Estrogens and Estrogenic Drugs

Estrogens

• Three major endogenous estrogens are estradiol (principal and most active), estrone, and estriol.
• Estrogens are synthesized from cholesterol in ovarian follicles.
• Estrogens contribute to development and maintenance of the female reproductive system, development of female secondary sex characteristics, shaping of body contours, and the development of the skeleton.
• Estrogens are cardioprotective.

Exogenous Estrogenic Drugs: Synthetic

• Steroidal exogenous estrogenic drugs include conjugated estrogens, estradiol transdermal, and estropipate.
• Diethylstilbestrol is a nonsteroidal exogenous estrogenic drug that can cause significant complications like reproductive system dysfunction in female and male offspring and cancers in DES daughters.
• Diethylstilbestrol has not been available in Canada since 1971.

Estrogenic Drugs

• Common estrogenic drugs include conjugated estrogens such as Premarin, Esterified estrogens (Estragyn), estradiol transdermal options such as Climara and Divigel, estradiol vaginal ring (Estring), estradiol valerate, estrone (Folliculum), estropipate (Ogen), ethinyl estradiol(Alesse), estradiol in vaginal dose forms (Vagifem, Estring), and estrone (Estrone Vaginal Cream).

Estrogens: Indications

• Estrogens can treat or prevent disorders resulting from estrogen deficiency such as atrophic vaginitis and hypogonadism.
• Oral contraception is an indication for estrogen use, although it requires being administered with a progestin.
• Estrogens can be used to treat uterine bleeding and vasomotor spasms of menopause, commonly known as "hot flashes".
• Estrogens are used to treat osteoporosis and can be used as a prophylaxis.
• This medication can be used as a treatment of breast or prostate cancer (palliative treatment).
• Estrogens are used during ovarian failure or castration, as well as for cross-gender hormone treatment for transgender individuals.
• They can also treat severe acne when combined with an antiandrogen.

Estrogens: Contraindications

• Drug allergy
• Any estrogen-dependent cancer
• Undiagnosed abnormal vaginal bleeding.
• Pregnancy
• Active thromboembolic disorder or history of thromboembolic disorder

Estrogens: Adverse Effects

• Thrombolytic events are the most serious.
• The most common is nausea.
• Other adverse effects include hypertension, thrombophlebitis, edema, vomiting, diarrhea, constipation and abdominal pain.
• Light sensitivity, amenorrhea, breakthrough uterine bleeding, tender breasts, fluid retention, chloasma, and alopecia are possible adverse effects.

Estrogens: Interactions

• Oral anticoagulants (estrogens decrease their activity)
• Rifampin (estrogens decrease its effect).
• St. John's wort
• Tricyclic antidepressants
• Smoking

Evidence-Based Information

• Cognitive-behavioral therapy, clinical hypnosis, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors, gabapentin, fezolinetant; oxybutynin; weight loss, stellate ganglion block are recommended by NPMS.
• Paced respiration; supplements/herbals, cooling techniques, avoiding triggers, exercise, yoga, mindfulness-based intervention, relaxation, suvorexant, soy foods and soy extracts, soy metabolite equol, cannabinoids, acupuncture, calibration of neural oscillations; chiropractic interventions, clonidine; dietary modification and pregabalin are all not recommended by NPMS.

Progestins

• Most commonly used progestins are medications such as levonorgestrel (Min-Ovral), medroxyprogesterone (Provera, Depo-Provera), megestrol (Megace), norethindrone acetate (Norlutate) and progesterone (Prometrium).
• Mirena and Kyleena are IUDs that act as progestins for long-term contraception.
• Progestins' MOA is the exertion of the same physiologic responses as progesterone.

Progestins: Indications

• Progestins can be used to treat functional uterine bleeding caused by hormonal imbalance, fibroids, or uterine cancer.
• Progestins can be used during treatment of primary and secondary amenorrhea.
• These can be used as an adjunctive and palliative treatment of some cancers and endometriosis.
• They can be prescribed alone or in combination with estrogens to prevent conception, along with prevention of threatened miscarriage.
• Progestins can be used to alleviate premenstrual syndrome symptoms.

Progestins: Adverse Effects

• Liver dysfunction (cholestatic jaundice)
• Thrombophlebitis, thromboembolic disorders such as PE
• Nausea and Vomiting
• Amenorrhea, spotting
• Some adverse effects include edema, weight gain or loss, pyrexia, somnolence or insomnia, and depression.
• Interacts with antidiabetic meds.

medroxyprogesterone (Provera, Depo-Provera)

• This medication inhibits the secretion of pituitary gonadotropins, prevents follicular maturation and ovulation, and stimulates the growth of mammary tissue.
• It has an antineoplastic action against endometrial cancer.
• It is used to treat uterine bleeding, secondary amenorrhea, and endometrial cancer.
• As a contraceptive, it comes via injection every 3 months and can cause bone loss with long-term use.

Contraceptive Drugs

• Available in monophasic, biphasic, and triphasic forms.
• Triphasic form most closely duplicates the normal hormonal levels of the female cycle.
• The medications most commonly used for new contraceptive drugs contrain estrogen-progestin combinations.
• Other forms include the long-acting injectable form of medroxyprogesterone, the transdermal contraceptive patch and the contraceptive vaginal ring.

Contraceptive Drugs: MOA

• These drugs prevent ovulation by inhibiting the release of gonadotropins, and increase uterine mucus viscosity.
• Contraceptives inhibit sperm movement and fertilization of the ovum, and can inhibit implantation of a fertilized egg (zygote).

Contraceptive Drugs: Other Effects

• Contraceptives can improve menstrual cycle regularity, decrease blood loss during menstruation, and decrease the incidence of functional ovarian cysts and ectopic pregnancies.

Contraceptive Drugs: Indications

• Contraceptives are primarily used to prevent pregnancy.
• Contraceptives are used in the treatment of endometriosis and hypermenorrhea.
• They induce production of cyclic withdrawal bleeding and can be used as a postcoital emergency contraception (72 hours).

Contraceptive Drugs: Adverse Effects

• Contraceptives can cause hypertension, thromboembolism, alterations in lipid and carbohydrate metabolism, and increases in serum hormone concentrations.
• Alterations in serum metal ion concentrations and plasma protein levels also occur.
• Adverse effects include edema, dizziness, headache, migraines, depression, stroke, nausea, vomiting, diarrhea, anorexia, increased weight, and jaundice.
• Amenorrhea, breast changes, cervical erosion, breakthrough bleeding, and dysmenorrhea are among other adverse effects.

Contraceptive Drugs: Contraindications

• Known drug allergy to a specific product
• Pregnancy.
• Contraindications include a known high risk for or history of thromboembolic events such as myocardial infarction, venous thrombosis, pulmonary embolism, or stroke.
• Avoid use in smokers >35 and in patients with migraines >35.

Contraceptive Drugs: Interactions

• Drugs that decrease the effectiveness of oral contraceptive drugs include antibiotics (especially penicillins and cephalosporins), barbiturates, izoniazid, and rifampin.
• Drugs that may have reduced effectiveness if given with oral contraceptives include B-Blockers, warfarin, tricyclic antidepressants, vitamins, hypnotics, anticonvulsants, theophylline, vitamins, and antidiabetic drugs.

Osteoporosis

• It is characterized as low bone density and deterioration of bone tissue.
• Leads to increased risk of fractures.
• 1 in 3 Canadian women are affected, compared to 1 in 5 Canadian men.

Osteoporosis: Risk Factors

• Gender and age are risk factors.
• Fragility fracture over 40 years of age and history of hip fracture.
• Use of glucocorticoid drugs for >3 months and vertebral compression fracture increases risk.
• Smoking, alcohol use, menopause before age 45 years, low estrogen levels, and weight under 60 kg.

Drug Therapy for Osteoporosis

• Bisphosphonates such as alendronate, etidronate disodium with 500 mg of calcium (Didrocal, Etidrocal), risedronate sodium hemipentahydrate.
• Selective estrogen receptor modifiers (SERMs) such as raloxifene and tamoxifen.
• Hormones such as teriparatide to stimulates bone formation and denosumab (Prolia) that prevents bone resorption.

Osteoporosis Drug Therapy: Bisphosphonates

• Bisphosphonates work by inhibiting osteoclast-mediated bone resorption, which in turn indirectly enhances bone mineral density.
• There is clinical evidence that bisphosphonates can reverse lost bone mass and reduce fracture risk.

Osteoporosis Drug Therapy: SERMs

• SERMS stimulate estrogen receptors on bone and increase bone density.

Osteoporosis Drug Therapy: Other Medications

• Calcitonin directly inhibits osteoclastic bone resorption.
• Teriparatide stimulates bone formation, and is action is similar to natural PTH, parathyroid hormone.
• Denosumab (Prolia) is a monoclonal antibody that blocks osteoclast activation, thereby preventing bone resorption.
• Denosumab is given as a subcutaneous injection once every 6 months along with daily calcium and vitamin D.
• raloxifene's primary use is the prevention of postmenopausal osteoporosis

Drug Therapy for Osteoporosis: Indications

• Bisphosphonates, calcitonin and teriparatide can be used for prevention and treatment of osteoporosis.
• teriparatide: for subset of osteoporosis patients at highest risk of fracture (those with prior fracture)

Drugs for Osteoporosis: Contraindications

• Bisphosphonates: drug allergy, hypocalcemia, esophageal dysfunction, and inability to sit or stand upright for at least 30 min
• SERMs: known allergy; those who are or may become pregnant; venous thromboembolic disorder
• Calcitonin: drug allergy or allergy to salmon
• Teriparatide: drug allergy
• Denosumab: hypocalcemia, renal impairment, and infection

Osteoporosis Drugs: Adverse Effects

• SERMs:
  • Hot flashes and leg cramps
  • Leukopenia
• Bisphosphonates:
  • Headache, gastrointestinal upset, and joint pain
  • Cause the risk of esophageal burns and of osteonecrosis of the jaw
  • Possible severe bone, joint, or muscle pain; energy fractures
• Teriparatide: chest pain, dizziness, hypercalcemia, nausea, and arthralgia
• Denosumab: infections

alendronate sodium (Fosamax)

• Oral bisphosphonate
• First non-estrogen nonhormonal option for preventing bone loss
• Inhibits or reverses osteoclast-mediated bone resorption
• Indications: prevention and treatment of osteoporosis in men and in postmenopausal women, as well as treatment of glucocorticoid-induced osteoporosis in men and treatment of Paget disease in women

raloxifene hydrochloride (Evista)

• SERM
• Use: prevention of postmenopausal osteoporosis
• Positive effects on cholesterol level
• Adverse effect: hot flashes

Fertility Drugs: clomiphene

• Nonsteroidal ovulation stimulant
• Blocks estrogen receptors in the uterus and brain, resulting in a false signal of low estrogen levels
• Increases production of gonadotropin-releasing hormone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)
• Maturation of ovarian follicles is stimulated, leading to ovulation and an increased chance of conception.

Fertility Drugs: menotropins

• This is a standardized mixture of FSH and LH.
• It stimulates development of ovarian follicles, leading to ovulation, and may also be given to men to stimulate spermatogenesis.

Fertility Drugs: chorionic gonadotropin alfa

• Recombinant form of human chorionic gonadotropin
• Causes rupture and ovulation of mature ovarian follicles and maintenance of corpus luteum
• Used to stimulate ovulation

Fertility Drugs: Indications

• Used primarily to induce ovulation in anovulatory patients and to promote spermatogenesis in infertile men.

Fertility Drugs: Adverse Effects

• Tachycardia, hypovolemia, deep vein thrombosis
• Dizziness, headache, flushing, depression, restlessness, anxiety, nervousness, fatigue
• Nausea, bloating, constipation, vomiting, anorexia
• Urticaria, ovarian hyperstimulation, multiple pregnancy, blurred vision, diplopia, photophobia, breast pain

Nursing Implications

• Assess baseline vital signs, weight, blood glucose levels, renal and liver function study results, if the patient smokes, and history and medication history to determine any contraindications, including potential pregnancy, before prescribing medication.
• For estrogens and progestins, give the smallest dose needed, administer intramuscular doses deep in large muscle masses and rotate sites and give oral doses with meals to reduce gastrointestinal problems.
• Nurses should teach patients about correct self-administration and what to do if a dose is missed, due to increased susceptibility to sunburn.
• Instruct patients taking fertility drugs to take the medication as ordered, keep a journal, and to discontinue selective estrogen receptor modulators 72 hours before and during prolonged immobility.
• With bisphosphonates, nurses should instruct the patient to take their medication with a full glass of water upon rising in the morning and 30 minutes before eating.

Men's Health: Androgens

• Responsible for normal development and maintenance of primary and secondary male sex characteristics, promotes development of bone and muscle tissue, inhibition of protein catabolism (metabolic breakdown), retention of various electrolytes, and stimulates the production of blood cells.
• Several synthetic derivatives of testosterone are available.
• Long-term dosage forms can last from 2 to 3 days to 2 to 4 weeks.

Other Information on Androgens

• Oral forms have a high first-pass effect: methyltestosterone, fluoxymesterone
• Transdermal forms are available.
• Anabolic steroids:synthesis of tissue and increasing tissue formation
• Anabolic steroids are Schedule IV drugs.
• Anabolic steroids are not available in Canada unless under Health Canada's Special Access Program.
• Anabolic steroids can cause cause sterility, CVD, and liver cancer, but they can also be Used for HIV wasting syndrome.
• Anabolic steroids include Oxandrolone and Nandrolone.
• Anabolic steroids can increase synthesis of body proteins, aiding in the formation of muscular and skeletal proteins, and enhance erythropoiesis.

Androgen Inhibitors and Androgen Receptor Blockers

• Androgen Inhibitors block the effects of naturally occurring (endogenous) androgens. (5-a reductase inhibitors)
• Androgen Inhibitors can treat benign prostatic hyperplasia (BPH).
• Androgen inhibitors include finasteride and dutasteride.
• Androgen Receptor Blockers block the activity of androgen hormones.
• Used in the treatment of prostate cancer:flutamide, nilutamide, and bicalutamide.

Finasteride (Proscar)

• Used for the treatment of BPH and prevents the thinning of hair caused by increased levels of 5α-dihydrotestosterone (DHT) - male pattern baldness.
• Contraindicated in women.
• Teratogenic in pregnant women.
• Women need to wear gloves when handling finasteride.

Gonadotropin-Releasing Hormone Analogues

• Used to treat prostate cancer
• Action: inhibit the secretion of pituitary gonadotropin, which eventually leads to a decrease in testosterone production
• goserelin, leuprolide, triptorelin.

alpha 1 -Adrenergic Blockers

• Used for symptomatic relief of obstruction caused by benign prostatic hyperplasia: doxazosin, tamsulosin, terazosin, alfuzosin, silodosin.
• 5-a Reductase inhibitors may take up to 6 months of continual therapy for clinical effects of prostate shrinkage.

Drugs to Treat Erectile Dysfunction: Phosphodiesterase inhibitors

• Used in the treatment of ED.
• Sildenafil is the first oral drug for treatment of ED: relaxes smooth muscle in the corpora cavernosa (erectile tubes) of the penis and permits the inflow of blood.
• Similar to sildenafil but longer duration of action include vardenafil and tadalafil.
• Sildenafil and tadalafil, under trade names Revatio and Adcirca, are also used to treat pulmonary hypertension.
• Alternative treatments are prostaglandin, administered by injecting alprostadil directly into the erectile tissue of the penis or by pushing a suppository form of the drug into the urethra.

Men's Health Drugs: Contraindications

• Known androgen-responsive tumours
• Sildenafil, vardenafil, tadalafil: contraindicated for men with major cardiovascular disorders, especially if they use nitrate medications such as nitroglycerin
• Use of finasteride is contraindicated for women (especially pregnant women) and children

Men's Health Drugs: Adverse Effects

• Androgens cause fluid retention.
• Anabolic steroids:
  • Peliosis of the liver
  • Hepatic neoplasms (liver cancer)
  • Cholestatic hepatitis
  • Jaundice
  • Can cause abnormal liver function
• Priapism: abnormally prolonged penile erection
  • Uncommon
  • Possible adverse effect of both the erectile dysfunction drugs and the androgens
  • Medical emergency that warrants urgent medical attention
  • Caused by an excessive therapeutic drug response
• Phosphodiesterase inhibitors: can cause unexplained visual loss
• finasteride: loss of libido, loss of erection, ejaculatory dysfunction, hypersensitivity reactions, gynecomastia, severe myopathy, and a 50% decrease in prostate-specific antigen (PSA) concentrations

Men's Health Drugs: Interactions

• Androgens, when used with oral anticoagulants, can significantly increase or decrease anticoagulant activity.
• Androgens with cyclosporine increase the risk of cyclosporine toxicity.
• Sildenafil, vardenafil, and tadalafil may cause severe hypotension when given together with nitrates.
• alpha-Blockers: additive hypotension when given with other drugs that lower blood pressure
• Effects of tamsulosin may be increased when it is taken with azole antifungal drugs, erythromycin and clarithromycin, cardiac drugs such as propranolol and verapamil, and protease inhibitors.

Nursing Implications - Men's Health Drugs

• Assess renal and liver function.
• Assess PSA level and perform a digital rectal examination before beginning any drugs for the treatment of prostate disease.
• Assess current medications for potential interactions.
• Follow exact instructions for sublingual, buccal, and oral forms.
• Transdermal Testoderm patches are applied to the scrotal skin.
• Transdermal Androderm patches are applied to the skin on the body, never to scrotal skin.
• Pregnant women should not touch crushed or broken hormone drugs.
• Educate patients on proper administration techniques for each drug.
• Monitor therapeutic responses.
• Watch for and monitor adverse effects.