Aromatase inhibitors

Aromatase is an enzyme that converts testosterone to estradiol and androstenedione to the main estrogen source in the postmenopausal female estrone.

Aromatase inhibitors markedly reduce estrogen levels in postmenopausal women by deactivating or inhibiting aromatase, the enzyme responsible for estrogen synthesis from androgens.

Decrease the amount of estrogen in the body


Aromatase inhibitors (AIs), are effective in reducing estrogen by blocking the enzyme aromatase, which is responsible for the peripheral conversion of androgens to estrogen. 

Impedes the production of the majority of estrogen in peri and post menopausal women.

In pre-menopausal women, aromatase inhibitors may not be very effective at blocking estrogen production because the levels of aromatase in the ovaries are high, and aromatase inhibitors are active in women who are in either natural or medically induced post menopausal state.

Inhibit the peripheral conversion of androgens into estrogens and reduces circulating estrogens by more than 95% in postmenopausal women.

AIs  substantially decrease the risk of breast cancer in postmenopausal women. 

Function as an anti-estrogen by decreasing the biosynthesis of estrogen fro androgens, the primary estrogen biosynthesis pathway in postmenopausal women.

After menopause estrogens are produced primarily in the adrenals and adipose tissue by the conversion of androgens to estrogens by aromatization.

Unlike other hormonal treatments there is no clinically important suppression of cortisol or aldosterone.

Work by preventing the conversion of male hormones to estrogen and on therefore suitable only for women whose ovaries are no longer producing estrogen.

Not beneficial for premenopausal women because the ovaries are the primary site of estrogen biosynthesis prior to menopause.

Aromatase is a cytochrome P450 enzyme involved in the synthesis of estrogen and aromatase in inhibitors function as anti-estrogen by decreasing the biosynthesis of estrogen from androgens, the primary estrogen biosynthesis pathway in postmenopausal women.

Aromatase Inhibitors suppress residual estrogen level by more than 90% in postmenopausal women. 

Aromatase inhibitors are contraindicated in pre-menopausal women who are not undergoing ovarian suppression, because compensatory physiological responses induce ovarian estrogen production.

The replacement of tamoxifen with aromatase inhibitors results in a 2.7% reduction in the rate of reoccurrence at five years.

The sequential use of aromatase inhibitors after tamoxifen results in an absolute reduction of 2 1/2 percentage points in the rate of recurrence.

Two-thirds of breast cancers have aromatase activity creating estrogens available for breast cancer cells so that aromatase inhibitors decrease circulating levels of estrogen and local estrogen production in the breast cancer.

More than 50% of women receiving aromatase inhibitors experience dyspareunia.

Purpose is to deprive patients of circulating estrogen which may be required for cancer cell growth.

Associated with osteoporosis, osteoporotic fractures, musculoskeletal and arthritic discomfort, hot flashes, night sweats,vaginal dryness and impaired sexual function.

AIs can induce musculoskeletal symptoms (AIMSS).
Musculoskeletal symptoms include: joint pain and stiffness, including morning stiffness, but also carpal tunnel syndrome, tenosynovitis, myalgia, and muscle weakness, such as reduced grip strength.

AIMSS can be continuous or intermittent and can involve central joints such as the spine, hips, and shoulders, or peripheral joints, the elbows, wrists, knees, feet, or both.

Median time to AIMSS after the initiation of an AI is approximately six weeks, but can occur at any time.

The median time to peak AIMSS symptoms and AI discontinuation due to discomfort is approximately six months.

Vaginal dryness and decreased libido may lead to poor compliance and early discontinuation of the drugs.

Prevalence of AIMSS is about 45% with AIs.
The incidence of aromatase inhibitor induced musculoskeleton syndrome is higher with women with the last menstrual period within five years.
AIMSS associated with a greater BMI, prior taxane chemotherapy.
Prior tamoxifen exposure associated with decreased risk of AIMSS.

Aromatase Inhibitors cause more vaginal dryness than tamoxifen, likely due to the pro estrogen effect of the latter on the vagina and endometrium.

Sexual dysfunction in patients taking AIs is common with up to 50% reporting low sexual interest and 74% reporting insufficient lubrication.

Can give premenopausal women the benefit of aromatase inhibitors by causing them to become postmenopausal through the use of luteinizing homeone-releasing hormone suppressing ovarian function or surgically removing the ovaries.

Almost completely eradicate estrogen production causing bone density loss and risk of fractures.

During the first year of treatment in postmenopausal women one mineral density is reduced by 1.1-3.4%, exceeding annual menopausal bone loss of 1-2%.

AIs decrease bone mineral density; however, prevention trials report no increase in fractures.

Tendon synovial changes seen on serial MRI studies observed carpal tunnel thickening in more patients with AIs compared to Tamoxifen (Morales).

In a retrospective analysis of 12,000 women on treatment risk of bone loss was 27% compared to a non AI group, where risk of bone loss was 21% (Mincey).

There is minimally excess fracture risk from Aromatase inhibitors compared with tamoxifen with 11% higher for non-vertebral fractures, not significantly increase for hip fractures.

In an observation study of 1775 patients on long-term aromatase inhibitor therapy risk for major osteoporotic fracture, hip fracture or any fracture eas similar to the general population ( Leslie WD).

Estrogen deficiency as seen in menopause and with the use of aromatase inhibitors cause the formation of resorption cavities beyond which the osteoblasts can not completely repair resulting in loss of bone and bone integrity.

There are two categories of aromatase inhibitors: steroidal inhibitor exemestane and nonsteroid inhibitors, such as anastrozole and letrozole.

Exemestane a type 1 steroidal AI, binds reversibly to aromatase, causing permanent inactivation of the enzyme even after the drug is cleared from the circulation.

A nonsteroidal, type II, AI searches anastrozole and letrozole bind reversely to aromatase, thereby inhibiting the synthesis of estrogen.

Majority of symptoms associated with estrogen deprivation that arises.

Both type Iand type II AIs may reversibly increase bone resumption, and may increase the risk of bone fractures.

AIs may be you associated with dyslipidemias and joint/pain stiffness.

33-50% of patients have associated musculoskeletal symptoms.

The most common musculoskeletal symptoms are arthralgias, bone pain, and joint stiffness.

The joints most frequently involved with symptoms on the hands and wrists, and knees, ankles and feet, and less frequently back, hip and spinal facets.

Musculoskeletal symptoms generally occur within the first one to 3 months after the beginning of treatment.

Musculoskeletal symptoms may worsen with continued therapy.

Early onset of musculoskeletal symptoms combined with persistent or worsening symptoms is associated with poor adherence to treatment.

Musculoskeletal symptoms associated with previous taxane-based chemotherapy, recent onset of menopause and vitamin D deficiency.

Patients musculoskeletal pain in the hands and wrists decrease in grip strength.

Musculoskeletal pain is not associated with any laboratory abnormalities.

Two types of aromatase inhibitors, irreversible steroidal activators and reversible nonsteroidal imidazole-based inhibitors.

Superior to Tamoxifen in metastatic disease and early breast cancer in postmenopausal women as far as disease free survival, time to recurrence and tolerability.

The addition of aromatase inhibitors after 2-5 years of Tamoxifen for early postmenopausal breast cancer has demonstrated improved outcomes.

Gains in progression free survival in the metastatic setting compared to tamoxifen has moved these agents into the adjuvant setting.

The absolute reduction in risk of recurrence with aromatase inhibitors compared with tamoxifen in the adjuvant setting is modest, typically amounting to less than 5%.

Virtually all studies that compared aromatase inhibitor-based therapy with tamoxifen has demonstrated small disease free survival benefits to those receiving aromatase inhibitors.
The incorporation of aromatase inhibitors as part of adjuvant endocrine therapy is recommended for postmenopausal women, and pre-menopausal women with high risk, hormone receptor positive tumors are considered for ovarian suppression within aromatase inhibitor

Adjuvant endocrine therapy with aromatase inhibitors in postmenopausal women either after if the initial diagnosis or after 2-3 years of tamoxifen, for a total treatment of five years reduces the proportion of patients with a recurrence by about 30% compared with five years of tamoxifen alone.

In postmenopausal women of the use of adjuvant aromatase inhibitors either as the primary therapy or after 2-3 years of tamoxifen have yielded equivalent outcomes in prospective studies.

Extending aromatase inhibitor treatment from 5 to 10 years improves disease free survival in postmenopausal women with early breast cancer (MA.17 trial)

Use in adjuvant endocrine therapy with provides modest improvements in disease-free survival compared to tamoxifen in postmenopausal hormone responsive breast cancer survivors, but has failed to improve overall patient survival.

Postmenopausal women with receptor positive early breast cancer entered the BIG-1-98 study which compared tamoxifen with an aromatase inhibitor, and two sequential treatments of tamoxifen followed by an aromatase inhibitor and a aromatase inhibitor followed by tamoxifen: letrozole given alone, as compared to tamoxifen given alone reduced the risk of recurrent disease, especially at distant sites.

At a median follow-up of 71 months the BIG 1-98 study a randomized double blind trial of the treatment of hormone positive breast cancer in postmenopausal women (6182) with 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of one agent followed by 3 years of treatment with the other: disease free survival was not significantly improved with wither sequential treatment compared to letrozole alone and the updated analysis showed no significant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen.

At 8.1 years of follow up the five-year disease free survival was significantly improved in letrozole treated women compared with tamoxifen treated participants.
In the  BIG-98 study of patients with luminal breast cancers, PIK3CA mutations were the most common at 49% of genetic alterations, and were significantly associated with a reduction in the risk of distant recurrence.
In the BIG-98 study PIK3CA Mutations derived significantly greater benefit from letrozole over tamoxifen compared with patients whose tumors did not.

In patients with hormone+dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole and the steroidal inhibitor exemestane: have similar outcomes at 5 years (Goss PE et al).

Have displaced antiestrogens and progesterone treatments for metastatic breast cancer.

Substantially reduce the incidence of second primary cancers in the contralateral breast.

Aromatase Inhibitor boosts fertility in polycystic ovarian syndrome.

Extending aromatase inhibitors in hormone receptor positive patients beyond 5 years does not improve disease free interval.

The greatest benefit of extended adjuvant aromatase inhibitor therapy for breast cancer patients is probably the reduction in new primary breast cancer cases rather than a decrease in more serious distant recurrences.

Extending use of aromatase inhibitors beyond 5 years is associated with increased risk of fractures.

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