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Gynae > Menopause > Flashcards

Menopause Flashcards

1
Q

What’s is the menopausal transition? Age of onset?

A

Time from start of declining ovarian function to last menstrual period.

Average age of onset 47.5yrs

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2
Q

What is the climacteric?

A

Period from when ovaries start to fail until 12 months AFTER the LMP.

Aka perimenopause

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3
Q

What is menopause? Age in onset? Risk factors for earlier onset?

A

Menopause is the LMP.

Avg age of onset 51yrs.

Risk factors for early onset:
Family History of early menopause, T1DM and
Smoking

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4
Q

What is Postmenopause?

A

The time after the LMP.

Only known with certainty after 12 months post LMP.

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5
Q

What is Primary Ovarian Insufficiency/POI?

A

Menopause that occurs before age 40yrs.

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6
Q

Briefly explain the physiology of menopause.

A

Number and sensitivity of primordial follicles decreases ➡️ decreased estradiol (E2) levels and inhibin B secretion from granules cells ➡️ loss of inhibitory effect on hypothalamus and ant. Pituitary ➡️ increased FSH and LH production ➡️ increased LH stimulates androgen production from stromal cells ➡️ peripheral aromatization to estrogen (low quantities).

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7
Q

Briefly explain the physiology of menopause.

A

With menopause there is reduced number and sensitivity of primordial follicles ➡️ decreased oestrogen production ➡️ loss of inhibitory effect on hypothalamus and ant. Pituitary ➡️ increased FSH and LH production ➡️ increased LH stimulates androgen production from stromal cells ➡️ peripheral aromatization to estrogen (low quantities).

Ovarian Inhibin B production also decreases and the loss of negative feedback on the ant. Pituitary increases FSH production

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8
Q

What are the endocrine changes in the menopause transition?

A

Low inhibin B
High FSH

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9
Q

What are major sources of estrogen in postmenopausal women?

A

Estradiol/E2- produced by ovarian stromal cells
Estrone/E1- produced in low levels from peripheral aromatization of androstenedione (from adrenals).

E1 is less biologically active than E2 and the amount produced is relatively miniscule.

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10
Q

What are acute clinical signs of oestrogen deficiency?

A
  1. Cessation of menses
    2.Vasomotor symptoms (hot flushes, palpitations, sweating)
  2. Mood swings (depression, anxiety, irritability)
  3. Cognitive decline - forgetfulness, reduced verbal memory and difficulty concentrating
  4. Headaches
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11
Q

What percentage of women are affected by vasomotor symptoms? How long do symptoms persist

A
  • Occurs in 70-80% of perimenopausal women.
  • Median duration is 7 years, however symptoms become less intense and less frequent after 5 years w/o treatment.
    -38% of women will have persisting symptoms 14years after initial onset.
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12
Q

What are the medium term symptoms of menopause (5-10yrs post menopause)?

A
  1. Vaginal dryness and dyspareunia
  2. Reduced libido (due to
    dyspareunia or testosterone
    deficiency)
  3. Vaginal ph >4.5
    due to change in vaginal
    epithelium; encourages
    enterobacterial growth which increases risk of UTI (recurrent)
  4. Atrophic urethritis, decreased urethral mucosa seal, loss of compliance and irritation
    - predisposes to stress and urinary incontinence
  5. Generalized aches and pains, thinning hair and skin, brittle nails
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13
Q

What are the long term health implications of menopause?

A
  1. Diminished collagen integrity
    • UV prolapse
  2. Fragility fractures (trabecular bone is weaker)
  3. Decreased neurotransmitters
    - less dopamine and serotonin causes depression, irritability and mood swings
    - less acetylcholine decreases cognition, dementia
    - change in adrenergic and noradrenergic transmission can cause panic attacks & palpitations
  4. Cardiovascular disease
    • difficulty maintaining a
      healthy endothelium causes
      atherosclerosis
    • Central obesity (male pattern)
      - increases risk of breast ca
      and T2BM
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14
Q

What is the effect of HRT on the risks of breast and endometrial cancer?

A

Breast ca
There is only a small increased risk of breast ca for women on short term (5yrs) therapy.
- No Increased breast ca risk for women who start HRT for premature menopause.

Combined HRT has increases breast density (may make tumours harder to detect) on mammogram. Oestrogen-only HRT does NOT do this.
- progestogen addition increases breast ca risk compared to oestrogen only.

-Tibolone (steroid analogue) doubles breast ca risk.

Risks associated with obesity, alcohol and smoking are far greater for breast cancer than those for long term oestrogen only or sequential combined HRT.

Endometrial ca
Sequential combined HRT use for >10years causes 30: increased relative risk of endometrial ca
- patients should counselled about the benefit of using a cyclical course which provides lower doses of oestrogen. The downside is monthly withdrawal bleeding.

  • However progestogens decrease risk of endometrial cancer.
  • Oestrogen-only HRT use for more than 3 years increases risk of endometrial hyperplasia and endometrial cancer.
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15
Q

What is the role of progesterone therapy in HRT?

A

To protect the endometrium

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16
Q

What is HRT?

A

HRT is a treatment discipline centered around oestrogen as the fundamental component with or without the use of progesterone or its synthetic analogue.

Progesterone is used solely for endometrial protection.

There are 4 regimens that are used to provide HRT:
1. Oestrogen only regimens
2. Sequential combined regimens
3. Continuous combined regimens
4. Continuous progesterone
regimen/Synthetic steroidal
alternative
-e.g tibolone

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17
Q

Briefly describe the difference between the different HRT regimens?

A
  1. Oestrogen only regimens
  2. Sequential combined regimens
    (cyclical or long cycle)
    • 28-30 day cycle of estrogen +
      10-14 progesterone ➡️ cyclical
      withdrawal bleed
    • 12 week long cycle of estrogen
      + 14 days of progesterone at
      the end ➡️ 3mthly withdrawal
      bleed
  3. Continuous Combined regimen
    Daily oestrogen + progesterone
    given together so no withdrawal
    bleeding
  4. Continuous progestogen regimen
    A synthetic steroid (Tibolone)
    with estrogenic, androgenic
    & progestational activity➡️
    continuous exposure to progestational effects so no withdrawal bleeding.
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18
Q

What are the different estrogen preparations?

A

For systemic use:
1.Estradiol: transdermal (patch/gel)
oral
- micronized
- esterified
pellets
- as subcutaneous
implants
2. CEE/Conjugated Equine Estradiol
- as tablets
- concentrates of urine from pregnant mares containing >18 estrogen metabolites;
-main component EQUILIN

Estrodiol as a vaginal application:
1. Cream
2. Vaginal tablet
3. Vaginal ring

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19
Q

Briefly explain the effect of synthetic progestogens on receptors.

A

These synthetic analogues are more potent than than natural progesterone and aside from binding to progesterone receptors, they also bind to androgen/glucocorticoid/mineralocorticoid receptors with different affinity, hence the variation in S/E profile for the various analogues.

One of the full effects of oestrogen receptors is to induce synthesis of progesterone receptors➡️ which when activated by progesterone/progestational agent causes suppression of oestrogen receptor synthesis and stimulates production of 17beta hydroxyl-steroid dehydrogenase ➡️ which converts E2 to E1 (less biologically active).

This shows how progesterone and its analogues can antagonize protective oestrogenic effects in some tissues

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20
Q

Outline the types of progestational agents.

A

There are 4 types:
1.Microionized natural progesterone
- as capsules, vaginal pessaries/creams
2. 19-nor-testosterone derivatives
- More androgenic activity
- estranes vs Gonzales
- noethisterone vs levonorgestrel/dedogestrel, norgestimate, levogestrelm
3. Acetylated C17 hydroxyprogesterone derivatives
- Less androgenic activity
-acetylated vs nonacetylated
- Medroxyprogesterone actetate and cyproterone acetate vs dydrogestetone/medrogestone
4. Spironolactone derivative
- drospirenone
- binds mineralocorticoid receptor

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21
Q

Which pt is the LNG-IUS contraindicated in?

A

Patients with a h/o breast cancer as it doubles the risk of breast cancer when used with estrogens.

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22
Q

Indication for use of LNG-IUS?

A
  • Perimenopausal patients who require contraception along with HRT.
  • Pts on sequential HRT with heavy withdrawal bleeds
23
Q

How does Tibolone work?

A

Tibolone is a synthetic steroid that has an agonistic effect on oestrogen, androgen and progesterone receptors.
- It is therefore useful for relief of vasomotor symptoms, preventing bone loss and improving libido (unknown whether secondary to androgenic receptors agonist effect or overall improvement in menopausal symptoms).

24
Q

Adverse effects of tibolone?

A
  1. Doubles risk of Stroke!
  2. Spotting/irregular bleeding
  3. Mood changes
  4. Leucorrhea
25
Q

What are the routes of HRT and the pros and cons of each?

A
  1. Transdermal 2.Oral
  2. Intrauterine 4. Intravaginal

Transdermal oestrogens:patches/gel
- Provides direct access to systemic circulation, therefore more estradiol enters circulation compared to oral.
- avoids gut and hepatic first pass effect therefore the serum E2:E1 ratio is near unity compared to the 1:4 ratio with the oral route
- avoids bolus first pass effect on liver & subsequent increase in hepatic globular synthesis and coagulation factors
- does not affect lipoprotein profile
CONS: Expensive; sensitivity to the patch adhesive or the alcohol in the gel

Oral oestrogens
- cost effective, hence usu first choice
-acceptable route of admission
-beneficial effect on HDL, LDL and total cholesterol
CONS: all tablets contain lactose, increases triglycerides, high doses required to achieve good blood levels, variation in absorption and metabolism, increases hepatic protein synthesis (SBHG, coagulation factors)

Subcutaneous E2 pellets
- good for persons who cannot tolerate oral or transdermal preparations.
CONS: placement requires a surgical procedure, cannot be quickly removed if an adverse reaction, associated w/ tachyphylaxis (symptoms of estrogen deficiency w/high serum levels).

Vaginal E2: tablets, cream, pessary
* pessaries are hard plastic impregnated with E2 and are generally not well tolerated.

  • Vaginal E2 is indicated for genitourinary symptoms (dryness, dyspareunia, urgency and recurrent cytitis) and is beneficial as 1. very little reaches the systemic circulation ➡️ reducing potential adverse systemic effects. 2. Endometrial protection is not required
26
Q

What determines the route of HRT?

A
  • the clinical situation
  • patient preference
  • poor symptom control w/ a particular route
  • side effects (nausea w/ oral treatment)
  • lactose sensitivity (oral pills)
  • allergic rxn to adhesive or alcohol in gel
  • preexisting medical conditions
    • bowel d/o that affects
      absorption
    • hypertriglyceridaemia
  • Risk of stroke/VTE
  • enzyme inducing meds e.g antiepileptic drugs
27
Q

What is the effect of HRT of colon cancer?

A

Decreases the risk by a third.

28
Q

What is the effect of HRT on osteoporosis?

A

Decreases risk of fragility fractures by 30%

WHI showed that HRT reduced the risk of osteoporosis fragility fractures in the spine, hip and other areas.
Because oesteogen restores bone loss due to oestrogen deficiency by suppressing osteoclastic activity and stimulating osteoblastic activity. Trabecular bone is strengthened.

29
Q

Advice to women w/ osteoporosis on HRT?

A

Weight bearing exercises
Calcium and Vit D supplementation
Stop smoking
Reduce alcohol intake

30
Q

How long does genitourinary symptoms take to improve after starting HRT? When can the treatment be stopped?

A

Maximal improvement by 1-3 months. In some, may take up to a year.

Symptoms usu. return shortly after stopping treatment. So long term treatment is usually required.

31
Q

Benefits of HRT

A
  1. Vasomotor symptoms improve - w/in 4 weeks. This is the benchmark of a successful HRT regimen.
  2. Improved mood/sleep disturbances
    - improved vasomotor symptoms improves sleep, which w/ improved vasomotor symptoms improves her QOL, making her happier.
  3. Improved genitourinary symptoms (vaginal dryness/soreness, superficial dyspareunia, urinary frequency/uti)
  4. Improved libido - refer to points 3 as Improved vag dryness/dyspareunia may restore libido
  5. Improves osteoporosis and reduces risk of fragility fractures
  6. Decreased risk of colon ca
32
Q

Should HRT be used to prevent cardiovascular disease?

A

HRT should not be provided primarily for this function as its role remains uncertain.

Coronary Heart Disease
WHI study:
- increased risk with combined therapy >10years post menopause, especially ages 70-79yrs
- Women <60yrs on oestrogen-only tx w/in 10yrs of menopause - no sig. reduction but they had a 30% lower total mortality from stroke/CHD.

Stroke
- Older women starting HRT have a higher absolute risk since risk of stroke increases w/age.
- WHI study:
Oestrogen-only: no increased risk
Continuous combined HRT was compared to baseline risk (11.3cases/1000 women) over 7.5yrs - showed increased risk by 6 more cases/1000 women.
- LIFT study (long-term intervention on fractures with tibolone) showed a 2.2 times increased risk of stroke, mainly ischaemic, especially for >60yrs.

33
Q

Incidence of VTE in women aged 50-70yrs?

A

100-200 cases per 100,000 woman/ years

34
Q

Relative risk of VTE in HRT users vs OCPs?

A

1.6-2.7

OCPs: 7.5 fold increased risk of DVT
5.3 fold pulmonary embolism

35
Q

What are the patient related factors to consider when counseling a pt about starting HRT?

A

Age
Obesity
Cigarette smoking
Varicose veins
Personal/family h/o varicose veins
Disease affecting coagulopathy/fibrinolytic function
- factor V Leiden, protein c
deficiency

36
Q

When does the risk of VTE occurs for patients on progestogens?

A

Risk peaks in the first 1-2 years now use then drops to natural risk afterwards.

37
Q

Can HRT be prescribed to prevent or treat Alzheimer’s disease?

A
  • No as more studies/data is
    required hence HRT should.not be started solely for this purpose.
  • Observational studies show that HRT started in early menopause may reduce or delay the onset of AD.
  • medroxyprogesterone actetate has been found to increase neuronal plasticity and neurotransmission.
  • The Women’s Health Initiative Memory Study/WHIMS looked at the impact of HRT on AD in women 65 and older
    • concluded that combined oestrogen and progesterone therapy increased the risk of probable dementia if started after the age of 65.
38
Q

What is the impact of HRT on ovarian cancer?

A

WHI study:
- no sig. increase w/ combined HRT.

Million Women Trial:
A 5yr course of HRT may cause one extra case of ovarian cancer in every 2,500 users.

39
Q

What is the follow up therapy for HRT? What is the aim of follow up?

A

3 months, 6 months then yearly.

Aim:
1.to assess response to treatment;
2. determine if medication needs to
be adjusted or changed
3. Observe for adverse effects - AUB

Advise to do 3 yeary pap smear and 3 yearly mammogram after age 50.

40
Q

HRT choice for pts with TAH & BSO?

A

Oestrogen only HRT or tibolone (once no h/o breast cancer)

41
Q

HRT choice for pts with TAH only or USO?

A

Oestrogen only or Tibolone (once no h/o breast ca)

42
Q

How to confirm cessation of ovarian activity in the absence of vasomotor symptoms?

A

FSH>30 iu/L on 2 separate occasions

These pts can be started on HRT

43
Q

Treatment for urogenital symptoms?

A

Vaginal estrogen - cream, tablets/inserts/ pessary (unpopular choice due to patient discomfort)

44
Q

What percentage of HRT discontinuation is due to adverse effects?

A

35%

Patients should be advised to continue with treatment for at least 3 months, because MOST adverse effects resolve with increased duration of use.

45
Q

Natural remedies for menopausal symptoms?

A

Black cohosh
Ginseng
Red clover

Contain phyto-oestrogens

46
Q

HRT in patients with breast cancer?
What were the findings of the Liberate study, Habits trial and Stockholm Trial?

A
  • continous combined HRT has been associated with increased risk of recurrence. Evidence shows that progestational agents play a role in mammary carcinogenic. Daily oral estrogen with shorter courses of progesterone (cyclical sequential combined HRT) have been shown to have a insignificant decrease in breast cancer recurrence, as evidenced by the Stockholm Trial.
    Further to this point Tibolone was found to increase the risk of breast cancer in the Liberate Study.
  • other alternative to HRT include non-hormonal therapy (red clover, black cohosh, ginseng) but the FDA warns that phyto-oestrogens can interfere with tamoxifen therapy.

If the patient has severe symptoms of oesgrogen deficiency, then HRT can be started under specialist supervision and After the possible risks have been carefully explained to the patient and informed consent has been obtained.

  • Liberate study: Tibolone increases recurrence of breast ca. Thus implicating progestational agents in breast ca.

Stockholm Trial reduced progesterone exposed and avoid ccHRT. They used oral oestradiol and short courses of progesterone (cyclical sequential combined HRT). Results however an insignificant decrease in breast ca recurrence.

Habits Trial showed recurrence of breast ca by 3 fold wishing 2.1years

47
Q

Can HRT be given to patients with a h/o endometrial Cancer?

A

There appears to be very little risk associated. With oestrogen therapy after endometrial cancer. Patients with endometrial stromal sarcoma should be counselled at there is a lack of data about recurrence on HRT and that only she can decide of the risk of recurrence is acceptable in order to achieve symptom relief.

48
Q
  1. Can a patient w/ a personal h/o VTE can receive HRT?
  2. Pt develops VTE on HRT. Next step.
A
  1. Yes, transdermal therapy may be a better option.
  2. Stop the HRT.and treat treat VTE. If HRT needs to be continued after treatment, consider lifelong thromboprophylaxis.
49
Q

What advise would you give to a patient to reduce her RISK of osteoporosis?

A
  1. To exercise and avoid a sedentary exercise. Weight bearing exercise (with light weights) is beneficial.
  2. Increase dietary intake of calcium
  3. Commence calcium and vitamin D supplementation.
  4. Bisphosphonates
  5. SERMS e.g Raloxifene (preferred over tamoxifen, no effect on uterus)
50
Q

What is the MOA of bisphosphonates?

A

-Bisphosohonates are used to treat osteoporosis in the postmenopausal woman and other metabolic diseases.
- They bind strongly to the bone matrix and inhibit osteoclastic activity, thereby preventing bone loss.
- They are classified as Nitrogen and Non-nitrogen containing bisphosphonates.
- NBPs inhibit farnesyl diphosphate synthase and is more POTENT.
- They stimulate osteoblast activity and differentiation
E.g. zoledronic acid
- NNBPs induce the production of toxic analogs of adenosine triphosphate.

51
Q

Benefits of NBP and S/Es?

A

**Moa: inhibits farnesyl
diphosphate synthase; increases osteoblastic activity and differentiation

Benefits:
-Increases bone mineral density
-Suppresses bone turnover
-Reduces incidence of vertebral and nonvertebral fragility fractures

S/Es:
- oesophagitis
- gi discomfort ( most common cause of discontinuation)
- acute phase rxn
- hypocalcaemia
- uveitis

52
Q

T/F. Use of HRT for 10yrs is assoc with significant reduction in risk of hip fractures?

A

False. HRT use for 5-10yrs doesn’t provide enough protection to prevent fragility fractures. Treatment is lifelong

53
Q

Sequential combined HRT is associated with a reduced endometrial ca risk?

A

False. Sequential combined is associated with a higher risk of endometrial cancer.

  • think of it this way. Continuous administration of progesterone prevents endometrial proliferation, thus decreasing risk of endometriosis ca

Gynae (9 decks)

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