Menstrual Cycle and Menopause Flashcards
1
Q
Hypothalamic-Pituitary-Ovarian Axis
A
-
Hypothalamus
-
Gonadotropin Releasing Hormone (GnRH)
- Pulsatile secretion
- Hypothalamic arcuate nucleus → hypothalamic-pituitary portal vascular system
- T½ of 2-4 mins
-
Ovarian function requires pulsatile secretion of GnRH in a specific pattern
- Changes throughout the cycle
- Ranges from 60 min to 4 hours
-
Gonadotropin Releasing Hormone (GnRH)
-
Anterior Pituitary
-
Gonadotropins
-
Follicle Stimulating Hormone (FSH) & Luteinizing Hormone (LH)
- Glycoprotein hormones
- Pulsatile secretion
- Magnitude and rate secretion determined by ovarian steroid hormone levels
-
Follicle Stimulating Hormone (FSH) & Luteinizing Hormone (LH)
-
Gonadotropins
-
Ovary
-
Ovarian Sex Steroid Hormones
- Estrogen and Progesterone
- Also Inhibit A and Inhibit B
-
Ovarian Sex Steroid Hormones
2
Q
Two Cell Theory of Estrogen Production
A
-
Theca cells ⇒ produce androgens
- Responsive to LH
- Androgens enter granulosa cells by diffusion and converted to estrogen
-
Granulosa cells ⇒ produce estrone and estradiol
- Responsive to FSH
3
Q
Menstrual Cycle
Characteristics
A
- Average age of menarche = 12.4 yrs
- Average age of menopause = 51.4
- Average duration of cycles = 28 days w/ range of 21-35
- Cycle length longer than 35 days = oligomenorrhea
- Cycle length shorter than 21 days = polymenorrhea
- Average blood loss = 20-60 mL (greater than 80 mL is abnormal)
4
Q
Menstrual Cycle
Ovarian Phases
A
-
Follicular Phase
- All hormones ↓ ⇒ no neg. feedback on FSH
- ↑ FSH ⇒ granulosa cells ⇒ cuboidal, make estradiol, LH receptors
-
↑ [Estradiol]
- Mixed action on pituitary gland ⇒ ↓ FSH / ↑ LH
- Several follicles begin to mature
- Dominant follicle emerges (most granulosa cells and FSH receptors, highest estradiol production)
- LH binds theca cells ⇒ prep for production of androgens and progesterone
- Dominant follicle secretes inc. amounts of estradiol (peaks ~ 24 hrs prior to ovulation)
- Feedback on pituitary switches from ⊖ to ⊕ ⇒ ↑↑↑ LH production
-
LH surge: cycle day 11-13
- Last for 48 hrs w/ ovulation occurring 36 hrs after the surge
- Non-dominant follicles ⇒ ↑ androgens
- Granulosa and theca cells ⇒ progesterone ⇒ slows follicular phase
-
Ovulation
- Process in which the oocyte is released from the follicle
- Occurs 36 hrs after LH surge
-
LH surge causes:
-
Meiosis of primary follicle resumes ⇒ completion of Metaphase I ⇒ 1st polar body released
- Oocyte arrests in metaphase II until fertilization
- Synthesis of proteolytic enzymes and prostaglandins ⇒ aid in follicular rupture
-
Meiosis of primary follicle resumes ⇒ completion of Metaphase I ⇒ 1st polar body released
-
Release of the oocyte from the follicle
- ⊗ Genes for follicular phase
- ⊕ Genes for ovulation and luteinization
- Mittelschmerz = brief discomfort noticed by some @ time of ovulation
-
Luteal Phase
-
Following release of the oocyte, follicle becomes a corpus luteum ⇒ progesterone and inhibin ⇒ ends ovulation
- Granulosa cells → granulosa-lutein cells / theca cells → theca lutein cells
- Estradiol ⇒ ↑ # of LH receptors on granulosa and theca cells
- LH surge ⇒ granulosa cells and theca cells switch from estrogen to progesterone
-
Progesterone production begins ~ 24 hrs before ovulation
- Peaks at 3-4 days after ovulation
- Maintained for 11 days after ovulation
- If implantation does not occur, then levels rapidly decrease
- Progesterone ⇒ ⊗ FSH and LH from ant. pituitary
- Inhibin A ⇒ ⊗ FSH
- Estradiol levels drop after LH surge, but then slowly begin to rise again throughout the luteal phase
- Lifespan of corpus luteum is 13-14 days if no conception occurs
- ↓ Estrogen and progesterone ⇒ ↑ FSH ⇒ reinitiate cycle
- Success of this phase dependent on follicular development and proper FSH production
-
Following release of the oocyte, follicle becomes a corpus luteum ⇒ progesterone and inhibin ⇒ ends ovulation
5
Q
Ovarian Menstrual Changes
A
6
Q
Uterine Menstrual Changes
A
- Ovarian follicular phase ⇒ uterine proliferative phase
- Prepares for implantation
- Ovulation ⇒ takes several days for uterus to respond
- Ovarian luteal phase ⇒ uterine secretory phase
- Process for zygote survival
- No pregnancy ⇒ menstruation
7
Q
Menstrual Cycle
Other Effects
A
-
Endocervix
-
Estrogens ⇒ clear, thin, watery mucus
- Max mucus production @ ovulation
- Mucus facilitates sperm capture, storage, and transport
- Ovulation and progesterone ⇒ ↓ mucus production
-
Estrogens ⇒ clear, thin, watery mucus
-
Breast
- Progesterone in luteal phase ⇒ tenderness and fullness
-
Vagina
- Estrogen ⇒ promotes growth of vaginal epithelium & maturation of superficial epithelial cells
- Progesterone ⇒ ↓ vaginal secretions
8
Q
Hormonal Contraception
A
-
Oral preparations:
- Estrogen + progesterone
- Progesterone only
- Transdermal, injectable, implantable, transmucosal
-
Progesterone component provides contraceptive effect
- ⊗ LH secretion ⇒ ⊗ ovulation
- Thickening of endocervical mucus
- ∆ Fallopian tube peristalsis ⇒ ⊗ sperm movement and fertilization
9
Q
GnRH Agonist
A
- ⊗ Pituitary gland⇒ ↓LH and FSH
- Initially ⊕ GnRH release ⇒ receptor saturation ⇒ receptor desensitization and down-regulation
- Treatment for endometriosis, uterine fibroids, precocious puberty
- Side effects: hot flushes, night sweats, vaginal dryness, osteopenia
10
Q
Menopause
Epidemiology
A
Natural age of menopause is ~ 51 years
In the US, currently 60 million perimenopausal and postmenopausal women
11
Q
Menopause-related
Disorders
A
- Major diseases affecting women begin to occur 10 years after menopause
- Cancer, cardiovascular disease, cognitive decline, arthritis, dementia, depression
- Cardiovascular disease = leading cause of death in postmenopausal women
12
Q
Postmenopausal Woman
Management
A
Institute prevention strategies @ onset of menopause:
-
Sx control and comprehensive issues of quality-of-life
-
Vasomotor sx: hot flashes and night sweats
- Affect the overall wellbeing of women, on average persist for 7.4 years
-
Vasomotor sx: hot flashes and night sweats
-
Promotion of bone health and prevention of osteoporosis
-
↓ [Estrogen] ⇒ ↑ bone resorption
- 35% of white postmenopausal women have osteoporosis
- Lifetime fracture risk of 40%
- DEXA scan
-
↓ [Estrogen] ⇒ ↑ bone resorption
- Cardiovascular health, combating obesity and metabolic concerns ⇒ education and lifestyle modification
- Prevention and surveillance of cancer ⇒ focus on breast, uterine, and colon
- Prevention of cognitive decline ⇒ lifestyle management and mental stimulation exercises
13
Q
DEXA scan
(Dual Energy X-Ray Absorptiometry)
A
- Assessment of bone mass @ hip and spine
- T score ⇒ comparison to peak bone mass of normative group
- Z score ⇒ comparison to age expected bone mass of normative group
- Osteoporosis = T-score more negative than -2.5
14
Q
Hormone Replacement Therapy
Indications
A
- Vasomotor sx: hot flashes, night sweats
- Vulvovaginal sx: dryness, painful intercourse
- Prevention of osteoporosis in women at risk
15
Q
Women’s Health Initiative
A
Large study w/ a focus on hormonal treatment of menopausal sx
Initial results: ↑ risk of breast CA, CAD, and decline in cognition
Upon further analysis: no sign. ↑ in CAD and actually ↓ coronary events in younger women; no ↑ breast CA risk; reduction in overall mortality; improved verbal memory in women < 60 y/o
16
Q
Hormone Replacement Therapy
Risks
A
-
Hypertension
- ± Slight ↑ in BP
- Essential HTN is not a contraindication
- Monitor for changes
-
Strokes
- Rare occurrence of ischemic strokes
- Highly related to co-morbidities (esp. HTN and obesity)
-
Thrombosis
- Related to oral estrogen dose related
- Generally occurs within 1st year of use (underlying thrombophilia)
17
Q
Alternatives to Hormonal Therapy
A
-
Selective Serotonin Reuptake Inhibitors (SSRI)
- Paroxetine is the only FDA approved medication (other than hormones) for tx of menopausal sx
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
- Gabapentin: generally used if a pt does not respond to SSRI/SNRI
-
Clonidine: centrally acting antihypertensive
- Need to use caution in normotensive women
- Soy isoflavones and Black Cohosh: natural remedies, no Rx needed
18
Q
Hormone Replacement Therapy
Summary
A
-
Disease prevalence inc. substantially ~ 10 yrs after menopause
- Opportunity to institute prevention strategies @ onset of menopause w/ HRT
- Women’s Health Initiative Study was largely misinterpreted
- HRT is efficacious for menopausal sx and prevention of osteoporosis
- HRT in younger women decreases mortality
- Several alternatives for vasomotor sx and preventing osteoporosis
- In younger, healthy women the benefits outweigh the risks
19
Q
Amenorrhea
Definitions
A
Amenorrhea: absence of bleeding for at least 3 cycles or at least 6 months in those w/ irregular cycles
Oligomenorrhea: cycles of bleeding w/ intervals longer than 35 days
Polymenorrhea: bleeding that occurs at intervals less than 21 days
20
Q
Types of Amenorrhea
A
-
Primary
- No menses by age 13 w/o secondary sexual characteristics
- No menses by age 15 w/ secondary sexual characteristics
-
Secondary
- Menstruating female w/o menses for 3-6 months or the duration of 3 typical cycles in a pt w/ oligomenorrhea
21
Q
Amenorrhea
Etiologies
A
- Pregnancy
- Hypothalamic pituitary dysfunction
- Ovarian dysfunction
- Alteration of outflow tract
22
Q
Pregnancy
A
Most common cause of secondary amenorrhea
Urine hCG (cheap and easy)
23
Q
Hypothalamic Pituitary Dysfunction
A
Low FSH, low LH
Hypogonadotropic Hypogonadism
-
Functional ⇒ low FSH, low LH, nl prolactin
- Weight loss (extreme)
- Obesity
- Excessive exercise (lean body mass)
-
Drug Induced ⇒ low FSH, low LH, nl prolactin
- Marijuana
- Psychiatric drugs: antidepressants
-
Neoplastic
- Prolactin secreting pituitary adenoma ⇒ low FSH, low LH, high prolactin
- Craniopharyngioma
- Hypothalamic hamartoma
- Radiation
-
Other
- Chronic medical illness: ESRD
- Inherited: Kallman Syndrome, Idiopathic hypogonadotropic hypogonadism
24
Q
Ovarian Dysfunction
A
High FSH, high LH
Hypergonadotropic Hypogonadism
-
Chromosomal Abnormality
- Gonadal dysgenesis
- Abnormal Karyotype
- Turner Syndrome 45X
- Normal Karyotype
- Single gene disorders
- Mutations in CYP17 gene: leads to ↓ estrogen
- Single gene disorders
-
Gonadotropin-resistant ovarian syndrome:
- Mutation of LH and/or FSH receptors
- Premature natural menopause: idiopathic
- Autoimmune ovarian failure: polyglandular failure (thyroid & adrenal)
25
Alteration of Outflow Tract
_Primary_
**Labial agglutination, imperforate hymen, transverse septum, cervical stenosis, Mullerian agenesis**
_Secondary_
**Asherman Syndrome**: synechia (scar tissue) following trauma to the endometrium
26
Amenorrhea
Evaluation
* **History**
* **Physical Exam**
* **Laboratory/Imaging**
* **Progesterone Challenge Test**
* **Determine adequate estrogen, competent endometrium and patent outflow tract**
* Give 10mg Provera daily for 10 days
* Induce a withdrawal bleed a few days after completing the oral course
* **⊕ Bleeding** ⇒ anovulation or oligo-ovulation
* **⊖ Bleeding** ⇒ hypo-estrogenic or anatomic
27
Amenorrhea
Treatment
* **Hyperprolactinemia**
* _Amenorrhea w/ galactorrhea_
* Treat w/ **cabergoline or bromocriptine**
* Dopamine agonists
* Check for **hypothyroidism** (5%)
* Low thyroxine levels ⇒ ↑ TRH & ↓ dopamine ⇒ ↑ prolactin
* _If pregnancy is desired:_
* **Clomiphene citrate, pulsatile GnRH, aromatase inhibitors**
* **Oligo/anovulation**
* **OCP** to regulate cycle
* **Clomiphene citrate** if pregnancy desired
* **Abnormal Genital Tract**
* Surgery
* Hymenotomy
* Removal of septum
* Mullerian agenesis cannot be repaired
* **Hypothalamic Pituitary Dysfunction**
* Pulsatile GnRH or human menopausal gonadotropins
28
Abnormal Uterine Bleeding
Definitions
* **Menorrhagia**: prolonged or excessive bleeding at regular intervals; \> 7 days or \> 80 mL
* **Metrorrhagia**: irregular intervals of bleeding
* **Menometrorrhagia**: prolonged bleeding at irregular intervals
29
Menstruation Pathophysiology
* _Endometrium consists of 2 distinct layers_
* **Basalis layer**
* Direct contact w/ myometrium
* Serves as the source of regeneration for functionalis layer
* Less responsive to hormones
* **Functionalis layer**
* Lies above basalis layer
* Lines endometrial cavity
* Responds to cyclic hormonal changes
* Layer that is sloughed during menstruation
* _Blood Supply_
* **Uterine and ovarian arteries** ⇒ uterus
* Uterine aa → **arcuate aa** → **radial aa** → basal and spiral aa
* **Basal aa** ⇒ basalis layer
* **Spiral aa** ⇒ functionalis layer
* Spiral aa → **arterioles**
* Become increasingly coiled and demonstrate _stasis_ of blood flow prior to menses
* Give rise to a network of capillaries which _vasodilate and bleed_
* Subsequent _vasoconstriction_ ⇒ **ischemia and necrosis**
* Process ultimately leads to **sloughing of the endometrial lining** w/ menstruation
30
Abnormal Uterine Bleeding
Etiologies
* Complications of Pregnancy
* Structural Causes (PALM)
* Nonstructural Causes (COEIN)
31
Abnormal Uterine Bleeding
Complications of Pregnancy
_First trimester spontaneous abortion (miscarriage)_
* **Threatened abortion** (threatened miscarriage) ⇒ Os closed
* **Inevitable abortion** ⇒ Os open
* **Incomplete abortion** ⇒ Os open, intrauterine tissue
* **Complete abortion** ⇒ Os closed, no intrauterine tissue
* **Missed abortion**
* **Septic abortion**
* **Ectopic pregnancy**
* **Hydatidiform mole, choriocarcinoma** (Gestational trophoblastic disease)
32
Abnormal Uterine Bleeding
Structural Causes
(PALM)
* **P**olyp
* **A**denomyosis
* **L**eiomyoma
* Submucosal Leiomyoma
* Other Leiomyoma
* **M**alignancy and hyperplasia
33
Abnormal Uterine Bleeding
Nonstructural Causes
(COEIN)
* **C**oagulopathy
* **O**vulatory dysfunction
* **E**ndometrial
* **I**atrogenic
* **N**ot yet classified
34
Abnormal Uterine Bleeding
History
* **Menstrual hx**: age at menarche, cycle length, number of days of flow, character of bleeding, and amount
* **Weight change**
* **Stress** (physical, mental/ chronic, acute)
* **Medical hx**: chronic systemic illnesses, unusual bleeding, prolonged bleeding or easy bruising, thyroid disease, etc.
* **Surgical hx**: especially gynecologic
* **Medications**
* **Family hx**
* **Social hx**: including abuse
35
Abnormal Uterine Bleeding
Physical Exam
* **Skin**: Hirsutism, acne, pigmentation/striae
* **Weight, heigh**t: obesity, leanness
* **Thyroid**: mass, diffuse enlargement
* **Breast**: development, galactorrhea
* **Abdominal**: mass
* **Pelvic**: abnormal development, clitoromegaly, mass
* **Rectal**: presence of hemorrhoids
36
Abnormal Uterine Bleeding
Diagnostic Evaluation
* _Laboratory tests_
* _Always:_
* **Pregnancy test** (β-hCG level)
* **CBC w/ platelet count** (iron studies if needed)
* _If indicated:_
* TSH
* Prolactin
* FSH, LH
* Testosterone
* DHEAS
* Progesterone
* Coagulation Profile
* Esp. in adolescents (at least 5% of hospitalized pts w/ bleeding dyscrasia and/or leukemia)
* PT; PTT; Factor VIII; von Willebrand’s Factor antigen
* Chlamydia trachomatis
* _Imaging_
* Pelvic US
* Sonohysterogram
* Hysteroscopy
* MRI
* _Tissue sampling methods_
* Endometrial Biopsy (office vs OR)
37
Abnormal Uterine Bleeding
Age-Based Common DDx
* **13-18 y/o**
* Anovulation (immature HPO)
* OCP use
* Pregnancy
* Pelvic infection
* Coagulopathies
* **19-39 y/o**
* Pregnancy
* Structural lesions
* Anovulatory cycles
* OCP use
* Endometrial hyperplasia
* **40 y/o – menopause**
* Anovulatory bleeding (declining ovarian function)
* Endometrial hyperplasia
* Endometrial atrophy
* Structural lesions
38
Anovulatory Bleeding
Treatment Overview
Primary goal in tx is to **ensure regular shedding of endometrium**
**Progesterone** for minimum of 10 days per month
**Oral contraceptive pills (OCP)**
39
Anovulatory Bleeding
Medical Management
**Acute episodes of bleeding**
* _Control the current episode_
* **High dose estrogen/progestin therapy**
* **OCP cascade** (monophasic regimen)
* Severe blood loss but pt hemodynamically stable
* Does not cause rapid endometrial proliferation
* Not as effective as combine equine estrogen (CEE)
* **IV estrogen** (combine equine estrogen [CEE])
* Rapid cellular proliferation of denuded and raw surfaces of endometrium
* ↑ Platelet aggregation
* _Prevent future episodes_
* **OCP/IUD**
* **Progestins** (progestogens which act like progesterone)
* Stop endometrial growth
* Allows stabilization of endometrium ⇒ organized sloughing
* ↑ Arachidonic acid ⇒ ↑ PGF2a (potent vasoconstrictor)
* Not for acute situations
* **NSAIDS**
* Prostaglandin inhibitors
* Reduction of blood loss up to 50%
* **GnRH analogs**
* Binds GnRH receptor ⇒ gradual downregulation ⇒ ↓ release of GnRH
* Induces medical menopause by suppressing HPO axis
* Temporizing measure because long term may lead to bone loss (osteopenia and/or osteoporosis)
* **Blood transfusion(s)** and **Iron supplementation** when indicated
40
Estrogen Risks
* **Estrogen**
* **↑ Risk of thrombosis**
* Contraindications:
* Estrogen dependent tumor
* Hx of DVT
* Some rheumatologic diseases
* In these cases, progestins should be used
* **OCPs**
* Relative contraindications: **cardiovascular disease, HTN, DM**
* Contraindicated: **women \> 35y/o who smoke, hx of thromboembolism**
41
Anovulatory Bleeding
Surgical Management
**1°** **tx for organic or structural cause** (e.g. leiomyoma, polyp, cancer)
**When medical tx fails or is contraindicated**
* **Dilation and curettage**
* Can be diagnostic and therapeutic
* Enhanced by use of hysteroscopy
* **Endometrial Resection or Ablation**
* Endometrium removed or resected w/ **electrocautery** or **heated saline** inside an intrauterine balloon, **microwave**
* **± Hormonal pretreatment** ⇒ thin endometrial lining
* Alternative to hysterectomy
* Low risk procedure in general but complications can be significant
* Fluid overload, uterine perforation w/ subsequent damage to major organs
* _Not for women who want to maintain fertility_
* **Uterine Artery Embolization**
* Effective and less invasive option for **women w/ leiomyomata**
* Performed by Interventional Radiology
* **Small microspheres** injected into uterine aa ⇒ ⊗ blood flow to uterus
* Causes necrosis of myomas
* With time reduces the amount of blood loss w/ menses
* Successful in approximately 90% of women
* _Not for women who want to maintain fertility_
* **Hysterectomy**
* Performed by laparotomy, laparoscopy or robot
* Definitive tx
* _Performed once childbearing is complete_
42
Polycystic Ovarian Syndrome
Overview
* _Most common cause_ of **androgen excess and hirsutism**
* Etiology is unknown
* Symptoms: **Oligomenorrhea/amenorrhea, Acne, Hirsutism, Infertility**
43
Polycystic Ovarian Syndrome
Diagnosis
* Primarily defined by **androgen excess**
* **Rotterdam Criteria** (must have 2)
* Oligoovulation or anovulation (irregular menstrual cycles)
* Biochemical or clinical evidence of hyperandrogenism
* Polycystic appearing ovaries on ultrasound
* _Need to rule out:_
* Congenital adrenal hyperplasia
* Cushing’s Syndrome
* Hyperprolactinemia
44
Polycystic Ovarian Syndrome
Pathophysiology
* **Anovulation** in PCOS ⇒ **constant, non-cyclic estrogen production**
* Stimulates **growth and development of endometrium**
* Endometrium **outgrows blood supply**
* **Sloughs at irregular intervals** and in **unpredictable amounts**
* Ultimately results in **irregular bleeding**
45
Polycystic Ovarian Syndrome
Associated Conditions
* **Obesity** is linked to PCOS in many pts
* **Metabolic Syndrome**
* 40% of pts w/ PCOS have impaired glucose tolerance
* 8% have Type 2 DM
* **Lipid abnormalities**
* **HTN**
46
Polycystic Ovarian Syndrome
Labs
* ↑ LH:FSH ratio
* ↑ Estrone compared to estradiol
* ↑ Testosterone
* ↑ Androstenedione
47
Polycystic Ovarian Syndrome
Complications
* Endometrial hyperplasia or cancer
* DM
* HLD
* Metabolic syndrome
* Cardiovascular disease
48
Polycystic Ovarian Syndrome
Treatment
* Most common tx is **OCPs**
* ⊗ Pituitary LH ⇒ ↓ androstenedione and testosterone
* Acne clear
* New hair growth is prevented
* _If conception is desired:_
* **Weight reduction**
* **Clomiphene citrate**
* **Metformin**
