Gondal Physiology and Pharmacology

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 Contraindications/Cautions:contraceptives
thrombophlebitis thromboembolic history cerebrovascular disease history (or active) bleeding: unknown cause
known/possible breast tumor; other estrogen-dependent cancer liver disease asthma migraine
eczema hypertension optic neuritis diabetes
retrobulbar neuritis epilepsy edema (e.g. CHF patients) adolescents, before epiphysial closure

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  •  Drug interactions with antibiotics:

    • antibiotics may decrease contraceptive efficacy (associated with a decrease in enterohepatic cycling secondary to decrease in gastrointestinal flora)

      •  enterohepatic cycling increases estrogen bioavailability

  •  Contraception: Progestin monotherapy

    • High incidence of abnormal bleeding

      • decreases with time

      • amenorrhea is common

    • Contraceptive Effectiveness: similar to IUD/combination formulations containing 20-30 ug ethinyl estradiol

    • Depot medroxyprogesterone acetate (DMPA)/three months provides extended inhibition of ovulation

      • suppression of ovulation may persist for over year in a half following

      • treatment discontinuation (after final injection)

      • Long-term DMPA

        • decreases as for blood loss

        • decreases endometrial cancer risk

    • Progestin implants (subcutaneous) -- L-Norgestrel

      • Extremely effective

      • Duration of effect: 5-6 years

      • capsules: release between 33% and 50% as much steroid as world contraceptive patients

        • low hormone levels resulted in:

          •  little effect on lipoproteins metabolism

          •  limited effect on carbohydrate metabolism

          •  limited effect on BP

      •  Disadvantages:

        • requirement of surgical of insertion/removal

        • irregular bleeding

      • Advantages: progestin contraception-- patients with:

        •  hepatic disease

        • hypertension

        •  psychoses/mental retardation

        •   history of thromboembolic disease

      •  Side Effects:

        • dizziness, headache, loathing, weight gain, decreased glucose tolerance

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  • Postcoital Contraceptives:

    • "morning-after" pill: estrogen only or estrogen + progestins

    • typically, treatment within three days (72 hours): 99% effective

    • used often come currently with antiemetics (40% incidence of nausea/vomiting)

    •  Adverse Effects:

      • nausea/vomiting

      • headache

      • dizziness

      • breast tenderness

      • leg/abdominal cramps

    • Mifepristone (RU-486)

      •  progesterone & glucocorticoid receptor antagonist

      •  luteolytic action

      •  effective postcoital contraceptive in combination with prostaglandin

  • Beneficial Effects: Oral Contraceptives:

    • reduction in risk of:

      •  ovarian cysts

      •  ovarian cancer

      •  endometrial cancer

      •  benign breast disease

    • decreased incidence:

      •  pelvic inflammatory disease

      •  ectopic pregnancy

      •  iron deficiency

      •  duodenal ulcer

      •  rheumatoid arthritis

    • Improvement in Conditions:

      •  premenstrual symptoms

      •  endometriosis

      •  acne

      •  hirsuitismin

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Estrogen/Progesterone Inhibitors & Antagonists

  • Tamoxifen

    • Competitive partial agonist inhibitor of estradiol at estrogen receptors

    • nonsteroidal; orally active

    •  Adverse/Side effects:

      • hot flushes, nausea/vomiting (frequency = 25%)

      • Tamoxifen: in adjuvant therapy for breast cancer: (35% decrease in contralateral breast cancer frequency)

      • No improvement in outcome associated with treatment > 5 years

      • Tamoxifen (due to agonist properties) stimulates the endometrium; increasing endometrial cancer risk

      • Raloxifene does not appear to stimulate the endometrial

    •  Used in treating breast cancer--NCI Guidelines (4/1999)

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    • Stage I Breast Cancer

      • Following Surgery: Adjuvant therapy

      • For suitable estrogen-receptor negative (ER)-negative patients, adjuvant chemotherapy with a proven effective regimen.

        • There is continuing controversy concerning the routine use of adjuvant chemotherapy in all patients with ER-negative, node-negative cancers.

      • For ER-positive patients, adjuvant chemotherapy or tamoxifen (20 milligrams daily).

    • Stage II: Breast Cancer

      • Following Surgery: Adjuvant Therapy

      • Following the treatment used to control local disease, adjuvant combination chemotherapy is given to reduce the rate of recurrence and improve survival in pre- and postmenopausal node-positive patients.

        • Many different drug regimens have been developed.

          • Numerous studies have shown that combination chemotherapy is superior to single-agent treatment, and single-agent adjuvant chemotherapy should be avoided outside a clinical trial.

        • The drug combinations listed have been tested and provide therapeutic benefit.

        • Not all have been compared to an untreated control group in prospective randomized trials.

          • CMF: cyclophosphamide + methotrexate + fluorouracil.

          • Various recognized combinations of cyclophosphamide , doxorubicin, fluorouracil

          • CA +/- tamoxifen: cyclophosphamide + doxorubicin +/- tamoxifen

      • Following the treatment used to control local disease, adjuvant endocrine therapy with tamoxifen alone is given to reduce the rate of recurrence and improve survival in postmenopausal patients with lymph node involvement and positive hormone receptors.

        • Tamoxifen, either alone or combined with chemotherapy, prolongs disease-free survival when administered for 24 months as adjuvant therapy to postmenopausal women with axillary lymph node metastases.

        • In a large trial of 3887 postmenopausal women with node-positive and node-negative breast cancer randomized to receive either 2 or 5 years of adjuvant tamoxifen, the longer duration of tamoxifen appeared to improve disease-free and overall survival.

      • For ER-negative patients or ER-positive patients with large tumors, adjuvant chemotherapy with a proven effective regimen.

      • For ER-positive patients, adjuvant chemotherapy or tamoxifen (20 mg/day)

        • Data from the NSABP-B-16 protocol indicate that patients 50 years of age and older who have hormonally responsive, node-positive tumors treated with chemotherapy (AC) and tamoxifen had a significantly increased disease-free and overall survival when compared with patients given tamoxifen alone.

        • There was no apparent drug interaction between chemotherapy and tamoxifen.

    • Stage IIIB Breast Cancer(locally advanced, including inflammatory)

      • see: http://cancernet.nci.nih.gov/clinpdq/soa/Breast_cancer_Physician.html#9 for most current NCI recommendations

      • In stage IIIB breast cancer, initial surgery is generally limited to biopsy.

        • Removal of residual tumor may be performed if a good response is achieved with chemotherapy with or without radiation therapy.

      • Treatment options: Standard:

        • 1. Core needle biopsy, fine-needle aspiration or incisional biopsy for diagnosis and receptor protein assay followed by preoperative chemotherapy.

          • If the patient has a good response, local therapy with surgery and/or irradiation is recommended. If the response is poor, palliative radiation therapy may be recommended.

          • Chemotherapy regimens with or without hormones are given in conjunction with the above surgical and radiotherapeutic procedures. Chemotherapy can be given prior to surgery in cases where primary resection is not feasible or is technically difficult.

          • Commonly used chemotherapy regimens include:

            • CMF: cyclophosphamide + methotrexate + fluorouracil.

            • CAF: cyclophosphamide + doxorubicin + fluorouracil .

            • CA: cyclophosphamide + doxorubicin.

        • 3. If combination chemotherapy is contraindicated, pretreatment with tamoxifen may be recommended for patients whose tumors are positive for estrogen- and progesterone-receptor proteins.

    • Stage IV Breast Cancer

      • see: http://cancernet.nci.nih.gov/clinpdq/soa/Breast_cancer_Physician.html#9 for most current NCI recommendations

      • Treatment Options Standard:

        • A biopsy to determine histology and ER and PR levels.

        • If visceral disease is minimal or absent and ER and PR status is positive, hormonal therapy is an excellent first treatment.

        • Tamoxifen or oophorectomy can be used for premenopausal patients.

        • For patients who relapse following a period of response or prolonged stability on initial hormone therapy, either megestrol acetate, anastrozole, or letrozole can be valuable palliative treatment.

        • Megestrol is associated with weight gain, which may be an undesirable side effect.

      • If visceral disease is present or ER and PR status is negative, one of the following combination chemotherapy regimens will produce equivalent results:

        • CMF: cyclophosphamide + methotrexate + fluorouracil.

        • CAF: cyclophosphamide + doxorubicin + fluorouracil.

        • CA: cyclophosphamide + doxorubicin.

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  • Clomiphene:

    • partial agonist; weak estrogen

    • competitive inhibition: endogenous estrogens

    • ovulation-inducing drug

  •  Mifepristone (RU-486)

    • Overview:

      • "19-nor steroid": high affinity for progesterone receptors

      • competitively inhibits progesterone action at the receptor

      • Luteolytic properties when administered in mid-luteal time frame

      • long half-life

      • effective emergency postcoital contraceptive (dosage: 600 mg)

    • Possible Clinical Uses:

      • endometriosis

      • breast cancer

      • other neoplasms (with glucocorticoid/progesterone receptors)

    •  Present major use: mefepristone

      •  early pregnancy termination (effective approximately 85% of the time)

      • Major Adverse Effect: prolonged bleeding

  •  Danazol

    • Overview:

      • isoxazole derivative of ethisterone

      •  Suppresses ovarian function

      • slowly metabolize; half-life > or 15 hours

    • Mechanism of Action:

      •  inhibits midcycle LH/FSH surge

      • does not affect basal LH/FSH levels

    • Binds to many receptor types/proteins including:

      • androgen

      • progesterone

      • glucocorticoid

      • sex hormone-binding globulin

      • corticosteroid-binding globulin

    • Inhibit several cytochrome P450 systems, including:

      • P450scc -- cholesterol side chain-cleaving form

      • P450c11 -- 11-beta-hydroxylase

      • P450C17 -- 17-alpha-hydroxylase

      • P450c21 -- 21-hydroxylase

    • Clinical Uses: Danazol

      • Primary use: treating endometriosis

      • Other uses:

        • breast fibrocystic disease

        • hematologic

          • Christmas disease

          • idiopathic thrombocytopenic purpura

          • hemophilia

    •  Adverse Effects:Danazol

      • weight gain, edema, reduced breast size, acne, voice deepening, headache, hot flushes, libido changes, muscle cramps, increased hair growth

      •  Cautious Use:Danazol

        • in presence of hepatic dysfunction (danazol may cause some mild/moderate hepatocellular damage)

      •  Contraindications: Danazol: may cause urogenital anomalies in the newborn

        • in pregnancy

        • breast feeding

Other Ovarian Inhibitors

  • Anastrozole:

    • inhibits aromatase -- required for estrogen synthesis

    • effective in tamoxifen-resistant breast cancer

    • FDA approved for this use

    • Stage IV Breast Cancer: For patients who relapse following a period of response or prolonged stability on initial hormone therapy, either megestrol acetate, anastrozole, or letrozole can be valuable palliative treatment.

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  •  Letrozole/Fadrozole:

    • nonsteroidal aromatase inhibitors

    • comparably effective as tamoxifen

    • Stage IV Breast Cancer: For patients who relapse following a period of response or prolonged stability on initial hormone therapy, either megestrol acetate, anastrozole, or letrozole can be valuable palliative treatment.

  • Ovulation-Inducing Drugs

    • Clomiphene

      • Overview:

        • partial estrogen agonist; orally active

        • related to chlorotrianisene

        • slowly excreted

      • Pharmacological Effects:clomiphene

        • Mechanism of Action:

          • partial agonist at estrogen receptors

          • promotes enhanced gonadotropin & estrogen secretion

        • Effects:clomiphene

          • stimulates ovulation in patients with amenorrhea/other ovulatory abnormalities

          • unknown mechanism

      • Clinical Uses:clomiphene

        • promote ovulation patients wishing to become pregnant

        •  not useful if abnormality is due to underlying ovarian or pituitary failure

        • 80% of patients with amenorrhea/anovulatory abnormalities will initiate ovulatory cycling: 50% of these patients are likely to become pregnant

      •  Adverse Effects:clomiphene

        • Most common: hot flushes

        • Ovarian enlargement

        • a variety of other symptoms probably secondary to hormonal changes (due to ovulatory menstrual cycle)

      • Multiple pregnancy:frequency = 10%

      • Contraindications/Cautions:clomiphene

        • considered dosage reduction in patients with enlarged ovaries

        • treatment > one-year: possible increase risk for low-grade ovarian cancer
Primary Reference: Goldfien, A., The Gonadal Hormones and Inhibitors, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 653-680.
Carr, B. R. and Bradshaw, K.D, Disorders of the Ovary and Female Reproductive Tract , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2097-2115.