Gonadal Hormones and Erectile Dysfunction Drugs Chapter 37 Gonadal Hormones and Erectile Dysfunction Drugs

SEX HORMONES Most produced by male and female gonads Ovaries secrete estrogen and progesterone Testes secrete testosterone Adrenal cortex does secrete small amounts Male and female hormones are present in both sexes

ESTROGEN Maturation of the reproductive organs Functions of estrogen in the female Maturation of the reproductive organs Appearance of secondary sex characteristics Metabolic effects on the brain, kidneys, blood vessels, and skin Maintain low blood cholesterol levels Facilitate calcium uptake by the bones Ovaries stop secreting estrogen about age 50–55 Stop secreting estrogen as women enter menopause.

PROGESTERONE Functions of progesterone (along with estrogen) in the female Promotes breast development Regulates menstrual cycle During pregnancy maintains endometrium Prevents premature labor contractions Regulates menstrual cycle- promotes the monthly changes in the ovaries and uterus. When progesterone levels fall sharply at the end of the cycle, the endometrium is shed and bleeding occurs. During pregnancy- progesterone is secreted by the placenta.

TESTOSTERONE Primary androgen (male sex hormone) Functions of testosterone in the male Maturation of the male sex organs Secondary sexual characteristics of the male Metabolic effects on muscle secondary sex characteristics include enlarged breasts of females and facial hair and adam's apple on males Unlike cyclic secretion of estrogen and progesterone in women, secretion of testosterone in men is relatively constant. Testosterone helps to build muscle mass…contributes to difference in muscle strength and body composition between men and women.

Hormonal Replacement Therapy Causes of hormonal deficiency: Removal of ovaries Perimenopause: Decrease in female sex hormones Decrease in ovulation Decrease in menstruation Menopause: Complete end of menstruation for 1 year and low circulating estrogen and FSH Learning Outcomes 37.2 Correlate the follicular, hormonal, and endometrial changes that occur in the menstrual cycle to the hormones released. The most frequent causes of female hormonal deficiency are removal of the ovaries (surgical-induced menopause; premature menopause) and menopause. Perimenopause is characterized by a significant decrease in female sex hormone production (estrogens, progestins), frequency of ovulation, and menstruation. Initially, there is a period of physiological and emotional adjustment. During this time, individuals may experience symptoms such as fatigue, hot flashes, vasomotor spasms, nervousness, anxiety, irritability, or depression. Tissue changes in the endometrium and vagina, such as atrophy, decreased metabolism, irritation, and dryness, also take place. Menopause, clinically defined, is the complete cessation of a menstrual period for 12 months accompanied by a circulating estrogen level less than 50 picograms/ml and an FSH blood level greater than 50 IU/ml. Insomnia, which contributes to depression, anxiety, myalgias, and vasomotor symptoms are effectively relieved by HRT. Hormone replacement therapy options include estrogen replacement only, estrogen with cyclic progestin, and continuous estrogen and progestin

Hormonal Replacement Therapy HRT is an effective treatment for the symptoms of menopause (USE): Distressing Menopausal Symptoms Hot flashes Sleep disturbances Vaginal dryness Dysfunctional uterine bleeding Endometrial cancer (palliative) Osteoporosis Options for replacement include estrogen only or estrogen with progestin. Adverse effects include: Nausea, vomiting, headache, fluid retention, and breast tenderness Learning Outcomes 37.2 Correlate the follicular, hormonal, and endometrial changes that occur in the menstrual cycle to the hormones released. Hormone replacement therapy options include estrogen replacement only, estrogen with cyclic progestin, and continuous estrogen and progestin. HRT is still the most effective treatment for relief of hot flashes, sleep disturbances and vaginal dryness. The recommendation now is to take the lowest effective dose for the shortest time (i.e., not indefinitely). As always, women are advised to have regular general medical and breast examinations with periodic mammograms during and after hormone therapy. The therapeutic goal after removal of the ovaries in women under 50 years of age is to restore the estrogen and progesterone levels to those that are more representative of endocrine support and provide adequate cyclic feedback to the hypothalamus. Adverse effects related to estrogen or progestogen use include nausea, vomiting, headache, dizziness, irritability, depression, fluid retention, breast tenderness, and weight gain.

Women’s Health Initiative Increased risk of heart attacks, stroke, breast cancer and dementia Increased risk of endometrial cancer with estrogen and no progestin Some good news! Risk of colon cancer and bone fracture decreased Learning Outcomes 37.5 Describe the Women’s Health Initiative, its findings, and the effects this study has had on hormonal replacement therapy in postmenopausal women. The Women’s Health Initiative (WHI), a very large clinical study involving more than 16,000 women over 50 years old, provided results that have curbed the overwhelming enthusiasm for HRT in postmenopausal women. The study provided evidence that women taking a combination estrogen-progestin daily for at least 5 years had an increased risk of nonfatal heart attacks, thromboembolism, stroke, breast cancer, and dementia including Alzheimer’s disease. Chronic estrogen use taken unopposed (no progestin) is associated with an increased risk of developing endometrial cancer in postmenopausal women. This risk is one to six times higher than the risk for endometrial cancer in women with an intact uterus who never took endogenous estrogen. Some good news from the Women’s Health Initiative is that the risk of colon cancer and bone fracture decreased in women taking estrogen. The Women's Health Initiative (WHI) study led health care providers to revise their recommendations regarding HRT. It showed that women who took estrogen with or without the hormone progesterone for 5 or more years had an increased risk for stroke, heart disease, breast cancer, and blood clots. Study stopped in the middle. Short-term use (2 - 4 years) of the lowest possible dose of HRT to treat the symptoms of menopause still appears to be safe at this time. WHI- launched in 1991, stopped in 2002 -looking at use of HRT for ht disease and osteoporosis -more than 16,000 healthy post-men women took part HRT had been used widely for the past 20 years to treat unpleasant symptoms of menopause Recent studies raised questions regarding the safety of HRT Increased risk of: Coronary artery disease Stroke Venous thromboembolism Breast cancer Collaborate with healthcare provider Women need to make an informed decision regarding HRT NC: Use the smallest dose for the shortest time possible to relieve symptoms

ESTROGEN REPLACEMENT THERAPY Used to treat distressing menopausal symptoms Estrogen usually combined with a progestin Higher doses are used than in oral contraceptives More side effects NC: Should be given short term at lowest doses possible Example- estrogen (Premarin) What protective measures does estrogen have? Bone, cholesterol Hormones may alter blood glucose levels - increased glucose

PROGESTINS Used to treat dysfunctional uterine bleeding Often caused by imbalance between estrogen and progesterone Estrogen increases the thickness of the endometrium, but bleeding occurs sporadically unless balanced by adequate progesterone secretion Progestin administration can help establish a normal, monthly cyclic pattern Example- Medroxyprogesterone (Provera) Natural function of progesterone is to prepare uterus for implantation of embryo. If implantation does not occur, progesterone levels fall and menses begins. May use oral contraceptives for DUB.

Male Sex Hormones Terms to know: Androgen: Anabolic steroid: Promotes body tissue-building processes Testosterone: Androgen that initiates sperm production and fertility, libido, muscle mass and strength, male hair pattern, aggressive behavior Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. During male embryonic development, the germ cells that migrate to the testes are called spermatogonia. The male also is born with a specific number spermatogonia; however, these cells go through mitosis continuously. One of the daughter cells does not differentiate so that the male has the ability to produce sperm throughout life. At puberty the secretion of testosterone stimulates spermatogenesis in the seminiferous tubules of the testes. The main sex hormone of the male is testosterone, which is produced by the testes. In addition to stimulating spermatogenesis, testosterone stimulates the development of male sex organs (prostate, seminal vesicles, scrotum, and penis) and maintains the secondary sex characteristics (hair distribution, vocal cord thickening, and changes in musculature) of the male. In addition, testosterone produces an anabolic effect that promotes synthesis and retention of proteins (muscle and bone) in the body. Male sex hormones are steroids generally referred to as androgens. The sex hormone is testosterone and the anabolic androgen drugs are oxandrolone and doxymetholone.

TESTOSTERONE Lack of testosterone In prepubertal men: Causes hypogonadism- lack of maturation of the sex organs In adult males: Can lead to impotence and low sperm counts Treated with testosterone or other androgens Example- testosterone (Andro 100)

ANDROGEN DRUG THERAPY USES Promotes normal gonadal development testosterone deficiency due to pituitary disorders or testicular failure May restore normal reproductive function High doses used occassionally to treat certain types of breast cancer Used as palliative measures in combination with other antineoplastics Endometriosis Fibrocystic breast disease Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. Deficiencies of testosterone may be caused by pituitary disorders, testicular failure, or castration. Androgens are administered as replacement therapy to maintain male sex characteristics and organ function. Androgens are approved for use in males as replacement therapy in primary hypogonadism, hypogonadotropic hypogonadism, delayed puberty, and impotence that is the result of androgen deficiency. In women, androgens are approved for the treatment of metastatic inoperable breast cancer. Androgen therapy has been beneficial in some cases of metastatic breast cancer. Androgen therapy has inhibited tumor growth while retaining the anabolic effects of increased protein synthesis and weight gain. In some clinical situations, androgens are administered because of their ability to stimulate protein synthesis (anabolism). In conjunction with a diet designed to increase caloric intake, patients usually experience an increase in appetite and weight. Androgens have been used to stimulate the production of red blood cells (erythropoiesis) in patients with refractory anemia, particularly those with renal disease.

ANABOLIC STEROIDS Testosterone-like compounds with hormonal activity Taken inappropriately by athletes to build muscle mass and strength

Anabolic Steroid Control Act Classified anabolic androgens and prohormones as CIII drugs High potential for abuse Used by men to increase strength and virility after the age of 50 Also used by some to increase muscle mass Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. Anabolic steroids have been used as adjunctive drugs to improve athletic performance. Anabolic steroids do increase lean muscle mass, partly through the tissue retention of sodium and water. Adverse effects associated with chronic use of these hormones may be serious and irreversible. Under federal law, the Anabolic Steroid Control Act of 1990 and 2004, anabolic androgens and prohormones are classified as Schedule III drugs because of their high potential for abuse and misuse. Testosterone has been shown to increase muscle mass and reduce bone loss through mineral excretion. While moods, libidos, and cholesterol levels improved, testosterone does not correct impotence.

ANABOLIC STEROIDS (CONTINUED) Large doses taken for prolonged periods have significant adverse effects Raise cholesterol levels Cause low sperm counts and impotence Menstrual irregularities Increase in masculine characteristics in women Permanent liver damage Behavioral changes Psychological dependence Illegal to use

Erectile Dysfunction Inability to perform sexual function Causes: May result from nerve damage Adverse effect of several medications Arteriosclerosis Smoking Diabetes mellitus Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. Impotence is the inability to perform sexual function often associated in men as erectile dysfunction (ED) or inability to achieve an erection. Impotence may result from nerve or spinal damage so that stimulatory impulses no longer reach the muscles of the penis to evoke a physical action. It is also an adverse effect of over 200 types of prescription medications. Arteriosclerosis, the hardening and narrowing of the arteries, causes a reduction in blood flow throughout the body and can lead to impotence. Other factors that contribute to diminished blood flow include smoking and diabetes mellitus. To establish and maintain an erection, there must be increased blood flow through the erectile tissue in the penis. During sexual arousal, the male brain receives a signal to release nitric oxide (NO), an endogenous vasodilator, in the area where the increased blood flow is needed (penis). NO stimulates the enzyme guanylate cyclase that produces cyclic guanosine monophosphate (cGMP), the chemical that relaxes arterial smooth muscle. Once the smooth muscle is relaxed, blood flows into tissue and the penis inflates (erection).

Erectile Dysfunction Drugs MOA: Increase blood flow to the penis, producing an erection Do not increase or affect erections in men who are not impotent or erections that are not a result of sexual stimulation Adverse effects: Headache, flushing, upset stomach, nasal congestion, diarrhea, rash, and priapism Life threatening hypotension can occur Should not be taken with nitrates (NC) Do not take more than once per day! Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. These drugs do not increase or affect erection in men who are not impotent, and do not affect erection that is not a result of sexual stimulation. The effects most frequently reported include headache, flushing of the skin, upset stomach, nasal congestion, diarrhea, and rash. Prolonged erections lasting longer than 4 hours and priapism (painful erections lasting longer than 6 hours) can occur. PDE inhibitors should not be used in patients who are taking nitrates because a synergistic decrease in blood pressure may produce severe hypotension and/or other cardiovascular sequelae that are life-threatening. These drugs should be used with caution in patients who may have conditions that predispose them to priapism such as sickle cell anemia, leukemia, or predisposing anatomical conditions.

Erectile Dysfunction Drugs Learning Outcomes 37.7 Describe the mechanisms of action of the classes of androgenic drugs. These drugs do not increase or affect erection in men who are not impotent, and do not affect erection that is not a result of sexual stimulation. The effects most frequently reported include headache, flushing of the skin, upset stomach, nasal congestion, diarrhea, and rash. Prolonged erections lasting longer than 4 hours and priapism (painful erections lasting longer than 6 hours) can occur. PDE inhibitors should not be used in patients who are taking nitrates because a synergistic decrease in blood pressure may produce severe hypotension and/or other cardiovascular sequelae that are life-threatening. These drugs should be used with caution in patients who may have conditions that predispose them to priapism such as sickle cell anemia, leukemia, or predisposing anatomical conditions.

BENIGN PROSTATIC HYPERPLASIA (BPH) Nonmalignant enlargement of prostate gland Obstructs the urethra, causing a progressive decrease in outflow of urine Symptoms Increased urinary frequency Increased urgency to urinate Excessive nighttime urination Decrease force of urine stream Sensation that the bladder is not completely empty Normally size of walnut.

TREATING MILD BPH Alleviates symptoms but does not cure the disease Must be taken the rest of the client’s life or until surgery is indicated Alpha1-adrenergic blockers MOA: Relaxes smooth muscle in prostate gland, easing urinary obstruction SE/NC: hypotension; monitor BP Examples: end in “-sin” Doxazosin (Cardura) Terazosin (Hytrin) Tamsulosin (Flomax) - no effect on blood pressure Usually used for HTN. 1st 2 are of particular value to pts who have both HTN and BPH.

FINASTERIDE (PROSCAR) (class) Antiandrogen drug used to promote shrinkage of enlarged prostate and to help restore urinary function in men with BPH MOA: Acts by inhibiting enzyme responsible for converting testosterone to one of its metabolites, 5-alpha-diydrotestosterone This metabolite promotes enlargement of the prostate This drug is also marketed as Propecia, prescribed to promote hair regrowth in pts with male pattern baldness. Doses are 5x lower.

SIDE EFFECTS Various types of sexual dysfunction Impotence Diminished libido Ejaculatory dysfunction Pregnancy Category X drug (NC): Women who are pregnant or may become pregnant should avoid the semen of men taking the drug or the drug itself Men taking this drug should not donate blood, it can be harmful to a male fetus (their male sex organs won’t develop) Will cause harm to a male fetus Men taking these drugs should not donate blood while on drug therapy (may be given to a female patient with resulting adverse effects) Causes a decrease in serum PSA levels by about 50% in patients with BPH, even in the presence of prostate cancer

Question 1 An older adult client with BPH is prescribed doxazosin (Cardura). What is important to evaluate after he has started this medication? A. Presence of postural hypotension B. Development of tachycardia C. Increase in difficulty voiding D. Gastrointestinal disturbances and rash A.

Question 2 Sildenafil (Viagra) is prescribed to treat a client with erectile dysfunction. A nurse reviews the client’s medical record and would question the prescription if which of the following is noted in the client’s history? A. Neuralgia B. Insomnia C. Use of nitroglycerin D. Use of multivitamins C

Question 3 Which of the following conditions is an indication for the use of androgen therapy? A. Benign prostatic hypertrophy B. Hypogonadism C. Prostate cancer D. Premature puberty B

Question 4 A nurse is reinforcing teaching for a female client who is beginning a prescription of conjugated estrogens(Premarin) for symptoms of menopause. For which of the following should the nurse plan to monitor the patient? lower leg pain Shortened stature Vulvar and vaginal atrophy Weight loss correct answer-- A. The client who takes estrogen is at an increased risk for cardiovascular events, including thrombophlebitis. The nurse should monitor the client for pain, swelling and redness in the lower legs. Shortened stature may occur in clients who has osteoporosis. Estrogen therapy can help prevent valvular and virginal atrophy in postmenopausal women. Weight loss is not nan expected effect caused by estrogen therapy.