a predominantly male sex hormone that promotes the development and maintenance of male sex characteristics; testosterone is the major androgen found naturally in the body.
Benign prostatic hyperplasia (BPH)
an abnormal enlargement of the prostate gland that may cause lower urinary tract symptoms.
the use of medications, devices, methods, or procedures to prevent or decrease the likelihood of pregnancy.
should not be used due to known risk of harm.
a condition in which tissue similar to that normally lining the uterus is found outside of the uterus (usually on the ovaries, fallopian tubes, and other pelvic structures).
tissue that lines the uterus.
primary female sex hormone responsible for normal female sexual development and reproduction.
Follicle-stimulating hormone (FSH)
a hormone released by the pituitary gland that is important for sperm and egg maturation, as well as maintaining normal human reproduction.
compounds made by the body or made synthetically, used to stimulate the ovaries (eg, follicle-stimulating hormone and luteinizing hormone).
Gonadotropin-releasing hormone (GnRH)
a hormone released by the hypothalamus that stimulates the pituitary gland to release luteinizing hormone and follicle-stimulating hormone.
the primary sex organs responsible for release of the reproductive hormones.
noncancerous enlargement of the breast tissue.
a condition resulting in not enough secretion of the sex hormones from the male or female gonads.
administration of a substance in the uterus.
administration of a substance in the vaginal canal.
Luteinizing hormone (LH)
a hormone released by the pituitary gland that stimulates release of the primary sex hormones and helps to maintain normal human reproduction.
the permanent cessation of menses.
abnormally heavy and prolonged menstrual period at regular intervals.
the monthly flow of blood from the uterus of nonpregnant women from puberty to menopause.
the primary female reproductive organs.
the part of the menstrual cycle when the egg is released from the ovaries.
the time after which a woman has experienced 12 consecutive months without a menstrual period.
the female sex hormone important for normal ovulation and maintaining healthy pregnancies.
a general term for synthetic progesterone.
the primary male reproductive organs.
the primary sex hormone important for maintaining normal sexual development and reproduction in males.
the tube connected to the bladder that carries urine from the bladder to be eliminated from the body.
a loss of voluntary control over urination.
a hollow muscular organ located in the female pelvis between the bladder and rectum; its main function is to nourish the developing fetus prior to birth.
hot flashes or night sweats that can occur due to hormonal fluctuations during perimenopause or menopause.
the development of secondary male sexual characteristics.
After completing this chapter, you should be able to
List the basic physiologic roles for each of the major reproductive hormones.
Recognize common therapeutic indications for the use of reproductive hormones.
Recognize available dosage forms and describe common and serious adverse effects, administration, storage, and handling techniques for the available estrogen and progestin preparations.
Recognize available dosage forms and describe common and serious adverse effects, administration, storage, and handling techniques for the available testosterone preparations.
Recognize available dosage forms and describe common and serious adverse effects, administration, storage, and handling techniques for the available preparations to treat benign prostatic hyperplasia.
The primary sex organs in the human reproductive system are called gonads. In males the gonads are the testes, and in females the gonads are the ovaries. The male and female reproductive systems are carefully regulated by numerous hormones that are secreted by various organs in the human body. These specific hormones must be released in appropriate amounts and at the right time for the reproductive organs of each sex to function properly. The hypothalamus is located in the brain and is responsible for secreting many hormones. Gonadotropin-releasing hormone (GnRH) is one hormone released by the hypothalamus that is important for maintaining normal functioning of the human reproductive system in both males and females. In response to the release of GnRH, the pituitary gland, another organ located in the brain responsible for hormone release, secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are responsible for controlling the production and release of the primary sex hormones, estrogen, progesterone, and testosterone, from the gonads.1,2Figure 11-1 illustrates how hormones involved in the human reproductive system work together.
The testes, the main sex organs of the male reproductive system, are responsible for producing male sex hormones called androgens (Figure 11-2). The main androgen is the hormone testosterone. The testes are also responsible for the production of sperm cells. In normal male reproduction, LH and FSH are released by the pituitary gland to stimulate the cells inside of the testes to produce testosterone. In response to the increase in testosterone levels, sperm formation and maturation begins after puberty. In males, this process of hormone release and sperm production can continue until death. Another important part of the male reproductive system is the prostate gland. The prostate itself is donut shaped and surrounds a portion of the urethra. It is responsible for making fluids that will be secreted into the semen to help activate sperm movement.
The ovaries are the main sex organs of the female reproductive system. Figure 11-3 illustrates the major parts of the female reproductive system, including the ovaries. Similar to the testes in males that produce sperm, in females, the main function of the ovaries is to produce eggs for fertilization. The ovaries are also responsible for secreting the main female sex hormones, estrogens and progesterone. When GnRH is released by the hypothalamus in the female body, it triggers the release of LH and FSH by the pituitary gland as well. LH and FSH are released in different amounts at various times in the female body to regulate the release of estrogens and progesterone from the ovaries, stimulate ovulation, and to control other parts of the female reproductive system. This repeating cycle of hormonal changes and egg release in the female is also known as menstruation or the menstrual cycle. In females, each menstrual cycle is approximately 28 days and will continue to repeat itself from puberty until menopause. It is during this period of a female’s life, when menstruation occurs, that a pregnancy can be maintained.1,2
Physiologic Effects of the Reproductive Hormones
The major sex hormones in the human body are estrogens, progesterone, and androgens. Each of these hormones plays a crucial role in either the male or female body to maintain a healthy reproductive system. To understand why medications are prescribed to affect the reproductive system, it is important to know the function of each of these hormones in the human body.
Estrogens are a group of hormones that act as the primary sex hormones involved in the female reproductive system. There are three main estrogens naturally produced by the female body. The most common estrogen produced is estradiol and the other two important estrogens are estrone and estriol. The estrogens’ main function is to maintain normal development of the female internal and external reproductive parts. They are also responsible for the development and maintenance of female sex characteristics. Estrogens are needed for proper breast development, growth of pubic and underarm hair, and fat distribution. They also have nonreproductive effects on bone health, blood clotting, and cholesterol levels.2
Progesterone is another major hormone that is important for the female reproductive system. In the female body, progesterone is important for maintaining normal ovulation and plays an important role in maintaining a healthy pregnancy until full term. Progesterone levels are highest when a female is pregnant. Outside of the reproductive system, progesterone can also affect metabolism and body temperature.2
Androgens are the main male sex hormones. The main active androgen produced is testosterone. Testosterone can be broken down in the body into inactive products that are eliminated by the body or converted into other active hormones that play a role in the human reproductive system. For example, testosterone can be converted by the liver into estrogens. 5-alpha dihydrotestosterone is another important androgen found in the male body that is created from testosterone by an enzyme called 5-alpha reductase. Testosterone and 5-alpha dihydrotestosterone are predominately involved in male reproduction and the development of male sex characteristics. They have many functions in the male body, such as maintaining proper growth and development of the male sex organs. Throughout adolescence and adulthood, testosterone regulates bone and muscle development and growth, sperm cell maturation, deepening of the voice, body hair growth patterns, sexual drive and performance, and aggressive behavior. In addition, testosterone also has effects on red blood cell production and cholesterol levels.1,2
Samantha Jones is a 16-year-old female who comes to the pharmacy with her first prescription for Tri-Sprintec®. She went to her gynecologist with complaints of heavy menstrual periods, menstrual cramps, and migraines every month related to menses. In addition, she is in a relationship and interested in an effective form of contraception. She has no medical conditions and is not currently taking any medications.
Based on the known physiologic effects of both estrogen and progesterone, a combination product of both hormones was initially approved by the Food and Drug Administration (FDA) in 1960 for the treatment of menstrual disorders and infertility. This combination, Enovid®, was found to prevent unplanned pregnancy by inhibiting normal mechanisms for menstrual cycle control and ovulation. Since then, Enovid® has been withdrawn from the market and newer contraceptives have been developed. Newer contraceptives are intended to improve efficacy, minimize side effects, facilitate adherence, and decrease the frequency of menstrual periods. Pharmaceutical contraceptives are now available as transdermal, intravaginal, injectable, implantable, and intrauterine, as well as oral dosage forms. In addition to providing an effective means of contraception, hormonal contraceptive agents also provide noncontraceptive benefits, including regulation of the menstrual cycle, reduction of menstrual symptoms, protection against endometrial and ovarian cancers, and improvement of acne.3,4
Combined Hormonal Contraceptives
Combined hormonal contraceptives (COCs) contain two hormones: estrogen and progesterone (see Medication Table 11-1 for examples; Medication Tables are located at the end of the chapter). Estrogen exerts its contraceptive effects by inhibiting the release of FSH from the pituitary gland (discussed at length in Chapter 8), resulting in the inhibition of egg formation and maturation. This leads to subsequent prevention of ovulation. Estrogen also improves menstrual cycle control by stabilizing the endometrium and minimizing breakthrough bleeding. The progesterone component of hormonal contraceptives provides contraceptive activity through several mechanisms. Progesterone blocks the activity of LH to inhibit ovulation, thickens cervical mucus to decrease sperm motility, and thins the endometrium making it a less suitable environment for implantation.4
What phasic formulation is Samantha’s COC?
COCs are the most widely used form of hormonal contraception in the United States. Although some COCs contain the estrogen named mestranol or estradiol valerate, most COCs contain a synthetic estrogen named ethinyl estradiol, which varies in dose based on the product. Standard doses of ethinyl estradiol range from 30–35 mcg and are considered low dose, while COCs that contain 20–25 mcg of ethinyl estradiol are considered very low dose. The progesterone (also referred to as progestins) component of COCs can vary greatly according to dose and type. The various progestins used in COCs differ in their estrogenic, androgenic, and progestogenic effects.
COC regimens can be categorized as monophasic, biphasic, triphasic, or four-phasic. Monophasic COCs contain the same amount of estrogen and progesterone in each active pill. Biphasic pills contain the same amount of estrogen but two different doses of progestin depending where in the cycle they are to be taken. Triphasic pills provide escalating estrogen and/or progestin doses weekly for 3 consecutive weeks, with the goal of decreasing breakthrough bleeding and amenorrhea. At the time of writing, there is only one 4-phasic contraceptive available, which contains four different dose combinations over a 28-day cycle. Studies have shown no difference in contraceptive efficacy between these regimens, but a possible reduction in dose-dependent adverse effects may be achieved.
Because many pill packs contain placebo pills during the last week of the regimen and even varying amounts of hormone in the initial weeks, it is important for patients to take contraceptive pills sequentially. Active pills of different strengths and placebo pills can usually be distinguished by a difference in color.
The standard cycle for COCs is 28 days (21 days of active pills and 7 days of placebo pills). This regimen was devised to mimic the average natural menstrual cycle of a nonpregnant female. Using this regimen, women experience a monthly menstrual period during the placebo week.
Some COCs have been designed to alter the frequency and/or duration of menses. These agents are also referred to as extended- or continuous-cycle oral contraceptive regimens. Extended- and continuous-cycle regimens typically shorten the menstrual cycle, decrease the frequency of menses to four times per year, or eliminate menses altogether. As a result, these regimens may be beneficial for patients with menstrual-related conditions such as menstrual migraines, cramps, or endometriosis.4
LOOK-ALIKE/SOUND-ALIKE—Although several similarities exist between Seasonale®, Seasonique®, and LoSeasonique®, they are not interchangeable and should not be substituted for one another without contacting the prescribing physician.
Seasonale®, Seasonique®, and LoSeasonique® are examples of extended-cycle regimens. Seasonale® contains 84 days of active pills and 7 days of placebo pills (84/7), while Seasonique® contains 84 days of active pills and 7 days of low-dose ethinyl estradiol. LoSeasonique® contains 84 active tablets but with lower doses of both the estrogen and progesterone components compared to Seasonale® and Seasonique®. Similar to Seasonique®, LoSeasonique® also contains 7 days of low-dose ethinyl estradiol in place of placebo. Using either of these regimens, women reduce the frequency of menses to four times per year.5
Yaz®, Minastrin 24 Fe®, and Lo Loestrin Fe® are also considered extended-cycle regimens because they have more than 21 days of active hormone. Yaz® contains 24 days of active pills and 4 days of placebo pills (24/4), while Minastrin 24 Fe® contains 24 days of active pills and 4 days of an iron supplement called ferrous fumarate. Lo Loestrin Fe® contains a lower dose of estrogen compared to Minastrin 24 Fe® and has 26 active pills. Using these regimens, women experience a monthly menstrual period but with a lighter flow and shorter duration.4,6
Caution should be taken not to confuse Yaz®with Yasmin 28® or Loestrin 21 1/20®with Loestrin 21 1.5/30®, Loestrin FE 1/20®, or Loestrin FE 1.5/30.® Yasmin 28®, Loestrin 21 1/20®, and Loestrin 21 1.5/30® are not considered extended-cycle regimens and contain different doses of estrogen and/or progestin.
Amethyst® is a continuous-cycle contraceptive. This product is packaged as a 28-day pill pack, but each package contains 28 days of active pills to be taken continuously for 1 year without a placebo. Although women using Amethyst® do not get a scheduled menstrual bleed, women may experience breakthrough bleeding or spotting during the first 3–6 months of use.7
Common side effects associated with COCs are related to the dose of estrogen and the activity of the progestin. Estrogenic effects include nausea, breast tenderness, increased blood pressure, and headache. Progestogenic effects include breast tenderness, headache, fatigue, and mood changes. Androgenic effects, due to the progestin component, include increased appetite, weight gain, acne, oily skin, hirsutism, and cholesterol abnormalities. In addition to these common side effects, patients should be counseled regarding the possibility for more serious adverse effects. Although not common in younger women, estrogen and progestin can increase a woman’s risk for blood clots, heart attacks, and strokes. These risks are further increased in older women, smokers, women who are genetically more prone to forming blood clots, those with existing high blood pressure or cholesterol, or those with certain migraine syndromes.4
Based on Samantha’s symptoms of heavy menstrual periods, menstrual cramps, and monthly migraines related to menses, do you think some physicians might prescribe a different COC for her? Why or why not?
The acronym ACHES can be used to help patients remember what symptoms may indicate a more serious side effect (A = abdominal pain—severe; C = chest pain—severe; H = headaches—severe; E = eye problems; S = severe leg pains).4Patients experiencing any of these symptoms should be advised to seek medical attention.
Initiation of COCs can occur a few different ways: Day 1 Start, Sunday Start, and Quick Start. Using the Day 1 Start, patients take the first pill of the COC on the first day of their menstrual period. The Sunday Start method involves starting COCs on the first Sunday after the start of their menstrual period. Using this method of initiation, women may avoid having their menstrual period on the weekends. More recently, the Quick Start regimen has been recommended. Using this regimen, women begin taking their first pill the same day they see their physician, which may help improve adherence. For women initiating COCs using the Sunday Start or Quick Start regimens, 7 days of backup contraception is recommended.
Examples of non-oral combined hormonal contraceptives include the patch and the intravaginal ring. Both of these products offer alternatives for patients who have difficulty remembering to take COCs on a regular basis. The two intravaginal rings available are NuvaRing® and Annovera®. NuvaRing® is a flexible vaginal ring that releases 15 mcg of ethinyl estradiol and 120 mcg of etonogestrel per day. It is available in a single size that can easily be inserted and removed at home and does not require fitting. NuvaRing® should be inserted between days 1 and 5 of the menstrual cycle. Each contraceptive ring is worn for 3 consecutive weeks followed by a 1-week, ring-free period. A new contraceptive ring is inserted 1 week after the previous ring was removed. If the user forgets to remove the ring on time, the NuvaRing® has the ability to provide protection for up to four weeks. A new ring should be inserted after a 1-week, ring-free period. Adverse effects are similar to that of COCs; however, NuvaRing® is associated with more vaginal complaints (inflammation, discomfort, and infections).4 Prior to dispensing, NuvaRing® should be stored in the refrigerator (2°C to 8°C). Once dispensed to a patient, NuvaRing® can be kept at room temperature for up to 4 months.8 Annovera® is a silicone vaginal ring that releases 13 mcg of ethinyl estradiol and 150 mcg of segesterone acetate per day. Annovera® is unique because it can be used for 13 cycles, unlike the NuvaRing®, which is discarded after one use. Annovera® should be stored in a black container during the 1-week, ring-free period. The black container is provided when the drug is dispensed to the patient.9
Caution should be taken if either of the rings slip out. If the NuvaRing® slips out or is left out for 3 hours or less, it can be rinsed with cool or lukewarm water and reinserted without losing effectiveness. Similar handling instructions apply to Annovera®; however, the maximum time is 2 hours. If the ring is left out for longer or if the duration is unknown, patients should rinse the ring, reinsert, and use a backup form of contraception for 1 week.8,9
Xulane® is a contraceptive patch that releases 150 mcg per day of norelgestromin and 35 mcg per day of ethinyl estradiol. Xulane® is dispensed in a package of three patches. The patch can be started using the Day 1 Start or Sunday Start methods. If therapy starts after the first day of the menstrual cycle, a backup form of contraception is recommended for the first 7 days of the first treatment cycle. Women should apply one patch every week and replace it with a new patch for 3 consecutive weeks. Each patch is removed and replaced on the same day of the week, also referred to as the Patch Change Day. A 1-week, patch-free interval allows for a menstrual period.
If a patch is partially or completely detached for less than 24 hours, a patient can use the same patch if it still contains adhesive. The Patch Change Day will remain the same. If the patch is partially or completely detached for more than 24 hours, a new patch should be applied immediately and 7 days of backup contraception is recommended. As a result, there is a new Patch Change Day. Side effects are similar to COCs, with the exception of increased breast tenderness during the first 2 months of use and skin irritation at the application site. Xulane® may be less effective in women weighing more than 90 kg (198 lb). Therefore, an alternative form of contraception may be preferred in these women.10
Although an estrogen patch is worn for 7 consecutive days, active hormone is still present after the patch is removed. Therefore, women should be reminded to fold the patch in half when discarding to minimize the potential for ingestion by or exposure to children, pets, or anyone else. Women should avoid the use of lotions or occlusive dressings at the patch application site.
Patient education is extremely important for patients initiating combined hormonal contraception. Written and verbal information regarding proper use of the medications, common and serious side effects, management of side effects, and when to seek medical attention must be provided, and the FDA requires a medication guide for these. While combined hormonal contraceptives provide an effective form of contraception, some women must be reminded that they do not protect against transmission of sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV). Information about how to initiate the various combined hormonal products (oral, intravaginal, transdermal) should be provided, as well as potential drug interactions (discussed below), which may decrease contraceptive efficacy. The importance of routine daily administration should be stressed, including suggestions on how to improve adherence (ie, alarms, calendars, associating medication administration with a daily routine, etc.). For patients interested in getting pregnant, return to fertility after discontinuing combined hormonal contraceptives is immediate, with an average delay to ovulation of 1–2 weeks.
On occasion, patients may miss a dose (a missed dose is considered any pill that contains active hormone). Recommendations on what to do regarding a missed dose may differ among various combined hormonal contraceptives and can be found in the respective package inserts.
Patients taking combined hormonal contraceptives can expect their menses to start 1–3 days after their last hormone exposure. Subsequent cycles of combined hormonal contraceptives should start every 28 days even if menses is not completed. Spotting is common during the first 1–3 months of starting a hormonal contraceptive.
Progestin-only products may be prescribed for women who are not good candidates for COCs or those who are breastfeeding. Similar to COCs, several formulations of progestin-only products exist, including oral, injectable, intrauterine, and subdermal.
Oral progestin-only products are referred to as progestin-only pills (POPs) or “mini-pills.” They contain lower progestin doses compared to progestins contained in COCs and no estrogen. When taken correctly, POPs are as effective as COCs in protecting against pregnancy. Examples include Ortho Micronor® and Norlyroc®. Like COCs, POPs are packaged as 28-day pill packs; however, each pill contains active hormone and none may be skipped or discarded. POPs can be initiated anytime during the menstrual cycle. Although women taking POPs experience less menstrual bleeding overall, side effects include irregular menses that range from amenorrhea to increased days of spotting and bleeding.
Depo-Provera® is an injectable progestin-only contraceptive agent. It is a good option for women who are not candidates for COCs, have difficulty remembering to take pills on a daily basis, or want a contraceptive agent that is convenient and discrete. Depo-Provera® may be administered by patients themselves or in a physician’s office every 3 months. Since this form of contraception relies little on patient cooperation, it is highly effective. Depo-Provera® is injected either intramuscularly (IM) in the gluteal or deltoid muscles or subcutaneously (SUBQ) in the thigh or abdomen. Side effects include irregular bleeding with eventual amenorrhea, breast tenderness, weight gain (average 1 kg annually), and decrease in bone mass. Return to fertility after discontinuation of Depo-Provera® may be delayed for approximately 9 months.11
Intramuscular Depo-Provera® is available as a 150 mg/mL vial or prefilled syringe. Depo-SubQ Provera 104® is available as a 104 mg/0.65 mL prefilled syringe. The lower dose of progestin in the SUBQ formulation is related to its slower and more sustained absorption. It is important not to interchange dosage forms.
Women using Depo-Provera® are often advised to consume 1,200–1,500 mg of calcium and 400 International Units of vitamin D daily through diet and/or supplementation to minimize risks for decreased bone mineral density and osteoporosis.
Mirena®, Kyleena®, Liletta®, and Skyla® are examples of intrauterine progestin-only contraceptive agents that provide another alternative for women who cannot take pills on a regular basis. It is a T-shaped contraceptive device that requires an office visit for physician insertion and removal from the uterine cavity. Mirena®, Kyleena®, and Liletta® are effective forms of contraception that last up to 5 years. Skyla® is effective for up to 3 years. In addition to being a highly effective contraceptive agent, Mirena® can also be beneficial in patients with dysmenorrhea, menorrhagia, anemia related to heavy menses, or endometriosis. The other agents have not been formally evaluated for these indications. Bleeding abnormalities are common during the first 3 months of use; however, with continued use patients experience amenorrhea. Side effects include headaches, acne, breast tenderness, and moodiness. Complications associated with the use of intrauterine devices include an increased risk for pelvic inflammatory disease, uterine perforations (incidence of 0–1.3 per 1,000 insertions), and expulsion (about 5% of users).12-15
Women using intrauterine devices should receive information about possible complications. The acronym PAINS is often used (P = period late— abnormal spotting or bleeding; A = abdominal pain—pain after intercourse; I = infection exposure (sexually transmitted infections)—abnormal vaginal discharge; N = not feeling well—fever, chills; S = string missing—shorter or longer).
Nexplanon® is the only subdermal contraceptive available on the U.S. market. It is a single implantable rod that is made of a nonbiodegradable solid composed of ethylene vinyl acetate that is just over 1.5 inches long and less than 1/10 inch in diameter. Each implantable rod contains 68 mg of etonogestrel and is effective for 3 years. Initially, Nexplanon® releases 60–70 mcg etonogestrel daily and decreases to 25–30 mcg etonogestrel daily by the end of 3 years. Nexplanon® is inserted just under the skin above the elbow of the nondominant arm. Both insertion and removal must occur in the physician’s office. Although Nexplanon® is associated with unpredictable and irregular bleeding initially, many patients transition to amenorrhea. As a result, Nexplanon® may be beneficial for patients with dysmenorrhea and anemia related to menorrhagia. Nexplanon® is associated with an immediate return to fertility after removal. Depo-Provera®, intrauterine devices, and Nexplanon® are sometimes prescribed for patients who are nonadherent as these methods of contraception require little patient effort.16
The use of reminder systems should be highly encouraged in patients using POPs to maximize compliance and contraceptive efficacy.
To preserve contraceptive efficacy, women should be made aware of the potential for drug-drug interactions. Medications have the potential to minimize contraceptive efficacy by interfering with gastrointestinal absorption, reducing intestinal reabsorption by altering gut bacteria, and increasing breakdown of the estrogens and progestins contained in hormonal contraceptives. In general, the lower the dose of hormones contained in the contraceptive agent, the greater the risk for compromised efficacy.
Samantha is picking up a 10-day prescription for amoxicillin, an antibiotic, and is concerned about possible contraceptive failure. What might the pharmacist advise her to do?
Medications that have been shown to interact with contraceptives include some HIV medications, anticonvulsants, and certain antibiotics. Anticonvulsants that have been implicated include carbamazepine (Tegretol®), phenytoin (Dilantin®), primidone (Mysoline®), and phenobarbital. The interaction between antibiotics and hormonal contraceptives can vary based on the antibiotic and on the individual patient. The interactions with rifampin (Rifadin®) and griseofulvin are most significant. It is recommended that women using either of these medications use an additional form of contraception during the course of treatment and for 4 weeks afterward.17 Studies of other antibiotics have shown less of an impact on contraceptive efficacy. Despite the potential lower risk for contraceptive failure, it is generally recommended that women use a backup form of contraception during the course of antibiotic treatment and for 1 week afterward as a precaution in patients receiving less than 30 mcg of ethinyl estradiol or 150 mcg of levonorgestrel.18
Paragard® is a copper intrauterine device that can be used for the prevention of pregnancy or emergency contraception. Paragard® releases copper ions, which cause inflammation to prevent the movement of sperm to the egg. Like the other intrauterine devices, Paragard® is inserted by a trained healthcare professional in a clinic. Paragard® has similar warnings to the other intrauterine devices. One main difference is that Paragard® is contraindicated in patients with Wilson’s disease, a disorder in which copper builds up in the body. Paragard® can be inserted for up to 10 years.19
Nonoxynol 9 is an over-the-counter medication that is available as a vaginal gel, suppository, sponge, film, and foam. Nonoxynol 9 works as a spermicide to stop sperm from moving. Spermicide can be irritating and may cause urinary tract infections. Patients should be counseled to review the individual instructions on the packaging since there are many different products available.20
Samantha comes to the pharmacy frantically on a Saturday morning and says she has been forgetting to take her birth control and she had unprotected intercourse. She would like to purchase Plan B One Step®. What might the pharmacist tell her?
Emergency contraception (EC) can be used to prevent pregnancy after a known or suspected failure of contraception or unprotected intercourse. It can be up to 90% effective in reducing the pregnancy rate when used within 72 hours of unprotected intercourse. Studies suggest that the primary mechanism of action of EC is the inhibition or delay of ovulation, or inhibition of fertilization and/or implantation. The Yuzpe method, Plan B One Step®, Ella®, and insertion of an intrauterine copper contraceptive are all FDA-approved methods of emergency contraception.
The Yuzpe method allows women to take their regular oral contraceptive pills as an emergency contraceptive regimen. This method requires patients to take multiple pills to equal 100 mcg of ethinyl estradiol and 0.5 mg of levonorgestrel per dose, administered as two doses 12 hours apart. Depending on the product they take at home, patients may have to take 4 to 6 pills with each dose. The Yuzpe method is approximately 75% effective in reducing the incidence of unplanned pregnancies. The most common adverse effect associated with the Yuzpe method is nausea. Many patients are counseled to take an antiemetic 1 hour before the EC dose is taken.21
Plan B One-Step® is a common EC agent. Plan B One-Step® is associated with nausea and vomiting but at a much lower rate compared to the Yuzpe method. Other side effects associated with Plan B One-Step® use include irregular bleeding and, less frequently, dizziness, fatigue, breast tenderness, headache, and abdominal pain. In 2014, the FDA announced that Plan B One-Step® and its generic products would be available over the counter without age limitations. These products no longer need to be kept behind the pharmacy counter and can be stocked in the family planning section of the pharmacy.21,22
Ella® is a prescription-only medication. While it may be more effective than Plan B One-Step®, it is often harder for patients to get since it is not stocked as routinely as Plan B One-Step® and its generics.23 Ella® should be taken within 5 days of unprotected sex. Adverse effects associated with Ella® are similar to other products and include headache, nausea, abnormal bleeding, and dizziness.24
If the patient vomits within 2 or 3 hours of taking a dose of the EC (Yuzpe or any Plan B®) the dose should be repeated.22
It is not required that Plan B One-Step® be purchased by the patient herself; it can be purchased by men and women.
Yuzpe, Plan B One-Step®, and Ella® should not be used as a regular form of contraception. They are also not effective for women who are pregnant.21
Postmenopausal Hormone Therapy
Paula Smith is a 52-year-old female who is picking up her blood pressure medications. She is complaining of several episodes of feeling hot and flushed throughout the day and waking up sweating at night and tells you a few of her friends are also “going through the change.”
As women age, their ovaries become less active and production of estrogen decreases. The changes are associated with alterations in the menstrual cycle, including a change in cycle length or skipped menstrual periods, known as perimenopause. Perimenopause typically lasts 1 to 2 years during which time menstrual periods become further apart and finally cease. After 12 consecutive months of amenorrhea, a woman is considered to be experiencing menopause. Most women experience menopause between the ages of 44 and 55, the average age is 50 to 52.25 Women who have had a hysterectomy are likely to have an earlier menopause. Symptoms associated with menopause and perimenopause are similar and can be categorized as vasomotor, psychological, or sexual.
Vasomotor symptoms, including hot flashes and night sweats, are commonly associated with low estrogen levels. Hot flashes occur spontaneously and can manifest as a sensation of warmth, which is accompanied by skin flushing and perspiration. A chill may follow afterward as the body temperature drops. When occurring at night hot flashes can cause insomnia, which may result in daytime sedation and difficulty concentrating. The frequency and severity of symptoms can vary, with some women experiencing occasional symptoms while other women may experience multiple hot flashes throughout the day. Vasomotor symptoms can have a profound impact on quality of life and can have a psychological impact, including depression, irritability, and anxiety. For most women, vasomotor symptoms are most pronounced during the first two postmenopausal years and will resolve spontaneously within 5 years of onset. However, some women will continue to experience symptoms beyond 5 years.
What is likely causing the symptoms Paula is experiencing?
In addition to vasomotor symptoms and subsequent psychological manifestations, women may also have vaginal changes. Dryness, atrophic vaginitis, a vaginal inflammation related to thinning tissues, and dyspareunia, painful intercourse, are common for postmenopausal women.
Treatment of menopausal issues focuses on symptomatic relief, improvement in quality of life, and minimizing the risk of side effects and complications relating to therapy. For some women, lifestyle modifications such as exercise, weight control, smoking cessation, and a healthy diet can effectively manage postmenopausal symptoms. Complementary and alternative therapies such as black cohosh should not be recommended to patients. They have not been shown to reduce hot flashes and some carry a risk of hepatotoxicity. For many women, estrogen therapy is needed to restore low hormone levels and provide postmenopausal symptomatic relief.26
Paula mentions that she has read a lot of “scary stuff” about hormone replacement therapy, and she does not currently want to even discuss it with her doctor. What remedies might she be able to try on her own? Should she still be directed to see her physician?
Hormone therapy (HT), including estrogen-only and estrogen–progestin combinations, has been the mainstay of menopausal and postmenopausal management for more than 50 years (Medication Table 11-2 lists examples). Estrogen is FDA approved for the treatment of moderate to severe vasomotor symptoms, moderate to severe symptoms of vulvar and vaginal atrophy (such as dryness, itching, and burning), and the prevention of postmenopausal osteoporosis. Several products, formulations, and routes of administration are available for estrogen, including oral; transdermal; intravaginal tablets, rings, gels, and creams; and sprays. The oral and transdermal routes are the most frequently used form of estrogen administration by women whose major complaints are vasomotor symptoms. Local products such as intravaginal tablets, rings, gels, and creams are reserved for women with vaginal complaints such as dryness and pain. The decision regarding the product, route, and method of delivery of estrogen should be made with the patient and her physician to ensure optimal acceptability and adherence.
Oral estrogen replacement products include conjugated equine estrogens (prepared from the urine of pregnant mares), synthetic conjugated estrogens, esterified estrogens, estropipate, and estradiol. When administered via the oral route, estrogens are absorbed into the circulatory system and broken down by the liver. Transdermal administration and use of some intravaginal rings may yield a slightly better side effect profile as less estrogen reaches the systemic circulation.26
Paula Smith has not had a menstrual period in more than 12 months. Is she a candidate for estrogen therapy?
Dosage requirements for estrogen depend on the individual and therapy is usually started with the lowest dose that provides effective relief of symptoms. Vasomotor symptoms may begin to improve within 1 to 2 weeks. Side effects of estrogen therapy include nausea, headache, breast tenderness, and heavy bleeding. Serious side effects include increased risk for coronary heart disease, stroke, venous thromboembolism, breast cancer, and cholecystitis.26
For women prescribed HT, estrogen and progesterone may be prescribed as separate medications or combination products. These products may have similar names so caution must be used to avoid dispensing the wrong product. Premarin® is an estrogen-only product available in several doses. Prempro® and Premphase® are both estrogen–progestin combination oral products. However, Prempro® contains a continuous dose of progesterone while Premphase® contains an intermittent dose of progesterone. They must not be interchanged unless authorized by the physician.
HT is usually considered to be contraindicated in women with the following conditions: current, past, or suspected breast cancer; known or suspected progesterone- or estrogen-dependent cancers; undiagnosed vaginal bleeding; untreated endometrial hyperplasia; previous or current clotting disorders; coronary heart disease, stroke, untreated high blood pressure; and active liver disease. When HT is dispensed, women must receive information about the potential risks and benefits associated with HT and when to seek medical attention.
In women with a uterus, progesterone should be added to the estrogen regimen to reduce the risk for endometrial cancer. Progesterone may be given intermittently or continuously. Intermittent dosing usually involves progesterone administration for 12–14 days every month or every 2–6 months and may be preferred to minimize overall hormone exposure. Continuous dosing involves daily administration of progesterone. Progesterone is typically given orally, although some combination products (with estrogen) are available in other formulations and contain various types of progesterone. Examples of progestin-only products include medroxyprogesterone (Provera®) and micronized progesterone (Prometrium®). Side effects may vary depending on the agent prescribed and the most common include irritability, depression, and mood swings. Other side effects are bloating, fluid retention, and sleep disturbance. Switching from an intermittent to a continuous regimen or from one progestin to another may reduce the incidence or severity of symptoms.
Vaginal creams, gels, rings, or tablets are available for intravaginal (local) administration of HT. These are often effective for patients with complaints of vaginal dryness, atrophic vaginitis, and dyspareunia. Although this route of administration results in some systemic absorption, significant systemic exposure is limited. Progesterone is generally not needed when estrogen is prescribed at low doses and administered vaginally. An exception is the vaginal ring, Femring®, which delivers high levels of estrogen to the body. Improvement in vaginal symptoms may take months of estrogen therapy. Nonhormonal vaginal moisturizers and lubricants can also be used to provide symptomatic relief of postmenopausal vaginal complaints of mild intensity. These products can be used alone or in combination with local administration of HT.
Some intravaginal estrogen products contain oils that can weaken latex condoms. The patient should check with the pharmacist or their prescriber if this precaution applies to the product they are prescribed.
Although controversial, the use of testosterone in women is becoming more widespread. In addition to estrogen and progesterone deficiency commonly seen in postmenopausal women, androgen deficiency has also been proposed. Symptoms that may be associated with androgen deficiency include a diminished sense of well-being, persistent or unexplained fatigue, decreased libido, decreased sexual receptivity, and decreased sexual pleasure. The use of testosterone therapy in women will be discussed in a later section of this chapter, “Testosterone Therapy in Females.”26
Infertility is typically defined as a failure to achieve pregnancy after 1 year of frequent, unprotected intercourse and affects about 10% to 15% of couples in the United States. Factors that can influence fertility include a history of previous fertility problems for the couple and each partner individually, frequency and timing of intercourse, impaired sperm quality or quantity, hypogonadism, ovulation disorders, disorders that affect the fallopian tubes, and uterine or cervical factors. This section focuses on the management of infertility of the female partner, specifically ovulation disorders.27,28
For more than 40 years, clomiphene citrate has been the first-line treatment for infertility due to ovulatory disorders. Although clomiphene citrate is very effective in inducing ovulation, pregnancy rates are only 10% to 40%. In women who conceive after a course of clomiphene citrate, there is a 10% to 20% chance of a multiple pregnancy. Clomiphene citrate is taken orally and is easy to use. The starting dose is typically 50 mg daily (one tablet) for 5 days starting on the fifth day of the menstrual cycle. If ovulation does not occur, the dose is increased to 100 mg daily (two 50-mg tablets given as a single dose) and may be started as early as 30 days after the previous dose. Increasing the dose or the duration of therapy beyond 100 mg/day for 5 days is not recommended.
For pregnancies associated with clomiphene citrate use, the risk for birth defects is reported to be the same as for the general population. The most common side effects are ovarian enlargement, flushing, abdominal problems (pelvic discomfort/distention/bloating, nausea, vomiting) breast discomfort, and visual disturbances. These side effects are mild and temporary and usually disappear after therapy is discontinued.
Women should be counseled about the possibility for ovarian hyperstimulation syndrome (OHHS), which has been reported with clomiphene citrate therapy. OHSS is an exaggerated response to fertility medications. It is a self-limiting disorder that usually resolves spontaneously within several days. Signs and symptoms associated with OHSS can range from mild illness requiring careful observation to severe disease requiring hospitalization and intensive care. Early warning signs include abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Women who experience these symptoms should be instructed to seek medical care.29
Some women seeking treatment for infertility have a condition known as polycystic ovarian syndrome (PCOS). These patients have developed small cysts on their ovaries and frequently have testosterone levels that are considered above normal. They are usually affected by menstrual irregularities and may also have problems with their heart and blood vessels. Some complain of excessive facial and body hair. In women with PCOS, clomiphene citrate alone may be ineffective for the management of infertility.
Exogenous gonadotropins, such as FSH and LH, can also be used for the management of infertility. These agents are given by injection. Gonadotropins are more effective than clomiphene citrate but are more expensive and are associated with a higher risk for OHSS and multiple pregnancies. Three main types of gonadotropins are available for the management of infertility: human chorionic gonadotropin (hCG), which is similar to LH; human menopausal gonadotropin (hMG), which contains natural FSH and LH purified from the urine of postmenopausal women; and recombinant human follicle-stimulating hormone (rFSH), which is synthesized in a laboratory. Multiple pregnancy is a common complication associated with gonadotropins. Compared to clomiphene citrate, gonadotropins are also associated with a higher risk for OHSS. Although the risk can be minimized by using a lower dose of hCG or a GnRH agonist, the risk cannot be completely eliminated.
Aromatase inhibitors are emerging as a potential replacement for clomiphene citrate as the first-line treatment for ovulation disorders. They are not FDA approved for ovulation stimulation. These agents are orally administered, easy to use, and relatively inexpensive. Traditionally used for the treatment of breast cancer, aromatase inhibitors exert their effect of inducing ovulation by inhibiting the production of estrogen, thus increasing the release of FSH and stimulating the production of eggs from the ovaries. Anastrozole (Arimidex®) and letrozole (Femara®) are examples of aromatase inhibitors. The rate of multiple pregnancies is lower with aromatase inhibitors than with clomiphene citrate. Aromatase inhibitors may also be used in combination with gonadotropins. Side effects are mild (gastrointestinal disturbances, weakness, hot flashes, headache, and back pain).30
Hypogonadism is a condition in which the primary sex organs, or gonads, are not functioning at all or are functioning at an inadequate level. As a result, the gonads fail to produce the reproductive hormones or produce inadequate amounts and cannot maintain development of either sperm or eggs. There are two major types of hypogonadism: primary and secondary. In primary hypogonadism, there is a defect with the gonads themselves, affecting their ability to produce and secrete appropriate amounts of reproductive hormones. Primary hypogonadism can occur due to a genetic or developmental defect. It can also occur when the gonads are damaged in any manner, such as after surgery, radiation exposure, infection, or an autoimmune disorder. Unlike primary hypogonadism, secondary hypogonadism is not caused by a defect with the gonads themselves but with the glands that help to regulate normal functioning of the gonads. This can occur at the level of the hypothalamus, which is responsible for the release of GnRH, or at the level of the pituitary gland, which releases LH and FSH. Secondary hypogonadism can be caused by cancerous tumors, damage from surgery, radiation exposure, infection, trauma, genetic problems, or nutritional deficiency.
In females, hypogonadism results in low levels of estrogen. In younger females, this can cause delays in growth and sexual development. Adult females with this condition cannot maintain normal reproductive cycles and experience either irregular menstrual cycles or amenorrhea, and may experience infertility. They are more likely to experience symptoms similar to female menopause, such as hot flashes or painful intercourse. Hormone replacement therapy is the main treatment for female hypogonadism. Both estrogen alone and estrogen–progesterone combination products may be used in females with hypogonadism. Estrogen is also available in combination with testosterone. The regular-strength tablets contain 1.25 mg of esterified estrogens and 2.5 mg of methyltestosterone; there is also a half-strength (H.S.) tablet containing 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone. Combination therapy with oral estrogen and methyltestosterone carry the same adverse effects and risk as use of either agent alone.
In males, hypogonadism results when the testes do not produce or release enough testosterone to maintain normal bodily functions that are dependent on testosterone. Besides primary (a problem within the testes) and secondary forms of male hypogonadism (eg, when the pituitary gland does not signal the testes to produce enough testosterone), more recently there has been evidence that points toward hypogonadism occurring as a result of male menopause, also known as andropause. Similar to female menopause, it is thought that during the natural course of aging in males, the level of testosterone produced by the testes decreases dramatically, leading to the same symptoms as hypogonadism. With this condition, there is no defect in the gonads or the hypothalamus or pituitary glands but just the natural decline in hormone production.
The signs and symptoms of low testosterone levels can include depressed mood, decreased muscle mass and/or strength, decreased energy, poor concentration, and sexual dysfunction, including decreased libido or impotence. Health complications that can result from untreated hypogonadism are anemia or low red blood cells, decreased bone density or bone loss that puts patients at increased risk of fractures, and infertility. If hypogonadism occurs in a child before he has completed puberty, the patient may experience a delay or impairment in development. This includes poor pubic or underarm hair growth, small testes and prostate size, decreased muscle development, and a high-pitched voice that fails to deepen. In adult males, particularly older men, with hypogonadism, the condition will be slower to develop and signs and symptoms are less noticeable. For example, adult men may experience decreased prostate size, decrease in muscle mass, sexual dysfunction, and low sperm production and secretion.
Testosterone Therapy in Males
Since the root of the problems associated with hypogonadism are related to the decrease in testosterone production and release, supplementing these patients with testosterone is the primary method of treatment. It is the same concept as HT to treat postmenopausal symptoms in women. In this case, the patient is supplied with an exogenous source of the hormone testosterone to provide what the body is deficient in. Testosterone supplementation is effective at restoring and keeping a patient’s testosterone levels within the normal range when given as continuous long-term therapy. Improvement in these symptoms may be noticed by the patient as quickly as a few days after initiation of testosterone supplementation.31
Testosterone replacement products are currently available in varying dosage formulations, including oral tablet, intranasal gel, IM injection, SUBQ injection, transdermal patch, transdermal gel, transdermal solution, implantable pellet, and buccal formulation (Medication Table 11-3). Testosterone products are also prescribed off label for many other conditions. One of the more common off-label uses for testosterone products is for sexual dysfunction in men with normal testosterone levels. It is still controversial whether men without hypogonadism who experience sexual dysfunction could benefit from testosterone replacement therapy. In addition, supplementing with testosterone in men with already-normal levels of the hormone may put patients at increased risk for side effects. For this reason, testosterone replacement therapy is not recommended for off-label use in these patients.31,32
As with all other drug treatment, testosterone replacement therapy is not without risks or side effects. Adverse effects when used in males can include headache, acne, gynecomastia, abnormal cholesterol levels, fluid retention, and weight gain. Major side effects that may be of concern are liver disease, benign prostatic hyperplasia (BPH), and polycythemia (increase in red blood cell mass). Some of the testosterone formulations carry an FDA black box warning on the increased risk of heart attack, stroke, and cardiovascular death due to blood pressure increases. The intramuscular testosterone undecanoate has an FDA black box warning for serious pulmonary oil microembolism reaction and the product is only available through the Aveed REMS program. All of the testosterone-only replacement products are indicated only for use in males. The use of testosterone replacement therapy is contraindicated in men diagnosed with cancers of the prostate and/or breast, because it may stimulate further growth of the cancer.32 Each of the various testosterone preparations is unique in its cost, adherence considerations, and application site.
All testosterone products are classified as schedule III controlled substances by the U.S. Drug Enforcement Administration because of their potential for abuse. Testosterone and its derivatives are also known as anabolic steroids, and the practice of taking large, unsafe doses to increase muscle mass and enhance performance in activities such as bodybuilding or competitive sports is not an approved use.
Testosterone preparations are contraindicated in patients who are pregnant or expecting to become pregnant because they have the potential to cause abnormalities in the fetus if administered at any time during pregnancy.
Oral Testosterone Products
Unmodified or natural testosterone is very poorly absorbed in the gut when given orally. Once natural testosterone is absorbed in the gastrointestinal tract, most of it is metabolized by the liver into its inactive forms. Oral formulations are seldom preferred because they are less effective and are associated with more toxicity than injectable therapies. Besides causing abnormal cholesterol levels, oral formulations are associated with serious liver toxicity that does not typically occur with the other testosterone dosage forms. Damage to the liver can be as severe as the development of liver cancer.
IM injections have traditionally been the preferred route of administration for testosterone replacement therapy. They are inexpensive and they can be dosed at longer time intervals. Testosterone cypionate (Depo-Testosterone®) and testosterone enanthate are two available testosterone preparations available in the United States for IM injection. Testosterone undecanoate (Aveed®), which is even longer acting, is more expensive. The injections are formulated as oil solutions to help prolong the time of absorption and are considered long-acting preparations. Testosterone enanthate and testosterone cypionate are typically dosed every 1 to 2 weeks. Testosterone undecanoate can be dosed every 10 weeks. The injectable testosterone products are only formulated to be given as deep IM injections to the buttock muscle. They should not be administered at alternate (nonrecommended) sites and should never be administered SUBQ or intravenously. The disadvantage to IM injections is that administration can be painful and the dosage form may be poorly accepted by patients who fear injections and find them to be invasive.32
Injectable testosterone vials should be stored at room temperature (between 68°F and 77°F). Multiple-dose vials should always be visually inspected before dispensing and prior to administration for discoloration and contaminates. When stored at temperatures lower than 68°F, crystals may form in the solution. Warming the vial by gently rolling it in the palm of the hands may help to dissolve these crystals prior to administration.
Injectable testosterone preparations may be supplied as single-dose or multiple-dose vials. Prescriptions should be carefully verified and dosages properly calculated to reflect appropriate dosing requirements, either in milligrams (mg) or milliliters (mL).
The transdermal patch (Androderm®) allows delivery of testosterone through normal skin layers into the bloodstream. It is recommended that this patch be applied to the skin on the upper arms, abdomen, back, or thighs, once daily in the evening. The most common side effect with the transdermal patch is local skin irritation at the site of patch application, specifically itching and redness. Although the testosterone patches are much less invasive then the injections, the disadvantage with this type of testosterone therapy is that it is also much more expensive.33,34
Patients using the transdermal testosterone patch should be reminded to apply the patch to a clean, dry area of skin. Application sites should be rotated daily, without repeating use of the same site for at least 1 week to minimize skin irritation.
Although transdermal testosterone patches should be changed daily, discarded patches may still contain active medication. Patients should be advised to discard patches in a manner that minimizes the potential for ingestion by or exposure to children, pets, or anyone else. The best method of disposal is to fold the patch in half over the adhesive portion before discarding in an enclosed waste bin. Patients should wash their hands after handling the patch.
Transdermal testosterone gel formulations are intended for once-daily application to the skin areas on the shoulders, upper arms, or abdomen. Although it is usually recommended that the transdermal testosterone gel be administered in the morning to a clean, dry skin area, it is more important that the medication be applied around the same time every day (whether morning or evening). The gels were originally supplied in unit-dose packets for convenience and ease of administration. More recently, transdermal testosterone gel was also made available in a multidose gel pump that delivers a metered dose per actuation of the pump. Like the transdermal patches, the gels can also cause local skin irritation but to a much lesser extent than the transdermal patches.35
Occasionally, multiple actuations of the pump or multiple packets are required to obtain the dose prescribed. Patients may be advised that the total dose may be applied to the skin area in multiple steps, one actuation or one gel packet at a time, or as a single application with the full amount of gel required combined together.
The transdermal gel formulations are not designed to be applied to the genital area.
Once applied, transdermal testosterone gel takes approximately 30 minutes for absorption, but complete absorption of the medication may take as long as several hours. To ensure maximum absorption of the product and for the best results, patients should be advised to apply the gel after showering. Patients should be advised to avoid showering, bathing, or swimming for at least 5 hours after application of the medication for those using AndroGel® and at least 2 hours for those using Testim®. Once the testosterone gel is applied to the skin, the drug can be transferred from person to person through direct contact with the skin area where the medication was applied. Studies have shown that people who come into direct skin contact with patients using testosterone gel are at risk for absorbing testosterone from the areas the gel was applied to. Cases of inappropriate virilization (development of adult male characteristics) in children have been reported to the FDA.
Patients should be reminded to wash their hands with soap and water as soon as they are done applying the gel, cover the application site with clothing, and wash the application site thoroughly with soap and water prior to engaging in skin-to-skin contact with another person to avoid the transfer of medication to others through skin contact.
The FDA requires that a medication guide be given to all patients with a prescription for AndroGel® and Testim®.
Transdermal testosterone gels are alcohol-based preparations and the alcohol in the gel is considered to be flammable until the gel is completely dried from the skin. Patients should avoid smoking or coming into close proximity with flames to avoid the potential for burns.35,36
An implantable testosterone pellet, marketed under the trade name Testopel®, is a small cylinder-shaped pellet that contains 75 mg of testosterone in each pellet. Multiple pellets can be inserted SUBQ at the same time through a minor surgical procedure to achieve the desired dose of testosterone. Patients who have testosterone administered by insertion of the pellet implant may experience pain and inflammation at the site of insertion. In addition, there is a risk for infection at the site of implantation.37
Patients who are already on warfarin and are starting on testosterone therapy or are undergoing a change, whether an increase or decrease, in testosterone dosing should be advised to inform their healthcare provider so they can receive closer monitoring of their warfarin therapy and laboratory values.
The most important drug interactions that are of concern with testosterone supplementation are when it is prescribed to a patient on warfarin or insulin therapy. There is potential for testosterone preparations to enhance the effects of warfarin and put patients at increased risk for bleeding. Testosterone also has the potential to affect glucose metabolism and possibly decrease blood glucose levels or increase insulin sensitivity. Dose changes may be required in patients with diabetes who are being treated with insulin.
Testosterone Therapy in Females
Although testosterone is predominantly a male reproductive hormone, it is also found in the female body and serves some very important roles. In the female body, testosterone is also made in the ovaries and is converted by the human body into estrogen. As women age, the level of testosterone in the body slowly decreases over time as they reach menopause. Low testosterone levels in women have been found to be associated with decreased sexual drive. For this reason, testosterone replacement therapy is sometimes prescribed off label for use by women to treat decreased sexual drive and performance. However, this practice is not recommended due to unknown long-term effects of testosterone supplementation in women and the potential for undesirable side effects. When used in females, side effects may include acne, hirsutism, male-patterned hair loss, and deepening of the voice. Currently, testosterone-only products are not recommended for use in females for any reason until there are more long-term studies to support its safety.
Benign Prostatic Hyperplasia
Mr. Johnson is a 66-year-old man who is picking up his monthly cholesterol and diabetes medications. Mr. Johnson says he has been having problems with urinating. His biggest complaint is going to the bathroom more often but still feeling as though his bladder is full.
Benign prostatic hyperplasia (BPH) is an abnormal but noncancerous enlargement of the prostate gland. It is one of the most common conditions affecting the older adult male population, affecting approximately 60% of men who are 60 years of age.38 In the earlier stages of BPH, patients may not be aware that they have prostate enlargement because it does not cause any noticeable signs or symptoms. As the prostate grows in size, it can push on the urethra, leading to problems with urination. Figure 11-4 shows how these urination problems can occur in a patient with BPH. The most common symptoms associated with BPH are lower urinary tract symptoms (which may include weak urine stream), dribbling of urine when trying to urinate, incomplete bladder emptying, urinating frequently especially during the night, and urinary incontinence.
Why might the pharmacist advise Mr. Johnson to schedule an appointment with his physician?
For most patients, BPH is a slowly progressing disease and, if treated, many can experience a reversal in symptoms. If left untreated, complications such as bladder stones, urinary tract infections, hematuria, or problems with kidney function can occur. Although not all patients require medication treatment to manage their BPH, many will be prescribed medications to help control their symptoms. The two main classes of medication therapy prescribed to treat BPH are alpha1-receptor blockers and 5-alpha reductase inhibitors. A brief summary of these medications can be found in Medication Table 11-4. Both classes of medications can be prescribed either as a single drug or in combination with each other (ie, an alpha1-receptor blocker plus a 5-alpha reductase inhibitor).
Alpha1-receptor blockers are commonly used to treat the urinary symptoms associated with BPH. They are typically used to treat patients with moderate to severe symptoms. These medications can cause the muscles in the urinary tract and the prostate gland to relax. This muscle relaxation helps to improve patients’ ability to urinate normally. Doxazosin (Cardura®), terazosin (Hytrin®), and prazosin (Minipress®) are the three older alpha1 blockers used in BPH that are also prescribed for the treatment of high blood pressure. This is because they also work to relax the muscles of the blood vessels in other areas of the body, which can lower blood pressure. Refer to Chapter 15 for detailed information regarding the three alpha1 blockers and their use for the treatment of high blood pressure.
Mr. Johnson saw his doctor, who told him he has developed an enlarged prostate but that medication might control his symptoms. Along with his other medications, Mr. Johnson presents a new prescription for tamsulosin. He asks what kind of medication this is and if there is any important information he should know before taking it. What would you expect the pharmacist to tell him?
There are three relatively newer alpha1-receptor blockers currently available that have unique properties compared to ones mentioned earlier that make them especially useful for treating BPH symptoms. Tamsulosin (Flomax®), alfuzosin (Uroxatral®), and silodosin (Rapaflo®) are alpha1-receptor blockers that work only on the receptors in the human prostate when prescribed at their normal doses. These medications are currently FDA approved only for the treatment of BPH. In patients with BPH and normal blood pressure, the use of the older alpha1-receptor blockers can cause unwanted side effects, such as low blood pressure. Unlike the older alpha1-receptor blockers, the newer medications are not as effective in lowering blood pressure because they work more specifically on the prostate itself. This selectivity for the prostate is the advantage to using these newer drugs. All are available in a generic equivalent.38
Patients who are prescribed the newer alpha1-receptor blockers for their BPH should not be taking the older alpha1-receptor blockers at the same time, even if these are being used to treat their high blood pressure. The pharmacist should be alerted to such duplication of therapy.
Tamsulosin is available as a 0.4-mg capsule, dosed once a day. It is recommended that tamsulosin be taken approximately 30 minutes after the same meal each day to achieve steady levels of the drug in the body. Even though tamsulosin is not effective at treating hypertension compared to the older alpha1-blockers, a drop in the blood pressure with positional changes (eg, from sitting to standing) may occur, especially after the first dose or when the dose is increased. Patients would need to use caution and watch for dizziness when first starting on the drug or when there is a dose increase, especially if they are taking blood pressure medications. Other side effects that may occur with tamsulosin treatment include runny nose and abnormal ejaculation. There have been reports of a rare condition called intraoperative floppy iris syndrome (IFIS) occurring in patients undergoing cataract surgery who are using, or have taken in the past, alpha1-receptor blockers, including tamsulosin. Patients who are on tamsulosin considering cataract surgery should inform their eye doctor that they are on this medication. Patients on tamsulosin should also be counseled that, although extremely rare, there may be a risk of developing priapism with the use of tamsulosin. Tamsulosin dosing does not require adjustment in patients with kidney or liver problems. The medication is broken down by liver enzymes in the cytochrome P450 system and should be used cautiously in patients on medications that inhibit these enzymes, such as cimetidine, ketoconazole, or paroxetine (Paxil®).39
LOOK-ALIKE/SOUND-ALIKE—Flomax (tamsulosin) can be confused with the medication Fosamax® (alendronate) that is used for the treatment of osteoporosis. When receiving prescriptions with poor handwriting and/or without any medication strength indicated, the medication prescribed should always be verified with the prescriber. When taking a verbal order, the drug names may sound similar.
Alfuzosin is also a selective alpha1-receptor blocker. It is available as a 10-mg extended-release tablet and is dosed once daily given after the same meal each day. Although alfuzosin can be used in patients with poor kidney function, it should not be prescribed to patients with moderate to severe liver dysfunction. Alfuzosin seems to be well tolerated, with the common side effects being dizziness, headache, and tiredness. In addition, it is associated with less abnormal ejaculation problems than tamsulosin. Similar to tamsulosin, patients on alfuzosin should also be counseled on the risk of IFIS if they will be undergoing cataract surgery. Alfuzosin is primarily broken down by the cytochrome P450 liver enzyme system. As a result, it should not be used together with medications that specifically block alfuzosin breakdown through these enzymes, including ketoconazole, itraconazole (Sporanox®), and ritonavir (Norvir®).40
Tamsulosin capsules should be swallowed whole and should never be crushed or chewed. Alfuzosin is an extended-release tablet and should also be swallowed whole and cannot be crushed, chewed, or split.
The newest selective alpha1-receptor blocker is silodosin, which is available in two strengths: a 4- or 8-mg capsule. The usual dose for silodosin is 8 mg once daily with a meal, but it can also be dosed lower at 4 mg once daily in patients with moderate kidney impairment. Like tamsulosin and alfuzosin, the most common side effects of silodosin include abnormal ejaculation, dizziness, drops in blood pressure with positional changes, and headache. Some patients may also experience diarrhea. Silodosin has similar drug-drug interactions as alfuzosin and should not be prescribed with medications such as ketoconazole, itraconazole (Sporanox®), and ritonavir (Norvir®).41
Mr. Johnson returns to the pharmacy months later and now has a prescription for finasteride. He says the doctor thinks this medicine will help his urinary symptoms even more than the tamsulosin alone. Should he be taking both these medications at the same time?
5-alpha Reductase Inhibitors
In the male body, testosterone is converted into another active hormone known as dihydrotestosterone (DHT) by an enzyme called 5-alpha reductase. DHT is a testosterone-like hormone that is responsible for causing the abnormal enlargement of the prostate gland in BPH. 5-alpha reductase inhibitors are a class of medications that lower the levels of DHT circulating in the body to reduce overgrowth of prostate tissue. Therefore, this particular class of medications works best to relieve BPH symptoms for patients who have larger prostates by shrinking the prostate gland. In the United States, there are currently only two medications in this class available: finasteride (Proscar®) and dutasteride (Avodart®). Both of these medications work the same way by reducing the testosterone responsible for enlarging the prostate. These agents can reduce the size of the prostate gland by an estimated 25%, which in turn leads to a reduction in urinary symptoms. However, they do not provide quick relief. Patients who are prescribed finasteride or dutasteride for their BPH should be made aware that the medication takes 6–12 months of continuous treatment to reach its full effect. Patients should keep taking their medication even if they do not feel any symptom relief initially. If the medication is discontinued, the effects of the medication will likely reverse over time and the patient may experience a return of his original symptoms.38
Mr. Johnson has been taking finasteride in addition to his tamsulosin for 2 months now, and he comes back for a refill of the tamsulosin but says he doesn’t think he wants to refill the finasteride because it doesn’t seem to be helping. Should the technician put in only the tamsulosin refill, or should something additional be considered?
Finasteride and dutasteride are both available as generics. Finasteride is only dosed as 5 mg given once a day with or without food. Common side effects are related to sexual function and include decreased sex drive, erectile dysfunction, or ejaculation problems. Recent data suggest that patients using finasteride for long-term therapy of BPH had a lower risk of developing prostate cancer, but those who did get prostate cancer while taking finasteride were more likely to be diagnosed with a more advanced form. Although the information regarding the use of finasteride and risk for prostate cancer is still unclear, patients should discuss these risks with their doctors. No dosing adjustments for poor kidney function is needed, but since it is broken down in the liver, finasteride should be used carefully in patients with poor liver function.38
Dutasteride is the newer of the two 5-alpha reductase inhibitors. It is only available in one strength, 0.5 mg, and is dosed as one capsule (0.5 mg) given once daily. Patients taking dutasteride most commonly complain of the same sexual side effects as patients taking finasteride. Also similar to finasteride, dutasteride does not need to be adjusted for poor kidney function and should be used cautiously in liver disease. Although dutasteride does not appear to have any significant drug-drug interactions, it is broken down extensively by the liver cytochrome P450 enzymes. Patients taking dutasteride should be monitored carefully by their physicians for increased side effects if they will be taking medications, such as ritonavir, that can block the breakdown of dutasteride by these enzymes. Dutasteride is also available in a capsule formulation in combination with tamsulosin under the brand name Jalyn® for the convenience of patients on both medications for their BPH.42,43
LOOK-ALIKE/SOUND-ALIKE—Finasteride is available on the U.S. market under two different brand names, Proscar® and Propecia®. Although each formulation contains the same active ingredient, each is FDA approved for separate indications and the products are formulated in difference dosage strengths. Proscar® is FDA approved for the treatment of BPH while Propecia® is approved and marketed for the treatment of male-pattern hair loss in men only. Special attention should be paid to not interchanging these two brand names.
Dutasteride capsules should be swallowed whole and cannot be crushed, chewed, or opened. Contact with the content of the capsules can cause irritation of the mouth and throat.
Androgen Receptor Blockers and GnRH Analogues
Antiandrogens and GnRH analogues are medications that are designed to block the effects of testosterone in the body. The main type of antiandrogen medications is androgen receptor blockers. The second group of medications is the GnRH analogues, which work indirectly to suppress the effects of testosterone. These two groups of medications are not very widely prescribed because they are used to treat conditions that are uncommon. One of the main medical conditions that both of these classes of medications are used to treat is prostate cancer in males. In prostate cancer, the sex hormones testosterone and 5-alpha dihydrotestosterone are responsible for stimulating growth of the prostate and causing further advancement of the cancer. Medication therapy with the antiandrogens and GnRH analogues is typically reserved for more advanced stages of prostate cancer.44
Finasteride and dutasteride are contraindicated in patients who are pregnant or expecting to become pregnant. These medications can be absorbed through direct contact with the skin. Women (including pharmacy technicians, nurses, and caregivers) who are pregnant or are trying to become pregnant should be advised not to handle the medications with their bare hands.
Androgen Receptor Blockers
The androgen receptor blockers (antiandrogens) directly block the effects of testosterone in the body by competing with natural androgens at their sites of action. These medications do not allow androgens such as testosterone to bind to their receptors to cause changes in the body. There are a number of androgen receptor blockers available in the United States. They are apalutamide (Erleada®), darolutamide (Nubequa®), enzalutamide (Xtandi®), flutamide (Eulexin®), nilutamide (Nilandron®), and bicalutamide (Casodex®). Apalutamide (Erleada®), darolutamide (Nubequa®), enzalutamide (Xtandi®) are all brand name only. Bicalutamide, nilutamide, and flutamide are available as generics. Darolutamide (Nubequa®) is dosed twice daily, while flutamide is dosed every 8 hours. All the others within the class are dosed once daily at the same time every day. Darolutamide (Nubequa®) should be taken with food, while the other medications in the class can be taken with or without food. Side effects associated with this class of medications include nausea, diarrhea or constipation, gynecomastia, hot flushes, and potential liver toxicity. Flutamide appears to be associated with more diarrhea than bicalutamide. Nilutamide also appears to be associated with visual disturbances and intolerance to alcohol. Enzalutamide increases the risk of patients having a seizure. Medication Table 11-5 lists these medications.44-50
Nilutamide and apalutamide are light sensitive and should not be removed from the original packaging until just prior to administration.
LOOK-ALIKE/SOUND-ALIKE—Thalidomide (Thalomid®) and flutamide have been confused as sound-alike drugs when taken as verbal prescriptions. Thalidomide is only available through a restricted program, which helps to avoid this confusion. However, verbal orders for these two medications should be avoided whenever possible.
Androgen Synthesis Blocker
Abiraterone is an antiandrogen that acts in a different way from the androgen receptor blockers described above. It works by blocking an enzyme needed for the production of testosterone, thereby decreasing the amount of testosterone available at the receptor sites. The usual dose is 1,000 mg once daily. Abiraterone is available as Zytiga®, which must be taken on an empty stomach. It is also available as Yonsa®, which can be taken without regard to meals. This dose may be reduced for patients with liver impairment. The most common adverse reactions associated with abiraterone are swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flushes, diarrhea, urinary and upper respiratory tract infection, cough, hypertension, cardiac arrhythmia, and urinary frequency.51,52
Zytiga® must be taken on an empty stomach. No food should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. The tablets should be swallowed whole with water.
Gonadotropin-Releasing Hormone Analogues
GnRH analogues work indirectly to suppress the actions of the androgens in the body. They are sometimes also called luteinizing hormone-releasing hormone (LHRH) agonists. When given as continuous therapy, GnRH analogues mimic natural GnRH that is usually released by the hypothalamus. In the first few weeks of treatment, this leads to stimulation of the pituitary gland to secrete more LH and FSH, which stimulates the testes to make and release more androgens. However, after this initial period, there is a drop off of LH, FSH, and testosterone production and release. Available GnRH analogues are leuprolide (Lupron®), goserelin (Zoladex®), and histrelin (Vantas®). Goserelin (Zoladex®) and leuprolide (Lupron®) are also FDA approved to be used for other conditions besides prostate cancer, such as endometriosis in females. Histrelin (Vantas®) is only FDA approved for prostate cancer. Goserelin is available as two different long-acting SUBQ implants, one lasts for 28 days while the other lasts for 12 weeks. Leuprolide is available as a daily injection or as long-acting formulations for SUBQ or IM injection. A list of available formulations for use in prostate cancer can be found in Medication Table 11-5. Common side effects that may occur with GnRH analogues include injection or insertion site reactions, hot flashes, and sexual dysfunction. In the first 2 weeks of starting treatment, patients should be made aware that they may experience an initial worsening of their condition due to the initial increase in androgen release. Combination therapy with an androgen receptor blocker may help to avoid this initial disease flare-up.53-55
GnRH analogues are also sometimes used for female patients in the treatment of endometriosis or infertility.
Leuprolide is available in multiple dosage formulations for use in prostate cancer under the brand names of Lupron Depot® and Eligard®. The short-acting version is the only one available generically. Prescriptions received for leuprolide should be verified and dispensed with extra caution to avoid confusing these formulations as they are all dosed and administered differently.
Hormones involved in the human reproductive system include gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens, progesterone, and androgens. The estrogens and progesterone are the primary sex hormones released by the ovaries that are involved in the female reproductive system. Androgens, specifically testosterone, are the primary sex hormones released by the testes that are involved in the male reproductive system. Medications containing both natural and manmade forms of the primary sex hormones are available for the treatment of disorders related to the human reproductive systems. Estrogens and progestins are used either alone or in combination with one another for planned or emergency contraception (EC) as well as hormone therapy (HT) in postmenopausal women. Testosterone is most commonly seen prescribed as hormone replacement in males with hypogonadism. In addition to these, there are other medication classes on the market that can affect levels of the major sex hormones and how the male or female reproductive system functions. These medications may include gonadotropins and aromatase inhibitors used for female infertility, alpha-blockers and 5-alpha reductase inhibitors used in benign prostatic hyperplasia (BPH), and androgen receptor blockers or GnRH analogues prescribed for the treatment of prostate cancer.
The authors wish to acknowledge and thank Jennifer Lee, PharmD, and Nina Yen, PharmD, coauthors of this chapter in the first edition of this book.
LevinER, VitekWS, HammesSR.Estrogens, progestins, and the female reproductive tract. In: BrutonLL, Hilal-DandanR, KnollmannBC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018:803–832.
LevinER, VitekWS, HammesSR.Estrogens, progestins, and the female reproductive tract. In: BrutonLL, Hilal-DandanR, KnollmannBC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2018:803–832.)| false
SulakPJ, SmithV, CoffeeA, et al.Frequency and management of breakthrough bleeding with continuous use of the transvaginal contraceptive ring: A randomized controlled trial. Obstet Gynecol. 2008;112(3):563–571.
SulakPJ, SmithV, CoffeeA, et al.Frequency and management of breakthrough bleeding with continuous use of the transvaginal contraceptive ring: A randomized controlled trial. Obstet Gynecol. 2008;112(3):563–571.)| false
MansourV, MurdicoAT, FundinJ. Oral contraceptives are susceptible to several interactions. Pharmacy Times.https://www.pharmacytimes.com/publications/issue/2019/may2019/oral-contraceptives-are-susceptible-to-several-interactions. Updated May 22, 2019. Accessed December 12, 2019.
What contraceptive agents would the pharmacist recommend for a patient who frequently forgets to take her daily oral contraceptive?
Sandy Nichols is a 55-year-old postmenopausal female who had a hysterectomy at the age of 32. She presents to your pharmacy counter to pick up her prescription for oral Estrace. However, she tells you her friends who are also taking postmenopausal hormone therapy are also taking progesterone. She wonders if she should also be taking progesterone. What information should the pharmacist tell her?
What are the primary reproductive hormones in the male and female body and what are their main functions?
What is hypogonadism and what classes of medications are available to treat male and/or female hypogonadism?
What are common symptoms of benign prostatic hyperplasia? Explain two types of medications to treat this condition.