Men's and women's health ACCP

Question 1

What are the common symptoms of menopause

Answer 1

Common symptoms
a. Vasomotor symptoms, also known as hot flashes
i. Most common reason for treatment
ii. May interrupt sleep and cause insomnia
iii. May affect quality of life
iv. Occur in 75%–85% of women, usually within 12–24 months after the last menstrual period.
v. May cause increased skin temperature, nausea, dizziness, headache, palpitations, diaphoresis,
and night sweats.
b. Genitourinary syndrome of menopause (GSM): This syndrome includes genital symptoms of dryness,
burning, and irritation; urinary symptoms and conditions of dysuria, urgency, and recurrent
urinary tract infections (UTIs); and sexual symptoms of pain and dryness. (Menopause 2014;
21:1-6, Menopause 2017;24:1-26, Menopause 2020;27:976-92)
i. Decrease in estrogen and other sex steroids causes thinning of hair of the mons and shrinkage
of the labia minora; vulvovaginal atrophy (VVA) leads to pruritus and pain.
ii. Loss of lubrication leads to dyspareunia (pain during sexual intercourse).
iii. Vaginal pH changes and becomes more basic (from 4.5−5 to 6−8), creating a favorable environment
for bacterial colonization.
iv. Thinning of urethra and bladder lining and decreased muscle tone result in recurrent episodes
of urinary frequency, urgency with dysuria, and urinary tract infections.

Question 2

What are various FDA approved indications of various HT?

Answer 2

Treatment of moderate to severe vasomotor symptoms
(VMS), treatment of moderate to severe GSM because of menopause, prevention of postmenopausal
osteoporosis, hypoestrogenism caused by hypogonadism, castration or premature ovarian
failure.

Question 3

What are the recommendations for HT?

Answer 3

i. Menopausal symptom relief
(a) Moderate to severe vasomotor symptoms (primary HT indication)
1. Recommend lowest effective dose.
2. For women younger than 60 or women who are within 10 years of menopause onset
without contraindications or at a high risk of CVD or breast cancer, assess the baseline
risk of breast cancer and CVD, and consider risk when making a recommendation.
(b) Moderate-to-severe GSM
1. Moderate to severe vaginal symptoms – Recommend local ET versus systemic therapy
if treating vaginal symptoms only AND
2. Urinary health – Systemic HT may worsen stress incontinence; local ET therapy may
help with overactive bladder

(c) Sexual symptoms – HT not recommended for sole treatment of diminished libido
(d) Osteoporosis – EPT and ET indication for prevention, ↓ osteoporotic fractures, used only
when alternative therapies are not appropriate; ER agonists/antagonists may also be used
for osteoporosis. See section below

Question 4

For women with a high risk of VTE who request HT recommendation

Answer 4

Nonoral route at lowest effective
dose is recommended (if not contraindicated).

Question 5

For women with a high risk or history of breast cancer

Answer 5

Nonhormonal treatment is recommended
for symptom relief.

Question 6

For women with a high risk of CVD (known myocardial infarction [MI], cerebrovascular
disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus,
chronic kidney disease, and 10-year CVD risk greater than 10%

Answer 6

Nonhormonal treatment
is recommended for symptom relief.

Question 7

For women with a moderate risk of CVD

Answer 7

Transdermal estradiol with appropriate use of
progestogen (individualized) is recommended if HT is needed.

Question 8

What are the benefits of estrogen?

Answer 8

(a) Relieves genitourinary atrophy (if only symptom, may use estrogen vaginal product locally)
(b) Relieves vasomotor instability
(c) Osteoporosis: Reduction in hip fractures by 25%; reduction in vertebral fractures by 50%.
Estrogen reduces the rate of bone resorption but does not reverse bone loss.
(d) It was once thought to lower LDL and increase HDL; however, it was not shown to lower
coronary heart disease (CHD) according to the Heart and Estrogen/Progestin Replacement
Study (HERS; JAMA 1998;280:605-13) and the Women’s Health Initiative (WHI; JAMA
2002;288:321-33) trials.
(e) May help improve sleep by decreasing hot flashes

Question 9

What are the risks of estrogen?

Answer 9

(a) Adverse effects: Bloating, headache, breast tenderness (5%–10%)
(b) Endometrial cancer: Risk increases with unopposed estrogen use in women with an intact
uterus.
(1) Cancer risk increases 8-fold for 10–20 years of estrogen use.
(2) Not recommended for use in women with a history of endometrial cancer. Women
with early stage, low-risk endometrial cancers (grade 1 and 2 endometrioid subtypes
with negative estrogen and progesterone receptors) who used HT may have similar
recurrence and death rates but overall recommendation is to avoid HT use in women
with endometrial cancer, especially advanced stages (Menopause 2017;24:1-26).
(3) A progestogen is recommended in all women with an intact uterus using estrogen
(JAMA 1996;275:370-5, Menopause 2017;24:1-26).
(c) Breast cancer with unopposed estrogen: Uncertain
(1) WHI showed no increased risk and a nonsignificant decrease in risk in women who
use estrogen for an average of 7.2 years. May increase relative risk among women
who take estrogen for longer than 5 years, though some studies have not shown this
risk (Menopause 2017;24:1-26).
(2) Not recommended for use in women with a history of breast cancer (Menopause
2017;24:1-26).
(3) Risk seems to increase with the addition of the progestogen and be related to the
length of use. The risk is small and decreases after discontinuation of use.
(d) CHD: Possible increased risk of cardiovascular outcomes; not recommended for coronary
protection at any age (see text that follows for further information).
(e) Gallbladder effects: Use of oral estrogen may increase risk of gallbladder disease that may
result in gallstones, cholecystitis, cholecystectomy. Risk is slightly lower with medroxyprogesterone
acetate in combination with estrogen (Menopause 2017;24:1-26).

Question 10

Benefits of progestogen (progestogen is an umbrella term for progesterone [natural] and progestins
[synthetic]):

Answer 10

(a) Decreased risk of estrogen-induced irregular bleeding
(b) Decreased risk of endometrial hyperplasia and carcinoma

Question 11

What are the risk of progestogen?

Answer 11

(a) Adverse effects: Bloating, weight gain, irritability, depression (dose related)
(b) Unpredictable endometrial bleeding with continuous estrogen/progestin during first 8–12
months (30%–50%)

Question 12

Selected outcomes related to EPT and ET- cardiovascular

Answer 12

(a) Cardiovascular outcomes with conjugated estrogens and medroxyprogesterone acetate
(JAMA 1998;280:605-13)
(1) A longer duration of use leads to a greater decrease in relative hazards in nonfatal MI
and CHD death; however, there was an increased risk of venous thromboembolism
(VTE) and gallbladder disease.

(2) Conclusions of study: HT was not appropriate to initiate for secondary prevention of
CHD, but for women already using HT, long-term use might result in a decrease in
CHD.
(3) A follow-up study suggested that older women with CHD who used HT for longer than
6.8 years had a higher risk of VTE and biliary tract surgery (JAMA 2002;288:58-66).
(b) Other findings related to cardiovascular outcomes from various trials
(1) Venous thromboembolism
(A) Observational studies indicated increased risk.
(B) A randomized controlled trial, the WHI (JAMA 2002;288:321-33), found
increased risk in the EPT arm (18 additional VTEs per 10,000 women per year of
EPT) and in the estrogen only therapy (ET) arm (7 additional VTEs per 10,000
women per year of ET).
(C) In WHI, when EPT and ET were initiated in women 50–59 years of age, the risk
of VTE was lower in this age group (11 additional VTEs per 10,000 women per
year of EPT and 4 additional VTEs per 10,000 women per year of ET).

Question 13

Selected outcomes related to EPT and ET- stroke

Answer 13

(A) Both EPT and ET showed an increased risk of stroke (8 additional strokes per
10,000 women per year of EPT and 11 additional strokes per 10,000 women per
year of ET).
(B) Women 50–59 years of age had no significant increase in stroke with EPT in
the WHI, but in the ET group alone, risk doubled. Nurses’ Health Study showed
similar results (Cochrane Database Syst Rev 2015;3:CD002229).

Question 14

Selected outcomes related to EPT & ET -CHD

Answer 14

(A) Observational studies indicated therapy may decrease CHD risk, but most women
were younger than 55 and had entered menopause within the past 2–3 years.
(B) Randomized controlled trials indicated an increased risk of CHD, but women
had an average age of 63–64 years and had entered menopause about 10 years
earlier. When adjusted for age, the estrogen-only arm of the WHI trial matches
observational data, indicating a lower risk of CHD in younger patients.
(C) Data show women who begin HT within 10 years of entering menopause may
have a lower risk of CHD, whereas older women may have a higher risk of CHD.
(D) Coronary artery calcium, a marker associated with atheromatous plaque burden
and CHD risk, has been decreased in some observational studies. In the
WHI study, estrogen-only arm participants had lower concentrations of coronary
artery calcium after 7 years of treatment.
(E) Subclinical atherosclerosis, measured as carotid intima-media thickness, is
reduced in women who started estrogen therapy with or without a progestogen
less than 6 years past the time of menopause compared with placebo. This was
not true in women who started hormone therapy 10 years or more after menopause
onset (N Engl J Med 2016;374:1221-31).
(F) WHI findings (JAMA 2002;288:321-33). The WHI trial included conjugated
estrogens and medroxyprogesterone acetate in healthy women 50–79 years of
age for primary prevention of CHD. Controversy exists because the average age
of women was older; thus, increases in breast cancer or CVD could be caused by
age (Table 1).

(c) Further information suggests increased risk of ovarian cancer (data conflicting); longterm
use greater than 5 years may increase risk, particularly in estrogen-only therapy;
overall risk of occurrence considered rare, according to WHI data (JAMA 2009;302:298-
305). A more recent meta-analysis showed that hormone therapy, regardless of type or
regimen, was associated with an increased risk of ovarian cancer (Menopause 2016;4:417-
24, Menopause 2017;24:1-26).
(d) Lung cancer may be increased in older women with a history of smoking (Lancet
2009;374:1243-51); some data are conflicting. Seems to be more associated with EPT use
than with ET use.
(e) Cumulative 18-year follow-up on WHI trials of conjugated equine estrogens
(0.625 mg/day) and medroxyprogesterone acetate (2.5mg/day) used for a median of
5.6 years or conjugated equine estrogens alone for a median of 7.2 years showed no
difference in all-cause and cause-specific mortality risk (JAMA 2017;318(10):927-938).

Question 15

When is oral is used?

Answer 15

Used for vasomotor symptoms, also covers GSM if concomitant

Question 16

When transdermal is used?

Answer 16

For women who are intolerant of oral preparations, used for vasomotor
symptoms, also covers GSM if concomitant, according to 2015 Endocrine Society clinical
practice guideline first-line formulation for women with moderate risk of CVD if estrogen
is needed.

Question 17

Vaginal and local preparations

Answer 17

For women with GSM. In general, topical treatment is sufficient
and should be tried before oral preparations for patients experiencing no other symptoms
(Femring vaginal ring is only vaginal preparation indicated for vasomotor symptoms).

Question 18

What is hormone therapy treatment duration?

Answer 18

Therapy duration: Lowest dose for least amount of time. Check after 3 months to 1 year,
and try to discontinue if asymptomatic; if symptoms recur, treat for an additional 3 months;
best to limit treatment to less than 5 years.

Question 19

When unopposed estrogen apply?

Answer 19

(1) Women with a uterus must have a progestogen and cannot use estrogen alone; use of
estrogen alone in women with a uterus causes endometrial hypertrophy and increases
the risk of endometrial cancer. (Original reference: JAMA 1996;275:370-5).
(2) Estrogen taken daily without interruption is suggested for women with a hysterectomy.
(A) Transdermal estradiol patches can be used in women who are intolerant of oral
preparations or want nondaily administration

Question 20

Estrogen plus cyclic progestogen regimen

Answer 20

(1) Continuous estrogen daily
(2) Cyclic progestogen such as medroxyprogesterone acetate 5−10 mg/day or the equivalent
for 10–14 days/month
(3) Similar to female cycle, with a withdrawal bleed each cycle

Question 21

Estrogen plus continuous progestogen

Answer 21

(1) Continuous estrogen daily
(2) Continuous progestogen such as medroxyprogesterone acetate 1.5–2.5 mg/day or the
equivalent without interruption
(3) Irregular menstrual cycle for the first 8–12 months of therapy, leading to amenorrhea

Question 22

Intermittent

Answer 22

1) Continuous estrogen daily
(2) Three days on progestogen, 3 days off
(3) Seldom used

Question 23

What are the monitoring parameters employed?

Answer 23

(a) Monthly: Breast self-examination
(b) Annually: Breast examination by provider, mammography (or biannually per U.S.
Preventive Services Task Force), pelvic examination
(c) Evaluation of vaginal bleeding
(1) Unopposed estrogen: Any episode of vaginal bleeding unless the woman has had a
health assessment deemed normal in the past 6 months
(2) Estrogen plus cyclic progestogen: If bleeding occurs other than at the time of expected
withdrawal bleeding
(3) Estrogen plus continuous progestogen: If bleeding is heavier than normal, is prolonged
(longer than 10 days at a time), is frequent (more often than monthly), or
persists for more than 10 months after beginning therapy