (BMD) measurement
18
Q
Primary dysmenorrhea: Pathogenesis
A
