Therapeutics of Estrogens/Progestins

Question 1

At what age does menopause most often occur naturally?

Answer 1

45-55 years

Question 2

What causes menopause?

Answer 2

The woman’s body stops ovulating, so estrogen levels drop significantly. The negative feedback of estrogen in the HPO axis is halted, so FSH levels rise sharply as well.

Question 3

How long must a woman go from her last period until the diagnosis of menopause?

Answer 3

12 consecutive months

Question 4

Name and describe the 3 stages surrounding menopause.

Answer 4

premenopausal: endocrine changes that occur leading up to menopause
perimenopause: endocrine changes that occur surrounding menopause, symptoms often occur starting here
postmenopause: endocrine changes after cessation of menstruation

Question 5

When do the worst symptoms of menopause occur?

Answer 5

usually during the first 1-2 years, but sx overall can occur for 7 or more years

Question 6

Describe the effect of estrogen/progesterone on the HPO axis, and the effects of high/low levels.

Answer 6

Estrogen and progesterone provide negative feedback (mediated by inhibin) on the hypothalamus and the anterior pituitary. When levels are low, as in menopause, the body tries to compensate by increasing GnRH, FSH, and LH as negative feedback is lost.

Question 7

What factors affect the age of onset of menopause?

Answer 7

(1) genetics
(2) ethnicity
(3) smoking
(4) hysterectomy with ovarian conservation

Question 8

clinical presentation of menopause

Answer 8

vasomotor sx (most common–hot flashes/night sweats)
irregular menses
mood changes
sleep disturbances
episodic amenorrhea
genitourinary syndrome (vulvovag. atrophy, dryness, dyspareunia)

Question 9

What are the long-term consequences of menopause?

Answer 9

CV dx
bone loss
osteoarthritis
skin changes (wrinkles)
balance issues
change in body composition

Question 10

When is hormonal therapy indicated in menopausal women?

Answer 10

severe vasomotor sx, vulvovaginal atrophy, osteoporosis prevention

Question 11

What are the absolute contraindications of hormone replacement therapy?

Answer 11

clotting disorders
unexplained vaginal bleeding
liver disease
estrogen dependent malignancies (endometrial/breast cancer)
stroke
pregnancy

Question 12

What is the main principle guiding estrogen monotherapy?

Answer 12

ONLY indicated for women without a uterus (no uterus -> do not have to worry about endometrial cancer)

Question 13

In estrogen/progestin combination therapy, what dosage forms of estrogen that do not require a progestin component?

Answer 13

topical products, low dose patches, Estring - stay relatively local, systemic exposure not great enough to warrant progestin

Question 14

What is the difference between Estring and Femring?

Answer 14

Femring has a higher level of estrogen, and therefore may require a progestin component, at least temporarily. Estring has a low enough estrogen dose that a progestin is not required.

“A ring is bigger than a string.”

Question 15

What is the general guideline for use of oral/transdermal estrogen use? Topical?

Answer 15

prescribe at the lowest dose for the shortest period of time for relief of vasomotor sx

topical exclusively for women experiencing vulvovaginal atrophy

Question 16

Women with an intact uterus require what in order to protect from risk of endometrial cancer/hyperplasia?

Answer 16

progestin

Question 17

Describe the results of the Women’s Health Initiative Study (in terms of number of CV events, cancers, and fractures).

Answer 17

Combo therapy resulted in increased CV events and breast cancers. There were, however, lower numbers of colorectal cancers and fractures. In estrogen monotherapy, there were increased strokes and VTEs. Heart attacks and cancers were not changed significantly. Fractures were still decreased.

Both studies demonstrated that there was no protection from cognitive impairment.

Question 18

What was the result of the extended post-intervention phase of the WHI? What recommendations came from these results?

Answer 18

The increased risk of these adverse effects from HRT depend on the age of initiation and the time since menopause. Thus, HRT is recommended only in women less then 60 y.o. and within 10 years of menopause with no evidence of CHD. Women outside 10 years of menopause are at an increased risk of CHD within the first two years of therapy. Women aged 70-79 and >20 years menopausal are at the highest risk. Women with previous CHD attain no additional protection from events with HRT.

Question 19

What was the ELITE trial designed to test?

Answer 19

the time-dependance of postmenopausal HRT. Women were divided into groups (within 6 years of MP, outside 10 years).

Question 20

What were the results of the ELITE trial?

Answer 20

Evidence showed that initiation of HRT within 6 years of menopause provided some protective effect, but not after 10 years of MP.

Question 21

What are the four types of estrogen/progestin combination therapies?

Answer 21

continuous cyclic, continuous long cycle, continuous combined, and intermittent combined

Question 22

Describe continuous cyclic hormone combination therapy.

Answer 22

Estrogen given daily, progestin given for at least 12-14 days every month. (Premphase and combipatch)

Question 23

How often will women on continuous long cycle therapy have a period?

Answer 23

every other month when progestin component is given

Question 24

What is one major concern with both continuous cyclic and continuous long cycle therapy?

Answer 24

both carry an increased risk of developing endometrial cancer

Question 25

Which hormone combination treatment is preferred due to its decreased risk of endometrial cancer?

Answer 25

continuous combined (Prepro, Angeliq, Activella, Combipatch, ClimaraPro)

Question 26

Continuous combination therapy is generally recommended for women __ years postmenopause.

Answer 26

2

Question 27

What is the advantage of the progesterone “pulse” created by intermittent combination therapy? Give an example.

Answer 27

Pulsing dose of progesterone prevents down-regulation of progesterone receptors that normally results in side effects (Prefest).

Question 28

Progestin administration helps with protection of the __________.

Answer 28

endometrium

Question 29

What is Duavee?

Answer 29

a combination therapy consisting of an estrogen and a SERM

Question 30

What is the selectivity of the SERM in Duavee?

Answer 30

antagonist in the breast and endometrium, agonist in the bone

Question 31

What are the disadvantages of Duavee?

Answer 31

increased VTE/DVT/stroke risk, overweight women less protected from endometrial hyperplasia

Question 32

Most, commonly, women will prefer this type of HRT.

Answer 32

transermal estrogen (+/-) progesterone depending on uterus

Question 33

What side effects are noted with estrogen/progesterone products? (both oral and transdermal)

Answer 33

N/V, HA, fluid retention, skin irritation

Question 34

Breast cancer risk during combination therapy increases after ___ years, while the risk with monotherapy increases after ___ years.

Answer 34

5, 7

Question 35

After women have been on HRT long enough to be at an increased risk for breast cancer, what changes should be made, if any, to their treatment regimen?

Answer 35

Evaluate dose/sx yearly, see if it is possible to start tapering down estrogen

Question 36

If a woman does not want to be on hormonal therapy for vasomotor sx of menopause, what alternatives are there?

Answer 36

SSRIs, SNRIs, gabapentin, pregabalin