Steroid Hormones

ADRENAL STEROIDS

•Nonendocrine uses: For use in inflammatory disorders (and accompany­ ing adverse effects), see Section VI, Drugs for Inflammatory and Related Disorders.

•Endocrine uses of glucocorticoids (e.g., prednisone, dexamethasone) and the mineralocorticoid (fludrocortisone) include:

Addison disease--replacement therapy

Adrenal insufficiency states (infection, shock, trauma)--supplementation

-Premature delivery to prevent respiratory distress syndrome-­ supplementation

-Adrenal hyperplasia--feedback inhibition ofACTH

•Adrenal steroid antagonists:

-Spironolactone

-Blocks aldosterone and androgen receptors (see Section III, Cardiac and Renal Pharmacology)

•Mifepristone:

-Blocks glucocorticoid and progestin receptors

•Synthesis inhibitors:

Metyrapone (blocks II-hydroxylation)

- Ketoconazole

ESTROGENS

•Pharmacology: Estradiol is the major natural estrogen. Rationale for synthet­ ics is to i oral bioavailability, i half-life, and i feedback inhibition of FSH and LH.

•Drugs:

-Conjugated equine estrogens (Premarin)-natural

-Ethinyl estradiol and mestranol-steroidal

-Diethylstilbestrol (DES)-nonsteroidal

•Clinical uses:

-Female hypogonadism

-Hormone replacement therapy (HRT) in menopause --7j,bone resorption (J, PTH)

-Contraception-feedback j, of gonadotropins

-Dysmenorrhea

-Uterine bleeding

-Acne

-Prostate cancer (palliative)

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Chapter 2 • Steroid Hormones

PROGESTIN

•Pharmacology: Progesterone is the major natural progestin. Rationale for synthetics is i oral bioavailability and i feedback inhibition of gonadotro­ pins, especially luteinizing hormone (LH).

•Drugs:

-Medroxyprogesterone

-Norethindrone·

Desogestrel is asyntheticprogestindevoidofandrogenicand antiestrogenic activities, common to other derivatives

•Clinical uses:

- Contraception (oral with estrogens)-depot contraception (medroxypro­ gesterone IM every 3 months)

Hormone replacementtherapy (HRT)-with estrogens to j, endometrial cancer

•Side effects:

-j, HDL and i LDL

-Glucose intolerance

-Breakthrough bleeding

-Androgenic (hirsutism and acne)

-Antiestrogenic (block lipid changes)

-Weight gain

-Depression

•Antagonist: mifepristone-abortifacient (use with prostaglandins [PGs])

ORAL CONTRACEPTIVES

•Pharmacology:

-Combinations of estrogens (ethinyl estradiol, mestranol) with progestins

(norgestrel, norethindrone) in varied dose, with mono-, bi-, and triphasic variants

-Suppress gonadotropins, especially rnidcycle LH surge

•Side effects:

-Side effects are those of estrogens and progestins, as seen previously

•Interactions: j, contraceptive effectiveness when usedwith antimicrobials and enzyme inducers

•Benefits:

-j, risk of endometrial and ovarian cancer

j, dysmenorrhea - j, endometriosis

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Chapter 2 • Steroid Hormones

Chapter Summary

Adrenal Steroids

•The nonendocrine uses in inflammatory disorders were discussed in the previous chapter.

•The glucocorticoids are used to treat Addison disease and adrenal insufficiency states, as a supplement in infantile respiratory distress syndrome, and in adrenal hyperplasia.

Estrogens

•Synthetic estrogens are used to increase the oral bioavailability and half-life relative to that obtained with estradiol and to induce feedback inhibition of FSH and LH.

•The uses and adverse affects of estrogens are listed.

•The clinical uses of anastrozole (decreases estrogen synthesis), danazol

(decreases ovarian steroid synthesis), clomiphene (decreases feedback inhibition), and the selective estrogen-receptor modulators tamoxifen and raloxifene are considered.

Progestin

•Synthetic progestins are used to increase oral bioavailability and half-life relative to progesterone and to induce feedback inhibition of gonadotropins, especially LH.

•The progestin-like drugs, their use in contraception and in hormonal replacement therapy, and their adverse effects are considered.

•Mifepristone is an antagonist used with PG as an abortifacient.

•The pharmacology of oral contraceptives and their adverse effects, drug interactions, and benefits are pointed out.

Androgens

•Clinically useful androgen analogs include methyltestosterone and 17-alkyl derivatives. Their clinical and illicit uses and side effects are presented.

•Clinically useful drug antagonists are flutamide (an androgen-receptor blocker used to treat prostate cancer), leuprolide (a GnRH analog used to treat prostate cancer), and finasteride (a 5-a-reductase inhibitor used to treat benign prostatic hyperplasia and male pattern baldness).

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Section VIII • Endocrine Pharmacology

•Thioamides: propylthiouracil and methimazole

-Use: uncomplicated hyperthyroid conditions; slow in onset

-High-dose propylthiouracil inhibits 5' deiodinase

-Common maculopapular rash

-Both drugs cross the placental barrier, but propylthiouracil is safer in pregnancybecause it is extensivelyprotein bound

•Iodide

-Potassium iodide plus iodine (Lugol's solution) possible use in thyrotoxi­ cosis: used preoperatively -+t gland size, fragility, and vascularity

-No long-term use because thyroid gland "escapes" from effects after 10 to 14 days

Chapter Summary

•The steps in thyroid hormone synthesis and the antithyroid agents' effects upon them are summarized in Table Vlll-3-1. The clinical uses and their potential complications are presented in greater detail for the thioamides (propylthiouracil and methimazole) and iodine.

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Table Vlll-4-1. Drugs Related to Hypothalamic and Pituitary Hormones

Definitionofabbreviations: ACTH, adrenocorticotropin hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PIH, prolactin-inhibiting hormone.

ChapterSummary

•The clinical uses of drugs used to treat functions associated with hypothalamic or pituitary hormones are summarized in Table Vlll-4-1.

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BISPHOSPHONATES

•Mechanisms: stabilize hydroxyapatite bone structure and also induce osteoblasts to secrete inhibitors of osteoclasts -+1. bone resorption .i. progression of osteoporosis

•Clinical uses:

-Established use in Paget disease

Efficacy in postmenopausal osteoporosis depends on individual drug, but alendronate is effective and with HRT causes I bone min­ eral density (BMD).

-Alendronate is drug ofchoice forglucocorticoid-induced osteoporosis

•Side effects:

-Etidronate and pamidronate bone mineralization defects

Gastrointestinal distress, including esophageal ulcers (alendronate)

TERIPARATIDE

•Mechanism: recombinant DNA PTH analog

•Clinical use: once dailyto stimulate osteoblasts and new bone formation

•Continuous infusion would stimulate osteoclast activity

•Used for less than 2 years; may I risk ofosteosarcoma

Chapter Summary

•The bisphosphonates decrease bone resorption and slow the progress of osteoporosis. Alendronate is effective fortreatment of postmenopausal and steroid-induced osteoporosis. The principal potential side effects are gastrointestinal distress and esophageal ulcers.

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