COVER STORY

FOR WOMEN ONLY

From menses to menopause, the many hormonal changes in a woman's life are spurring new treatments

Probably very few men would disagree that females are complex. It's all part of a woman's charm, right? In actuality, many clinicians might agree that the female body also presents them with many challenges.

Throughout a woman's life, she may experience complications or medical problems unique to females because of the many varied hormonal changes that occur over the decades. From the teenage years, when menses begins, throughout her reproductive life, a woman requires medical attention that is vastly different from that required by age-matched males. That medical attention relates to premenstrual syndrome (PMS), unique contraceptive needs, challenges associated with pregnancy, and significant changes that occur physically and emotionally during and after menopause.

Just a few decades ago, if a woman brought these issues up to her health-care provider, it was all too common for the clinician to dismiss the topic as "being all in her head." Fortunately for women, things are changing. The hormonal fluctuations that occur at all stages of a woman's life are now being more fully studied and understood. This has resulted not only in new diagnoses but also in new therapeutic options for women.

Choices for contraception

More often than not, it is up to the woman to take a proactive approach toward contraception. It is no surprise then that whatever method of contraception suits the lifestyle of the woman best becomes her method of choice. According to the Centers for Disease Control & Prevention, among U.S. women ages 15 to 44, oral contraceptive pills (OCs) are the method of choice for reversible contraception. Of U.S. women using contraception, 17% reportedly rely upon OCs, which are second only to female sterilization (considered irreversible), at 18%.

With more than 45 to choose from, OCs can be categorized broadly in terms of their components. On a large scale, only two different types of OCs exist: estrogen/progestin combinations or progestin-only pills. The function of the estrogenic component found in many OCs is believed to involve suppression of follicle-stimulating hormone secretion and prevention of the formation of a dominant follicle. Additionally, estrogens are assumed to potentiate the activities of progestins.

On the other hand, progestins also have dual effects. They suppress the luteinizing-hormone surge, preventing ovulation, and also thicken cervical mucus, which is suspected to decrease sperm motility. In addition to OCs, long-acting progesterone implants (levonorgestrel, Norplant, Wyeth-Ayerst) and progesterone depot injections (medroxyprogesterone, Depo-Provera, Pharmacia Corp.) are also reportedly utilized by 1% and 2% of U.S. women requiring contraception, respectively. (See Table 1 to differentiate between estrogen- and progestin-related side effects.)

Table 1
Considerations for selecting oral contraceptives based upon side effects

Recently, a new long-acting injection for contraceptive purposes made its debut. Marketed by Pharmacia, Lunelle provides another option for women. Carl Swanson, Pharm.D., in the medical and drug information division of Pharmacia, described it as "a combination of estrogen [estradiol cypionate] and progestin [medroxyprogesterone acetate]. It may be most beneficial for patients who can't remember to take their oral contraceptives daily and who want a monthly bleed." Perhaps one of the greatest disadvantages of Depo-Provera is irregular and unpredictable bleeding. "With the addition of estrogen, irregular bleeding should, in theory, be less frequent" with Lunelle than Depo-Provera, which contains only progesterone, Swanson said. Unlike Depo-Provera, which is administered every three months, Lunelle must be given monthly by a health-care provider as an intramuscular injection, which may present a drawback for some women since office visits will need to be scheduled every 30 days. Due to its dual estrogen and progestin component, Lunelle will not be an option for women with contraindications to combination OCs.

It seems surprising that with so many choices in OCs, some women still don't use any. How does a clinician select an appropriate agent? A complete understanding of each woman's prior medical conditions is essential. For OCs, both absolute contraindications and relative contraindications exist. For example, any history that is positive for cerebrovascular disease, coronary occlusion, or thromboembolic disorders is an absolute contraindication for use of combination OCs. Other absolute contraindications include known or suspected pregnancy, smoking in those over the age of 35 years, abnormal vaginal bleeding, known or suspected breast cancer, or markedly impaired liver function.

For other women, certain medical disorders or concurrent administration of drugs that alter the effectiveness of OCs may serve as relative contraindications. A partial list of relative contraindications to OCs includes: a history positive for migraine headaches, hypertension, uterine leiomyoma, gestational diabetes or diabetes mellitus, sickle cell disease, gallbladder disease, and obstructive jaundice. Also, certain medications may render OCs less effective.

The American College of Obstetrics & Gynecologists (ACOG) recently provided recommendations with regard to OCs. These new guidelines (summarized in Table 2) provide suggestions to clinicians treating women with coexisting medical conditions and describe situations in which women may still be considered candidates for combination OCs versus the women for whom progestin-only therapy may be indicated.

Table 2
Special considerations in use of combination oral contraceptives

Regarding the new guidelines from ACOG, Elena Umland, Pharm.D., assistant professor in the department of pharmacy practice at the Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, stressed the importance of knowing each woman's personal history when selecting an OC.

Although most OC users take the medication to prevent pregnancy, these agents may also be used as a method of "emergency contraception" or a backup method after unprotected sexual intercourse. Two products are on the market with approval for this indication. Preven (ethinyl estradiol/ levonorgestrel, Gynetics) contains four pills containing both estrogen and progestin. Two pills are supposed to be taken within 72 hours of unprotected sexual intercourse, followed 12 hours later by the remaining two pills. In contrast, the other product, Plan B (levonorgestrel, Women's Capital Corp.) is made up of two pills containing only a progestin, with the first dose to be taken within 72 hours of unprotected intercourse and the second dose, again, taken 12 hours later.

"While both 'morning-after' methods appear to be efficacious, the levonorgestrel [Plan B] method is associated with fewer side effects," said Umland. A recent study published in The Lancet confirmed that not only was the progestin-only emergency contraceptive associated with less than half the incidence of nausea and vomiting as the estrogen/progestin regimen, it was also more effective in preventing unwanted pregnancies. Sharon Camp, Ph.D., president of Women's Capital Corp., compared Plan B with Preven. "With Plan B, the incidence of nausea is cut in half, from over 50% with Preven to 23% with Plan B. And the incidence of vomiting is reduced by 70%, from 19% to 5.6%."

Of OCs used for emergency contraceptive purposes, Umland said, "These regimens appear to be safe for use in all women. Studies have not shown an increased risk of thromboembolic disorders. No changes in clotting factors have been observed; nor do these regimens disrupt a pregnancy that may have already occurred earlier in the cycle."

"There are no contraindications for emergency contraceptives except for pregnancy, and that is because they are not effective if a patient is already pregnant," said Melissa Sanders, Pharm.D., assistant professor, department of pharmacy practice, Temple University School of Pharmacy.

Since many risks associated with contraceptive use are caused by long-term use rather than intermittent use, as emergency contraceptives are utilized, there has been talk recently of switching emergency contraceptives to over-the-counter status. Neither of the companies that manufacture emergency contraceptive products has, to date, filed the necessary documents with the Food & Drug Administration required for an OTC switch. However, when asked about emergency contraceptives going OTC, Camp said, "Yes, I believe it will happen, and we are pursuing it." Among the experts, opinions seem to vary widely with regard to the risks versus benefits that OTC status might bring for emergency contraceptives. For example, some argue that increased availability of "morning-after pills" might lead women to engage in more high-risk activities, using less effective means of protecting against sexually transmitted diseases.

With regard to these concerns about emergency contraceptives going OTC, Camp said, "We need to weigh the risks and the benefits. If women have emergency contraception in their nightstands in advance, they are two to three times more likely to use it and the incidence of unintended pregnancy goes down versus the hypothetical chance that they may possibly take more risks. We are in the process of sponsoring studies that look at these issues. It is important to reassure the public that we are doing no harm."

On the other hand, keeping emergency contraceptives as prescription-only products may have some benefits, according to pharmacists. Umland said, "In states like Washington, where pharmacists have authority to dispense under protocol, pharmacists provide emergency contraceptives now, along with contraceptive counseling for later." Sanders also echoed Umland's view by saying, "I would like to see more states adopt collaborative practice clauses.... Pharmacists could educate women about contraceptive options and counsel on the importance of yearly gynecological visits. They could provide a service and help get patients into a health-care loop." In this way, it is hoped that women would have the protection that is needed in the short-term to prevent pregnancy, but would also turn to more effective means of protection in the future, so as not to rely on emergency contraceptives. From the perspective of providing women with information to make informed decisions in the future, it seems that having a pharmacist's intervention may be beneficial.

From prevention to termination

Regarding pregnancy termination rather than pregnancy prevention, RU-486 was recently approved by the FDA. Although the drug will be dispensed only by physicians, there are many questions that pharmacists need to be primed to answer when women inquire.

RU-486, or mifepristone, will be marketed as Mifeprex by Danco Laboratories and is indicated for the termination of pregnancy through the first seven weeks. A total of three doctor visits will be required for treatment with mifepristone. At the initial visit, a woman will be given 600 mg of mifepristone. After 48 hours, she will return to the office and receive 400 mcg misoprostol (Cytotec, Searle), the prostaglandin analog, unless a complete abortion can be confirmed before that. Approximately two weeks later, a third visit is required to confirm termination of the pregnancy.

Mifepristone's actions involve antagonism of progesterone receptors, which interfere with the development of the placenta leading to deterioration of the uterine lining, and ultimately resulting in termination of pregnancy. Misoprostol, which is known to induce uterine contractions, is utilized in a follow-up manner to expel the embryo from the uterus. Although the dual-drug combination is reportedly 92%-95% effective in terminating pregnancy, a surgical procedure is required in women for whom the pharmacological agents do not result in complete termination.

Side effects with the regimen include bleeding, uterine cramping, abdominal pain, nausea, vomiting, and diarrhea. Vaginal bleeding reportedly lasts for an average of nine to 16 days, and as many as 1% of women experience heavy or life-threatening bleeding that requires surgical intervention. Interestingly, since the approval of mifepristone, Searle has been sending out "Dear Doctor" letters in full force. The letter reads as follows, "The purpose of this letter is to remind you that Cytotec administration by any route is contraindicated in women who are pregnant because it can cause abortion. Cytotec is not approved for the induction of labor or abortion."

Janice Chapman in Searle's information services said, "We have not conducted any studies of Cytotec for either terminating pregnancy or for cervical ripening, nor do we intend to do so. As a result, we cannot support the use of the product for indications other than its intended use." Women who are not considered candidates for the dual-drug regimen include those with hemorrhagic disorders or concurrent anticoagulant therapy, those with ectopic pregnancies, women with IUDs already in place, women on long-term corticosteroid therapy, and women who have chronic adrenal failure.

Is it all in her head?

Just as there have been new therapies for birth prevention and termination, new data are emerging on sexual dysfunction in females. The new data not only cover diagnosis, but they also assist clinicians in developing treatment plans based upon women's complaints of low desire and pain during intercourse. In the past, women may have been told, "It is all in your head," but there are indications that medical reasons may underlie sexual function complaints. Sexual dysfunction appears to be age-related and highly prevalent, affecting as many as 30%-50% of women. Sexual dysfunction may encompass complaints of diminished vaginal lubrication, pain during intercourse, decreased arousal, or difficulty achieving orgasm.

"Sexual dysfunction may result from many things, including lubrication changes and sensation changes," said Jennifer Berman, M.D., codirector of the Center for Women's Urology & Sexual Medicine at the UCLA Medical Center.

Although sildenafil (Viagra, Pfizer) has been a magic bullet in revolutionizing sexual dysfunction in males, studies in females appear contradictory at this point. But, said Berman, "Multicenter studies in the United States are continuing." She also noted that, in addition to sildenafil, "other products, including testosterone, blood flow-enhancing agents—both oral and topical combinations—are being investigated." Blood flow-enhancing therapies that seem to be useful include L-arginine, an amino acid that relaxes vascular and nonvascular smooth muscle, and phentolamine, an agent that causes vascular smooth muscle relaxation and enhances genital blood flow. Both agents have been studied initially in males, with some improvements demonstrated, and may become options for females as well.

Some products that may be effective treatments for sexual dysfunction in women revolve around the male hormone, testosterone. Two testosterone patches (Procter & Gamble) and testosterone gels (Cellegy) are in clinical trials. "We believe we are developing a user-friendly, effective product," said Rich Juelis, CFO at Cellegy. Under the trade name Tostrelle, the product Cellegy envisions marketing will come in a "metered-dose dispenser." When activated, a plunger will cause a certain dose to be dispensed for application onto the skin. "We completed a phase I/II study and have moved on to an expanded phase I/II trial where we are evaluating safety and pharmacokinetics," said Juelis. "We are doing dose-ranging studies to optimize the correct dose and looking at different areas of the body to determine the best site to apply the gel."

What is PMDD?

Another condition exclusive to women is premenstrual dysphoric disorder. PMDD is a term that denotes severe premenstrual symptoms. Unlike the symptoms of cramping and bloating that are commonly thought of as "PMS," PMDD is actually characterized as a psychiatric disorder, with criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV). In order to diagnose PMDD, timing is very important; that is, symptoms must occur during the week preceding menses and remit several days after the onset of menses. Symptoms may include five of the following: markedly depressed mood, anxiety or tension, affective lability, anger or increased irritability resulting in increased interpersonal conflicts, decreased interest in usual activities, difficulty concentrating, lethargy or easy fatigability, changes in appetite, sleep disturbances (hypersomnia or insomnia), and a feeling of being overwhelmed, plus physical symptoms such as breast tenderness, headaches, joint/muscle pain, bloating, or weight gain.

Temple University's Sanders stated, "It is important to understand the difference between PMS, which involves mostly physical symptoms, and PMDD, which involves more psychological symptoms." As many as 5% of American women are believed to suffer from PMDD.

The current treatment of choice for PMDD is a selective serotonin reuptake inhibitor (SSRI). Unlike when utilized for the treatment of depression, SSRIs do not take four to six weeks for maximal effectiveness when treating PMDD; in fact, they may be effective right away. Only fluoxetine (Lilly) has received an FDA-approved indication for the treatment of PMDD, although other SSRIs may also be effective options. Although Lilly's approval was for 20 mg fluoxetine administered on a continuous basis, after receiving the expanded indication, Lilly began marketing fluoxetine in seven-day blister packs under the trade name Sarafem. This is due to studies, such as those published in Psychopharmacology Bulletin, which found that intermittent dosing may also provide an effective means of treatment. For women without a history of depression or other psychological disorders, intermittent dosing during the luteal cycle—that is, during the two weeks prior to the onset of menses—may be just as effective as continuous dosing.

Is tide turning on HRT?

As women age, menopause supplants menstruation. Estrogen-replacement for postmenopausal women, once praised for bone-enhancing, heart-protecting effects, has come under new scrutiny. Only a few years ago, it seemed as if the benefits outweighed the risks, and women were often put on hormone replacement therapy (HRT) at menopause and kept on it, essentially for life. It seems that studies in both the Journal of the American Medical Association (JAMA) and the New England Journal of Medicine are questioning whether the benefits are worth the risks. Risks previously associated with estrogen replacement therapy centered on increased risks of breast cancer, particularly with long-term therapy, and endometrial cancer in women with an intact uterus who were not using a concomitant progestin. Data emerging from both the Heart & Estrogen Replacement Study (HERS) and the Estrogen Replacement & Atherosclerosis trial now call into question the cardioprotective effects of estrogen.

"Everything is changing," said Umland. "HERS found that in women with a primary cardiovascular event, there was an increased risk for a second myocardial event after HRT was initiated." Due to the unexpected findings, the study was halted early. In the atherosclerosis study, HRT did not halt or slow the progression of atherosclerosis in women with coronary disease, despite providing significant improvements in lipid levels. In both of these studies, women enrolled in the clinical trials had been diagnosed with cardiovascular or coronary artery disease prior to initiating HRT.

Another HRT trial is expected to continue until 2005. The Women's Health Initiative Randomized Trial does not require participants to have a history of cardiovascular disease. Therefore, this study may provide information on using HRT in otherwise healthy women. Sanders cited the JAMA study with regard to HRT suddenly being called into question: "The HERS study showed that hormone replacement therapy provided no benefit in women for secondary cardiovascular prevention. We do, however, have a large body of epidemiological evidence supporting the role of estrogen as offering primary cardiovascular protection in women without coronary heart disease. From these studies, HRT is believed to decease the risk of cardiovascular disease by 35%. One-third of the benefit is believed to be related to decreases in lipid levels."

Perhaps the trial expected to be completed in 2005 will shed more light on the effects of estrogen for primary cardiovascular prevention. Meanwhile, Umland said of women desiring HRT primarily for cardiovascular protection, "in postmenopausal women, statins are still the drugs of choice for lipid-lowering effects."

With regard to HRT and osteoporosis, the latest guidelines stress that HRT has beneficial effects on preventing loss of bone mineral density but should not be utilized as a treatment for already-existing osteoporosis. Umland feels that for women considering HRT because of concerns over osteoporosis, "we now have much better options." She cited bisphosphonates as possible alternatives. Again, Sanders concurred: "Much of the osteoporosis data we have with estrogen are epidemiological. We now have large trials using bisphosphonates that show that these agents are unequivocally effective. We know bisphosphonates prevent the risk of fractures."

Sanders mentioned that for treatment of menopausal symptoms, HRT is still the gold standard. However, he said, as a result of newer studies, it is important to evaluate a woman's risk of osteoporosis and cardiovascular disease. For treating these other conditions, there are alternatives to estrogen.

According to Leigh Ann Ramsey, Pharm.D., assistant professor in the department of clinical pharmacy practice at the University of Mississippi, natural products including soy-based products are currently being investigated for treatment of menopausal symptoms. "There is a huge movement looking into phytoestrogens. Soy provides a source of phytoestrogens and may be obtained through either diet or supplementation. There are data that show the benefits of soy on treating vasomotor symptoms associated with menopause and also promising data on its effects in osteoporosis and cardiovascular disease," she said. With the older guidelines for treating menopause currently being revisited, it may not be so far-fetched for a natural product such as soy to one day become a standard treatment for women suffering from menopause and its related symptoms.

Kelly Dowhower Karpa, R.Ph., Ph.D.

Based in the Philadelphia area, the author writes frequently on clinical subjects.

Kelly Karpa. FOR WOMEN ONLY.

Drug Topics

2001;2:51.