Women’s Health Drugs



Women’s Health Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



Drug Profiles



Key Terms


Chloasma Hyperpigmentation from the melanin in the skin, characterized by brownish macules on the cheeks, forehead, lips, and/or neck; a common dermatologic adverse effect of female hormonal medications (also called melasma). (p. 547)


Corpus luteum The structure that forms on the surface of the ovary after every ovulation and acts as a short-lived endocrine organ that secretes progesterone. (p. 545)


Endocrine glands Glands that secrete one or more hormones directly into the blood. (p. 544)


Estrogens The term for a major class of female sex steroid hormones; of the estrogens, estradiol is responsible for most estrogenic physiologic activity. (p. 544)


Fallopian tubes The passages through which ova are carried from the ovary to the uterus. (p. 544)


Gonadotropin The hormone that stimulates the testes and ovaries. (p. 544)


Hormone replacement therapy (HRT) The term used to describe any replacement of natural body hormones with hormonal drug dosage forms. Most commonly, HRT refers to estrogen replacement therapy for treating symptoms associated with menopause-related estrogen deficiency. It is also referred to as simply hormone therapy. (p. 547)


Implantation The attachment to, penetration of, and embedding of the fertilized ovum in the lining of the uterine wall; it is one of the first stages of pregnancy. (p. 545)


Menarche The first menses in a young woman’s life and the beginning of cyclic menstrual function. (p. 545)


Menopause The cessation of menses for 12 consecutive months that marks the end of a woman’s childbearing capability. (p. 545)


Menses The normal flow of blood that occurs during menstruation. (p. 544)


Menstrual cycle The recurring cycle of changes in the endometrium in which the decidual layer is shed, regrows, proliferates, is maintained for several days, and is shed again at menstruation unless a pregnancy begins. Also referred to as the uterine cycle. (p. 544)


Nucleic acids The term used for specific molecules in the cell that are composed of strings of repeating units that serve to encode information. The two most common ones are DNA and RNA whose functions have to do with the storage and expression of genetic information. (p. 546)


Osteoporosis A condition characterized by the progressive loss of bone density and thinning of bone tissue; it is associated with increased risk of fractures. (p. 551)


Ova Female reproductive or germ cells (singular: ovum; also called eggs). (p. 544)


Ovarian follicles The location of egg production and ovulation in the ovary; the follicle is the precursor to the corpus luteum. (p. 544)


Ovaries The pair of female gonads located on each side of the lower abdomen beside the uterus. They store the ova (eggs) and release ova during the ovulation phase of the menstrual cycle. (p. 544)


Ovulation The rupture of the ovarian follicle, which results in the release of an unfertilized ovum into the peritoneal cavity, from which it normally enters the fallopian tube. (p. 544)


Progesterone A sex hormone that is produced by the corpus luteum and serves to prepare the uterus for possible implantation. (p. 544)


Progestins Synthetic or natural substances that have properties similar to progesterone, but are not considered to be the naturally occurring progesterone that is present in the human female body. (p. 549)


Puberty The period of life when the ability to reproduce begins. (p. 544)


Uterus The hollow, pear-shaped female organ in which the fertilized ovum is implanted (see implantation) and the fetus develops. (p. 544)


Vagina The part of the female genitalia that forms a canal from its external orifice through its vestibule to the uterine cervix. (p. 544)


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http://evolve.elsevier.com/Lilley



Anatomy, Physiology, and Pathophysiology Overview


Female Reproductive Functions


The female reproductive system consists of the ovaries, fallopian tubes, uterus, vagina, and the external structure known as the vulva. The development of these primary sex structures, initiation of their subsequent reproductive functions (starting at puberty), and their maintenance are controlled by pituitary gonadotropin hormones and the female sex steroid hormones—estrogens and progesterone. Pituitary gonadotropins include follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Both play a primary role in hormonal communication between the pituitary gland (see Chapter 30) and the ovaries in the continuous regulation of the menstrual cycle from month to month.


Estrogens are also responsible for stimulating the development of secondary female sex characteristics, including the characteristic breast, skin, and bone development and distribution of body fat and hair. Progesterone helps create optimal conditions for pregnancy in the endometrium just after ovulation and also promotes the start of menses in the absence of a fertilized ovum.


The ovaries (female gonads) are paired glands located on each side of the uterus. They function both as endocrine glands and as reproductive glands. As reproductive glands, they produce mature ova within ovarian follicles, which are then ovulated or released into the space in the peritoneal cavity between the ovary and the fallopian tube. Fingerlike projections known as fimbriae lie adjacent to each ovary and catch the released ovum and guide it into the fallopian tube. Once inside the fallopian tube, the ovum is moved through its lumen to the uterus. This movement is accomplished through the muscular contractions of the tube walls and the actions of ciliated cells inside the lumen of the tube, which “beat” in the direction of the uterus. Fertilization of the ovum, when it occurs, takes place in the fallopian tube.


As endocrine glands, the ovaries are responsible for producing the two sex steroid hormones, estrogen and progesterone. Chemically speaking, the estrogens and progestational hormones include several distinct substances. However, only two of these hormones occur in significant amounts, and have the greatest physiologic activity. These are the estrogen estradiol and the progestational hormone progesterone. Estradiol is the principal secretory product of the ovary and has several estrogenic effects. One of these effects is the regulation of gonadotropin (FSH and LH) secretion via negative feedback to the pituitary gland. Others include promotion of the development of women’s secondary sex characteristics, monthly endometrial growth, thickening of the vaginal mucosa, thinning of the cervical mucus, and growth of the ductal system of the breasts. Progesterone is the principle secretory product of the corpus luteum and has progestational effects. These include promotion of tissue growth and secretory activity in the endometrium following the estrogen-driven proliferative phase of the menstrual cycle. This important secretory process is required for endometrial egg implantation and maintenance of pregnancy. Other progestational effects include induction of menstruation when fertilization has not occurred and, during pregnancy, inhibition of uterine contractions, increase in the viscosity of cervical mucus (which protects the fetus from external contamination), and growth of the alveolar glands of the breasts.


The uterus consists of three layers: the outer protective perimetrium, the muscular myometrium, and the inner mucosal layer known as the endometrium. The myometrium provides the powerful smooth muscle contractions needed for childbirth. The endometrium is the site of the following:



The vagina serves as a common passageway for birthing and menstrual flow. In addition, it is a receptacle for the penis during sexual intercourse and for the sperm after male ejaculation.


The menstrual cycle usually takes roughly 1 month to complete. Menstrual cycles begin during puberty with the first menses (menarche) and cease at menopause, which in most women occurs between 45 and 55 years of age. The hormonally controlled menstrual cycle consists of four distinct but interrelated phases that occur in overlapping sequence. Phase names correspond to activity in either the ovarian follicle or the endometrium (Table 34-1).



• Phase 1: the menstruation phase (uterine cycle), which initiates the cycle and lasts from 5 to 7 days.


• Phase 2: the follicular phase (ovarian cycle), during which a mature ovum develops from an ovarian follicle. This phase is also called the proliferative or preovulatory phase and is characterized by rising estrogen secretion from the ovary and LH secretion from the pituitary gland. It terminates on or about day 14 of the cycle.


• Phase 3: the ovulation phase, which involves release of the unfertilized ovum from the ovary. This process occurs over a roughly 24- to 48-hour period starting at about day 14. Both estrogen and LH levels peak near this time.


• Phase 4: the final phase of the cycle, called the luteal or postovulatory phase. It is also known as the secretory phase. It occurs when the corpus luteum forms from the ruptured ovarian follicle. The corpus luteum is a mass of secretory cells on the surface of the ovary. Its primary function is to produce progesterone, which helps to optimize the endometrial mucosa for implantation of a fertilized ovum. The corpus luteum also serves as an initial source of the progesterone needed during early pregnancy. This function is later assumed by the developing placenta. If fertilization does not occur, the corpus luteum then degenerates causing a fall in progesterone levels. The menstrual cycle begins again on or about day 28.



Figure 34-1 illustrates the sequence of hormone secretions and related events that take place during the menstrual cycle.



Pharmacology Overview


Female Sex Hormones


Estrogens


There are three major endogenous estrogens: estradiol, estrone, and estriol. All are synthesized from cholesterol in the ovarian follicles and have the basic chemical structure of a steroid, known as the steroid nucleus. For this reason, they are sometimes referred to as steroid hormones. Estradiol is the principal and most active of the three and represents the end product of estrogen synthesis.


Exogenous estrogenic drugs, those used as drug therapy, were developed because most of the endogenous estrogens are inactive when taken orally. These synthetic drugs fall into two categories: steroidal and nonsteroidal. Nonsteroidal estrogen products are no longer available in the United States because major adverse effects occurred when one of them, diethylstilbestrol (DES), was used in obstetrics. Box 34-1 describes this important episode in medical history. The estrogenic drugs currently in use are as follows:




The most widely used estrogen product is an estrogen mixture known as conjugated estrogens. This mixture contains a combination of natural estrogen compounds equivalent to the average estrogen composition of the urine of pregnant mares, hence its brand name of Premarin. A nonanimal source for this conjugated estrogen mixture is also available. Cenestin is composed of various conjugated estrogens obtained from soy and yam plants. This product was developed in response to consumer demand from women who wanted an alternative to an animal-derived product (see the Safety: Herbal Therapies and Dietary Supplements box on p. 547). Some women obtain other natural estrogen products from naturopathic prescribers and prefer these to standard prescription drugs such as Premarin.


Patients report varying degrees of satisfaction with the numerous products available, and it can take both time and patience to find the best choice for a given individual. Ethinyl estradiol is one of the more potent estrogens and is most commonly found in oral contraceptive drugs. Another commonly used form of estrogen is the patch formulation. Several patches exist, all of which are dosed differently, thus patient education is necessary to ensure proper use. The most commonly used patch is Climara (estradiol).


Mechanism of Action and Drug Effects

The binding of estrogen to intracellular estrogen receptors stimulates the synthesis of nucleic acids (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]) and proteins, which




are the building blocks for all living tissue. Estrogens are also required at puberty for the development and maintenance of the female reproductive system and the development of female secondary sex characteristics, a process known as feminization.


Estrogens produce their effects in estrogen-responsive tissues, which have a large number of estrogen receptors. These tissues include the female genital organs, the breasts, the pituitary gland, and the hypothalamus. At the time of puberty, the production of estrogen increases greatly. This causes initiation of the menses, breast development, redistribution of body fat, softening of the skin, and other feminizing changes. Estrogens play a role in the shaping of body contours and development of the skeleton. For instance, long bones are usually inhibited from growing, with the result that females are usually shorter than males.


Indications

Estrogens are used in the treatment or prevention of a variety of disorders that result primarily from estrogen deficiency. These conditions are listed in Box 34-2. Hormone replacement therapy (HRT) to counter such estrogen deficiency is most commonly known for its benefits in treating menopausal symptoms (e.g., hot flashes).



Contraindications

Contraindications for estrogen administration include known drug allergy, any estrogen-dependent cancer, undiagnosed abnormal vaginal bleeding, pregnancy, and active thromboembolic disorder (e.g., stroke, thrombophlebitis) or a history of such a disorder.


Adverse Effects

The most serious adverse effects of the estrogens are thromboembolic events. The most common undesirable effect of estrogen use is nausea. Photosensitivity also may occur with estrogen therapy. One common dermatologic effect of note is chloasma. Chloasma consists of brownish, macular spots that often occur on the forehead, cheeks, lips, and neck. This and other adverse effects are listed in Table 34-2.



Interactions

Estrogens can decrease the activity of the oral anticoagulants, and the concurrent administration of rifampin and St. John’s wort can decrease their estrogenic effect. Their use with tricyclic antidepressants may promote toxicity of the antidepressant. Smoking should be avoided during estrogen therapy, because this, too, can diminish the estrogenic effect and add to the risk for thrombosis.


Dosages

For dosage information on some of the many available estrogen products, see the table on p. 548.


Drug Profile


♦ estrogen


Estrogen is indicated for the treatment of many clinical conditions, primarily those resulting from estrogen deficiency (see Box 34-2). Many of these conditions occur around menopause, when the endogenous estradiol level is declining. Any estrogen capable of binding to the estrogen receptors in target organs can alleviate menopausal symptoms. As a general rule, the smallest dosage of estrogen that relieves the symptoms or prevents the condition is used. Although many women receive estrogen or estrogen-progestin therapy for many months or years, some clinicians (and patients) may prefer that the patient be weaned from such therapy in light of the known adverse effects.


Two studies that were performed as part of the Women’s Health Initiative (WHI), a large research program sponsored by the National Institutes of Health, demonstrated the possible detrimental effects of estrogen and estrogen-progestin therapy.




Both studies attempted to determine the value of HRT, if any, in preventing diseases and conditions commonly affecting older women, including breast cancer, heart disease, stroke, and hip fracture. The WHI was launched in 1991 under the direction of the National Heart, Lung, and Blood Institute (NHLBI). In one of the WHI studies of HRT, research subjects who took a certain estrogen-progestin combination product were found to have an increased risk of breast cancer, heart disease, stroke, and blood clots, although their risk of hip fractures and colon cancer was reduced. These preliminary results were so alarming that this study of combined estrogen-progestin therapy was discontinued in 2002.


A part of the WHI investigation focusing on cognitive function, the WHI Memory Study, also identified adverse cognitive effects in women receiving combination estrogen-progestin therapy. These patients showed an increased risk of developing dementia and demonstrated reduced performance on tests of cognitive function. A second HRT study was begun in which women who had undergone hysterectomy received estrogen alone without progestin. In March 2004, however, these participants were advised to stop taking their assigned medication, because the estrogen-only therapy appeared to be associated with an increased risk of stroke. The data also indicated that estrogen therapy had no effect on the rates of coronary heart disease or breast cancer but was associated with a reduced rate of hip fracture.


Since publication of the WHI studies, much confusion and controversy has arisen. One of the biggest challenges to the WHI study is that the majority of the women studied were at least 10 years postmenopause. Recent data have suggested that the use of estrogen in women who are younger is beneficial. Follow-up of the WHI study subjects began in 2010. The North American Menopause Society (NAMS) also updated its position statement in 2010 regarding estrogen use in perimenopausal and postmenopausal women. The updated recommendations support the initiation of HT (hormonal therapy) around the time of menopause to treat menopause-related symptoms and to treat or reduce the risk of certain disorders, such as osteoporosis or fractures. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause. Hormone replacement is not recommended for women with histories of endometrial cancer. In women with breast cancer, estrogen therapy has not been proven safe and might raise recurrence risk. When hormone therapy is discontinued after several years of use, assess bone-mineral density and begin treatment if indicated. Because this is a topic about which views are so rapidly changing, the reader is referred to the website of the North American Menopause Society at www.menopause.org for the latest position statements.


The pharmacologic effects of all estrogens are similar because there are only slight differences in their chemical structures. These differences yield drugs of different potencies, which in turn make them useful for a variety of indications. They also allow the drugs to be given by different routes of administration and at often highly customized dosages.


Many fixed estrogen-progestin combination products have been developed over the years. Their use is commonly referred to as continuous combined hormone replacement therapy. The use of estrogen therapy alone has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial cancer. The addition of continuously administered progestin to an estrogen regimen reduces the incidence of endometrial hyperplasia associated with unopposed estrogen therapy. Examples of these fixed combinations are conjugated estrogens with medroxyprogesterone, norethindrone acetate with ethinyl estradiol, and estradiol with norethindrone.


Progestins


Available progestational medications, or progestins, include both natural and synthetic drugs. Progesterone is the most active natural progestational hormone and is the primary progestin component in most drug formulations. It is produced by the corpus luteum after each ovulation and during pregnancy by the placenta. In addition, there are two other major natural progestational hormones. The first is 17-hydroxyprogesterone, an inactive metabolite of progesterone. The second is pregnenolone, a chemical precursor to all steroid hormones that is synthesized from cholesterol in the ovary. Because orally administered progesterone is relatively inactive and parenterally administered progesterone causes local reactions and pain, chemical derivatives were developed that are effective orally and are also more potent. Their actions are also more specific and of longer duration. The following are some of the most commonly used progestins:



Mechanism of Action and Drug Effects


All of the progestin products produce the same physiologic responses as those produced by progesterone itself. These responses include induction of secretory changes in the endometrium, including diminished endometrial tissue proliferation; an increase in the basal body temperature; thickening of the vaginal mucosa; relaxation of uterine smooth muscle; stimulation of mammary alveolar tissue growth; feedback inhibition (negative feedback) of the release of pituitary gonadotropins (FSH and LH); and alterations in menstrual blood flow, especially in the presence of estrogen.


Indications


Progestins are useful in the treatment of functional uterine bleeding caused by a hormonal imbalance, fibroids, or uterine cancer; in the treatment of primary and secondary amenorrhea; in the adjunctive and palliative treatment of some cancers and endometriosis; and, alone or in combination with estrogens, in the prevention of conception. They may also be helpful in preventing a threatened miscarriage and alleviating the symptoms of premenstrual syndrome. Medroxyprogesterone is the one most commonly used. Norethindrone and norgestrel are commonly used alone or in combination with estrogens as contraceptives. Megestrol is commonly used as adjunct therapy in the treatment of breast and endometrial cancers. When estrogen replacement therapy is initiated after menopause, progestins are often included to decrease the endometrial proliferation that can be caused by unopposed estrogen in women with an intact uterus. Formulations of progesterone itself are also used to treat female infertility (see Dosages table on p. 550).


Contraindications


Contraindications for progestin are similar to those for estrogens.


Adverse Effects


The most serious undesirable effects of progestin use include liver dysfunction, commonly manifested as jaundice, thrombophlebitis, and thromboembolic disorders such as pulmonary embolism. The more common adverse effects are listed in Table 34-3.



Interactions


There are reports of possible decreases in glucose tolerance when progestins are taken with antidiabetic drugs, and the dosage of the antidiabetic drug may need to be adjusted. The concurrent use of medroxyprogesterone or norethindrone and aminoglutethimide or rifampin induces increased metabolism of the progestin.


Dosages


For recommended dosages of selected progestins, see the Dosages table on p. 550.


Drug Profiles


♦ medroxyprogesterone


Medroxyprogesterone (Provera, Depo-Provera) inhibits the secretion of pituitary gonadotropins, which prevents follicular maturation and ovulation, stimulates the growth of mammary tissue, and has an antineoplastic action against endometrial cancer. Medroxyprogesterone is used to treat uterine bleeding, secondary amenorrhea, endometrial cancer, and renal cancer and is also used as a contraceptive. Its most common use is to prevent endometrial cancer caused by estrogen replacement therapy. It is also sometimes used as adjunct therapy in certain types of cancer (see Chapter 46). Medroxyprogesterone is available in both oral and parenteral preparations. It is also available in a long-acting injection formulation called Depo-Provera.



megestrol


Megestrol (Megace) is a synthetic progestin that is structurally very similar to progesterone. Although megestrol shares the actions of the progestins, it is primarily used in the palliative management of recurrent, inoperable, or metastatic endometrial or breast cancer. Because it can cause appetite stimulation and weight gain, it is also used in the management of anorexia, cachexia, or unexplained substantial weight loss in patients with acquired immunodeficiency syndrome (AIDS) and in patients with cancer. It is available only for oral use.


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May 9, 2017 | Posted by in NURSING | Comments Off on Women’s Health Drugs

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