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New Progestins in Women’s Health

Progestins: An Evolution

Paralleling the development of orally active estradiol was a similar process aimed at making progesterone orally active. For both hormones, micronization enabled the goal. Since then, progestins have been developed that are safer, have greater potency, and offer antimineralcorticoid effects such as prevention of weight gain due to water retention, and antiandrogenic effects such as relieving the severity of acne and other skin disorders. Speaker Ian H. Thorneycroft, PhD, MD, Professor of Obstetrics and Gynecology at the University of South Alabama and Program Chair, reviewed the history of progestins, which fall into two main groups — those derived from progesterone and those derived from ethisterone (a testosterone derivative) (Table 1).

Most progestins found in oral contraceptives today, and in HRT formulations, are third generation agents. But efforts continue to develop a better progestin, and the progestin, drospirenone, is a recent product of this search. It is based on the testosterone molecule forming the backbone of the norethindrone-type progestins, Dr. Thorneycroft explained. The result of modifications to this molecule is drospirenone, which is related to spironolactone. Drospirenone, a spironolactone analogue, has a unique pharmacologic profile that is similar to that of natural progesterone. It combines progestogenic, antimineralocorticoid properties and has virtually no androgenic activity. (Drospirenone is the active progestational agent in the oral contraceptive, Yasmin®). As a component of oral contraceptives and of HRT regimens, drospirenone may offer unique advantages. Its antimineralocorticoid effects may prevent estrogen-related bloating and weight gain secondary to water retention. It may decrease blood pressure. And its antiandrogenic effects have the potential to reduce the severity of acne, seborrhea, and related skin conditions.

The Clinical Utility of Progestins in the Reproductive Years

Oral contraceptives have developed to the extent that it is no longer enough to demonstrate efficacy. “The focus today is on ease of use, lack of side effects, a better risk profile, and perhaps most of all, non-contraceptive benefits,” said Vivian Dickerson, MD, Associate Professor and Director of General Obstetrics and Gynecology at the University of California, Irvine.

Still, patients commonly experience progestin-related side effects, and discontinuation of OC use is often attributed to their nuisance side effects, most often bleeding irregularities (12%), but also nausea (7%), weight gain (5%), mood changes (5%), breast tenderness (4%), and headaches (4%) (Rosenberg et al. Am J Obstet Gynecol. 1998;179: 577.)

Drospirenone, which of the available progestins most closely resembles progesterone clinically, has data that suggest that it may be associated with improvements in quality of life. In its U.S. clinical trials, a drospirenone product produced a Pearl Index of 0.407. It was associated with a low breakthrough bleeding rate of 1%, and spotting of 9.3%. Amenorrhea occurred in only 3.2% of cycles (Parsey et al. Contraception. 2000;61:105-111). In safety evaluations, the most common possible or probable drug-related adverse events occurring at a rate of 5% or greater with the drospirenone OC combination were headache (4.9%) and breast pain (8.6%). Six percent of patients discontinued due to adverse events; no serious adverse events were reported in clinical studies.

Weight gain is a significant concern for young women taking oral contraceptives. Parsey and Pong, in a drospirenone/EE study published in Contraception (2000;61:105-111), reported no significant weight gain through 13 cycles. In fact, the investigators noted some weight loss during the first 6 cycles with drospirenone/EE.

Luteal phase complaints such as mood changes, breast tenderness and bloating are among menstrual symptoms that OCs may potentially alleviate, but data have been mixed regarding the effects of OCs on these monthly symptoms. The drospirenone/EE U.S. clinical trial included an evaluation of menstrual symptoms among its enrolled study population of 326 patients and 3200 cycles (Parsey et al. Contraception. 2000;61:105-111). Symptoms were analyzed using the “Menstrual Distress Questionnaire”, a modification of the validated Women’s Health Assessment Questionnaire. Premenstrual data from this assessment showed a statistically significant change (improvement) in the mean score for negative affect, water retention, and increased appetite.

Given evidence that drospirenone/ EE may improve emotional parameters, Freeman et al. undertook a randomized, double-blind trial with the new drospirenone combination, versus placebo, in 83 individuals who fulfilled the DSM IV criteria for premenstrual dysphoric disorder (PMDD) (Freeman EW et al. J Womens Health Gend Based Med 2001;10:561-569). (PMDD is a form of severe premenstrual syndrome in which psychological symptoms are emphasized and physical symptoms may or may not be present.) Their primary assessment tool was the Calendar of Premenstrual Experiences (COPE), which grouped 22 psychological symptoms under four factors. “At the conclusion of the study,” said Dr. Dickerson, “Freeman was able to say that there was a consistent trend in the reduction of some symptoms with drospirenone/EE in the treatment of PMDD.” Although the study had the limitations of small sample size, and perhaps a lack of sensitivity of COPE as an instrument, the two studies have been consistent in findings of improvement in water retention symptoms, negative affect symptoms, a decrease in appetite, and an improvement in acne with the drospirenone OC.

Newer progestins have been introduced in other forms of contraception. Mirena®, a levonorgestrel (LNG) IUD is indicated for five years of continuous use. With the levonorgestrel IUD, there is decreased menstrual flow, and decreased dysmenorrhea. Its Pearl Index of 0.14 is comparable to surgical sterilization. Not only can the new IUD be used therapeutically for the menorrhagia and dysmenorrhea, and is undergoing evaluation for endometrial protection against tamoxifen-induced endometrial changes, it may also be effective in oocyte donors during ovarian stimulation, Dr. Dickerson said.

Also new is the first transdermal contraceptive system, in the form of a weekly patch containing the progestin norelgestromin (NGMN), and delivering 150 mcg/day of norelgestroming plus 20 mcg of EE/day (Ortho-Evra®). Transdermal pharmacokinetics enable serum hormone levels to remain constant over the dosing interval, in contrast to the peaks and valleys that characterize the oral contraceptives. Efficacy of the transdermal patch is comparable to OCs, with a Pearl Index of 0.71 to 1.2. However, a concern relating to the patch is its efficacy in heavier women. (In studies, about 50% of pregnancies occurred in women weighing 90 kg or greater.) (Zieman M. Fertil Steril. 2001;76:S19). Patch adhesion is also a natural concern, but under study conditions of humidity and perspiration, only 1.8% of patches were replaced due to complete detachment and 2.9% were replaced due to partial detachment (Zacur H. Fertil Steril. 2001;l76:S19). Breakthrough bleeding was significantly higher than in the first two cycles, but there were no differences in remaining cycles for up to one year (Smallwood GH. Obstet Gynecol. 2001;98:799).

Recently introduced is a new injectable contraceptive, effective for one month, containing 25 mg of medroxyprogesterone acetate (MPA) and 5 milligrams of estradiol cypionate (Lunelle®). The efficacy of this new product is excellent, with an overall Pearl Index of 0.0% in 8008 cycles of use (Kaunitz A. Contraception. 1999;60:170). Break-through bleeding was more frequent in the first 3 cycles than with oral contraceptives, but consistent with other OCs. Return to fertility is significantly improved over an older injectable, DMPA (Depo-Provera). The most common adverse event with the medroxyprogesterone acetate (MPA)/estradiol cypionate injectable is weight gain.

The first flexible transvaginal ring (NuvaRing®) provides contraception for three weeks. (Patients’ remove the ring after the three-week active period, for the menstrual period.) The ring releases 120 mcg/day of etonorgestrel (3-keto-desogestrel) and 15 mcg/day of EE. The Pearl Index, at 0.65, is comparable to other methods, and cycle control is better than most other contraceptives, especially in the first months (Roumen FJME. Hum Reprod 2001;16:469; Mulders TMT. Fertil Steril 2001;75: 865.). It is also effective while women are breastfeeding.

Concluding her review of new contraceptive options, Dr. Dickerson recommended that routine provision be provided to patients for postcoital (emergency) contraception. The at-hand availability of emergency contraception has not been shown to cause patients to fail more frequently with their normal contraception. And widespread use of postcoital contraception has been estimated to decrease unintended pregnancies by 50%. (A progestin-only product is branded as Plan B.)

Cardiovascular Effects of HRT: Therapeutic Options

Cardiovascular disease, popularly thought of as a man’s health issue, may be the most significant issue in women’s health in the United States, said Speaker Benjamin J. Ansell, MD, Assistant Professor, Internal Medicine at the University of California-Los Angeles School of Medicine. In women, the prevention of coronary heart disease (CHD) is usually made more difficult by the absence of symptoms prior to a myocardial infarction (MI) and a high risk for sudden death, relative to men. But it is crucial; over 600,000 American women have heart attacks each year. Of these, two-thirds have never had the warning symptoms of chest pain. “Their heart attack is their first symptom of heart disease,” Dr. Ansell said, adding that nearly 40% of these women die suddenly.

A major predisposing factor for CHD is the metabolic syndrome, especially common in postmenopausal women. The syndrome is characterized by mild abnormalities in three of the following parameters: abdominal girth, blood pressure, fasting glucose, triglycerides, and HDL cholesterol. Taken together, these factors predict an increased risk for CHD that approaches levels seen in Type 2 diabetes patients. Other factors common in the metabolic syndrome include abnormal markers of inflammation and coagulation.

The role of HRT in the prevention of CHD has been challenged in recent trial results, which have shown an increase in risk for MI in the first 6-12 months after initiating treatment with HRT. This finding was seen in the Heart and Estrogen Replacement Study (HERS), which evaluated conjugated estrogen/medroxyprogesterone in women with existing CHD. The Estrogen Replacement and Atherosclerosis (ERA) study, which assessed conjugated estrogen with or without medroxyprogesterone, also produced results showing an increased risk for cardiac events early in treatment. Perhaps most widely known are results from the Women’s Health Initiative (WHI), which showed an increased cardiac risk in healthy women receiving conjugated estrogen/medroxyprogesterone, compared to placebo. Women taking this HRT regimen were told to stop treatment immediately, and the study itself was stopped, although this was due to a significant increase in the risk of breast cancer.

Despite the recent disappointment in HRT as a protection against CHD, newer HRT regimens are showing promise. Some produce favorable effects on blood lipids (especially triglycerides), and some improve blood pressure. Transdermal HRT has more favorable lipid effects than oral formulations, Dr. Ansell said, especially in improving triglyceride values. Preliminary data also suggest that the use of the selective estrogen receptor modulator, raloxifene, used in women with osteoporosis, might decrease the risk of coronary events.

In all instances, Dr. Ansell concluded, women at high risk for CHD should undertake aggressive non-hormonal risk reduction strategies, typically involving statins, ACE inhibitors, and aspirin. When HRT is deemed appropriate for women not at increased risk for CHD, careful selection of both the regimen and the route of delivery may help to ensure that dyslipidemia and/or blood pressure are not worsened by the therapy.

In addition to its role in a new oral contraceptive, drospirenone in combination with estradiol may provide a safer and more beneficial HRT. Studies with this HRT have shown favorable effects on lipids and on blood pressure (Tables 1, 2). “Estradiol on its own lowers total cholesterol by lowering LDL, but raises triglycerides and has a positive, but slight, effect on HDL.” In combination with drospirenone, said Dr. Ansell “…there is a much more significant (17-18%) reduction in total cholesterol, not only due to a more profound effect on LDL cholesterol, but also a reduction in triglycerides.”

The drospirenone/EE HRT regimen also appears to lower blood pressure in women, an effect that “may well be due to its antimineralocorticoid effect.” The trend with this combination shows a reduction of roughly 9-13% in systolic blood pressure, and a small trend toward reduction in diastolic blood pressure as well. Dr. Ansell added that while HRT is not the way to treat high blood pressure, “it certainly speaks to the issue of managing symptoms of menopause [in a woman with high blood pressure.] (Table 1 and Table 2).

Use of Progestins in HRT: Risks, Benefits, and New Possibilities

The main reason — probably the only reason — to use progestogens in HRT is to attenuate the endometrial proliferative effects of estrogen, asserted speaker Rogerio A, Lobo, MD, Willard C. Rappleye Professor of Obstetrics and Gynecology at the College of Physicians and Surgeons at Columbia University. However, there may be a secondary effect of progestogens in HRT regimens in the form of possible enhancement of the estrogen effect on bone and on vasomotor symptoms (hot flushes). This suggestion was supported by data from the HOPE Study (Lindsay R et al. JAMA 2002;287:2668-2676) which showed a dose-response relationship in reduction of hot flushes and bone mass effects, and by another study (Recker et al. Ann Intern Med. 1999l130:897-904). The enhancement of bone mass that may be afforded with the addition of a progestin to an HRT regimen is “probably even more convincing with the 19 norprogestins”, said Dr. Lobo.

Nevertheless, several concerns have been linked with most progestins. Among these are somatic complaints (including bloating, cramps and bleeding); mood disturbances; cardiovascular risk/benefit; and breast cancer risk. Cardiovascular risks associated with the progestogen component of HRT have yet to be specifically described but there appears to be an attenuation of blood flow and reductions in insulin sensitivity, depending on the type of estrogen and the dose. On a contrary note, the same observational studies that have shown CV benefit in women using HRT have not found any difference in effect between ERT and HRT. These data, in other words, do not show a detrimental CV effect resulting from using or adding a progestin.

The greatest concern with progestogens in HRT is an increase in breast cancer risk, shown via increases in mammographic breast density with progestin use, such as in the PEPI trial. Several studies, both old and new, have seemed to confirm an increased risk with the addition to a progestin to an estrogen. There is biological plausibility for the contribution of progestins to changes in breast tissue, Dr. Lobo remarked. “Mitotic activity in the breast is highest in the luteal phase of the menstrual cycle. So, the addition of progestin would add increased mitotic activity, which in turn leads to a greater propensity for a cellular mishap [leading to malignant transformation].”

What are the possible options for a safe HRT, given these data? “My perspective has always been to use the lowest possible dose to prevent endometrial disease,” Dr. Lobo offered, “… avoid the biochemistry, and decrease mitotic activity. You don’t need full secretory changes.” Data from Moyer (Fertil Steril 1993;59:992-7), in which standard doses of estrogen but a low dose of sequential micronized progesterone were used, showed no proliferation of the endometrium, reduction in mitotic activity, and nearly 90% amenorrhea.

Vaginal delivery of progesterone, while messy and impractical, is useful in that it positions the progestin in “the only place you need it.” In addition to the growing list of alternatives, drospirenone/ EE “has all the features of a good HRT,” he said, with inhibition of hot flushes, inhibition of hyperplasia, amenorrhea, a good lipid profile, and positive effects on blood pressure. Its antimineralocorticoid properties counter estrogen- related increases in sodium and water retention, reducing symptoms such as bloating and weight gain. And, it has shown a beneficial effect at the spine and hip compared with placebo.

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