CME/CE

AUGUST 2008

Noncontraceptive Health Benefits of Progestin-Only Contraceptive Agents

Ronald T. Burkman, MD; Sandra A. Carson, MD

Progestin-only contraception provides a range of benefits beyond prevention of pregnancy, including amelioration of endometriosis pain, treatment of menstrual disorders, and protection against uterine leiomyomas and cancer—factors to consider when individualizing the patient's contraceptive choices.

Continuing Medical Education

GOAL To describe the significant noncontraceptive benefits associated with various forms of progestin-only contraception (POC). OBJECTIVES To explain how POC can alleviate a variety of menstrually associated and gynecologic disorders, as well as nongynecologic conditions. To discuss the use of POCs to reduce the risk of certain gynecologic cancers. To show how contraception selection can be individualized to relieve certain conditions as well as protect against unplanned pregnancy. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, Professor of Clinical ObGyn, Albert Einstein College of Medicine. Review date: July 2008. It is designed for -ObGyns, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 53 and mail your answers according to the instructions on page 54. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to publish. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. Dr Burkman reports that he is a Consultant for Ortho-McNeil-Janssen Pharmaceuticals, Inc, Pfizer Inc, Columbia Laboratories, Inc, and Bayer HealthCare Pharmaceuticals. The disclosure reported by the author presents no conflict of interest to this article. Dr Carson reports that she has received Grant/Research support from Pfizer Inc. The authors report discussion of off-label use of progestins in this article. Dr Cohen reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine have no conflicts of interest with commercial interest related directly or indirectly to this educational activity.

Progestins are synthetic compounds that produce effects similar to those of progesterone. They represent the central component of progestin-only contraceptives (POCs), and act in a number of ways to prevent pregnancy, including:

• Thickening the cervical mucus to hinder the movement of sperm
• Inhibiting the egg’s ability to travel through the fallopian tubes
• Suppressing ovulation
• Partially suppressing the ability of sperm to penetrate and fertilize the egg
• Altering the uterine lining to prevent implantation of a fertilized egg.

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Table. Examples of Progestin-Only Contraceptive Options

With the contraceptive effects of POCs clearly confirmed, this review highlights their noncontraceptive health benefits. These benefits include:

• Amelioration of endometriosis pain
• Treatment of some menstrual disorders
• Protection against uterine leiomyomas and cancer
• Treatment of anemia associated with sickle cell disease
• Reduction in seizure frequency in some patients with epilepsy.

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ENDOMETRIOSIS

Endometriosis is a chronic, recurrent disease characterized by the presence and proliferation of endometrial-like tissue (glands and stroma) outside the uterus. It is an estrogen-dependent disorder with a prevalence of 2.5% to 10% in women of reproductive age, although rates are as high as 25% to 40% in infertile women. Symptoms include dysmenorrhea, dyspareunia, chronic nonmenstrual pelvic pain, tenderness, and induration, which can result in diminished quality of life and infertility.

Management

Endometriosis does not require treatment unless it is symptomatic or the patient cannot conceive. If treatment is sought, progression and symptoms of endometriosis can be addressed by surgical removal of the endometriotic implants or by medical therapies that induce a hypoestrogenic, anovulatory state with subsequent atrophy of the glandular tissue. However, endometriosis has a high recurrence rate after these interventions, and repeat treatments are often required. Alternatively, gonadotropin-releasing hormone analogs (eg, leuprolide) and androgenic agents (eg, danazol) can be used to manage endometriosis-associated pain. However, long-term use of these agents may lead to significant reductions in bone mineral density (BMD) that cannot always be reversed by add-back therapy. Weight gain and androgenic adverse events (eg, breast atrophy, acne) are also well-documented side effects of these treatments.

Symptomatic Treatment With Progestins

Progestins, either alone or combined with estrogens, are often considered the drugs of choice for addressing the symptoms of endometriosis as they are well tolerated, have a limited metabolic impact, are inexpensive, and provide multiple delivery options. Progestins have been used to treat endometriosis pain for more than 40 years, yielding relief rates of 70% to 100%.1 In this indication, progestins act to suppress intraperitoneal inflammation by inhibiting the hypothalamic–pituitary–ovarian axis, exerting a direct effect on endometrial growth, implantation, and maintenance. Long-term medical therapy with progestins has been found to limit the progression of endometriosis, lower the rates of resultant infertility, and improve patient quality of life.

Progestin-only oral contraceptive (OC) pills require further investigation before they can be definitively recommended to treat endometriosis pain, but the role of long-acting POCs in this indication is better established. Depot medroxyprogesterone acetate (DMPA) is available as an intramuscular injection (DMPA-IM) and, more recently, a low-dose subcutaneous injection (DMPA-SC). The latter has been approved by the FDA for the management of endometriosis pain, demonstrating statistically equivalent reductions in pain at 6 and 12 months compared with leuprolide.2 Patients with endometriosis using DMPA-SC also report improved quality of life similar to that noted with leuprolide, and the overall incidence of adverse events is likewise comparable.2 A notable advantage of DMPA-SC over leuprolide is that reductions in total hip and lumbar spine BMD are significantly less (P<.001) at 6 and 18 months with the progestin. In addition, BMD returned to pretreatment levels by 12 months after therapy cessation in the DMPA-SC group, but not in the leuprolide group.2 A number of open-label case series have reported that the levonorgestrel-releasing intrauterine system (LNG-IUS) relieves the dysmenorrhea experienced by women with endometriosis, but larger studies are required before recommendations can be made regarding its use for this indication.

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MENSTRUAL-RELATED BENEFITS

Dysfunctional Uterine Bleeding

Dysfunctional uterine bleeding (DUB) is abnormal uterine bleeding that is not the result of pelvic pathology or pregnancy. It is typically estrogen or progesterone breakthrough bleeding or estrogen withdrawal bleeding due to anovulatory menstrual cycles. Approximately 20% of affected individuals are adolescent, and 50% are aged 40 to 50 years. Chronic DUB in adolescents and premenopausal women can usually be managed by episodic or continuous exposure to a progestin. Contraceptive progestin treatments for DUB include DMPA injections and LNG-IUS, both of which reduce blood loss among users and often lead to secondary amenorrhea. Progestin-only pills (eg, norethindrone) can also be used.

Menorrhagia

Menorrhagia is defined as either idiopathic excessive menstrual bleeding (more than 80 mL) that occurs over the course of several regular cycles, or as prolonged menstrual bleeding (more than 7 days). Menorrhagia occurs in approximately 10% to 15% of women of reproductive age,3 and anemia is reported in approximately 60% of cases.

Hysterectomy is indicated for women with severe menorrhagia who are unresponsive to other measures, although this may be considered extreme even in women who do not want more/any children. Endometrial ablation is an alternative treatment with a shorter recovery period than hysterectomy, but its success rate is variable.

Progestins represent an effective, noninvasive option for the treatment of menorrhagia. The LNG-IUS, for example, has been reported to reduce menstrual blood loss by 86% to 97%, and was equivalent to hysterectomy in a 5-year study in terms of treatment satisfaction and improvement in quality of life.3 Alternatively, both DMPA-IM and DMPA-SC have been reported to induce amenorrhea in a significant proportion of women (52% to 64% at 12 months and 71% at 24 months for DMPA-SC),4 which may make them particularly appropriate contraceptive choices for women who experience menorrhagia, dysmenorrhea, or menstrual-associated anemia.

Dysmenorrhea

Primary dysmenorrhea is defined as painful menstruation in women with normal pelvic anatomy, and is thought to occur due to the release of prostaglandins that cause uterine contractions, cramps, and pain. It is a common condition, affecting up to 90% of women. Secondary dysmenorrhea is used to describe dysmenorrhea occurring as a result of a pelvic pathology, such as endometriosis.

Nonsteroidal anti-inflammatory drugs are the first-line treatment for dysmenorrhea, exerting their effect via the inhibition of prostaglandins. However, compliance with an effective treatment regimen is an issue with NSAIDs owing to their gastrointestinal side effects. Progestin-only and combination estrogen-progestin OCs are up to 90% effective in relieving dysmenorrhea, and act by reducing menstrual fluid volume and suppressing ovulation.5 Progestin-only OC pills may decrease menstrual flow, and up to 10% of users will develop amenorrhea. In addition, menstrual cramping may also be decreased, but no definitive studies of this effect have been conducted to date.

As DMPA use may ultimately lead to amenorrhea, this effect eliminates dysmenorrhea as well. Dysmenorrhea has also been shown to improve in LNG-IUS users, with a decrease in prevalence from 60% to 29% after 36 months of use.6 Furthermore, the etonogestrel implant has been reported to improve dysmenorrhea in more than 85% of women in a 3-year contraceptive efficacy study, although 4% of subjects reported new or worsened dysmenorrhea while receiving etonogestrel.7

Premenstrual Syndrome

Premenstrual syndrome (PMS) occurs in approximately 12 to 25 million women in the United States, occurring 1 to 2 weeks before menstruation and resulting in significant functional impairment. Long-term therapy with ovulation-suppressing agents (eg, OCs) can be used to treat PMS. In addition, DMPA-IM has been reported to result in a 50% decrease in PMS symptoms.8 However, it should be noted that the role of progesterone and progestins in the treatment of PMS is by no means established, and the data so far are equivocal.

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RISK REDUCTION AND DISEASE PREVENTION

Uterine Leiomyomas

Uterine leiomyomas (fibroids) are benign tumors of the uterine smooth muscle that can cause menorrhagia, pelvic pain, infertility, and recurrent loss of pregnancy. The reported prevalence of this condition varies widely from 5.4% to 77%, depending on the method of diagnosis. Treatment of symptomatic leiomyomas with hysterectomy is relatively common, although uterine-sparing interventions (eg, uterine fibroid embolization, endometrial ablation, laparoscopic myomectomy) may also be employed.

It has been reported that current use of an injectable progestin is associated with a 40% reduction in the risk of developing uterine leiomyomas compared with noncurrent use of contraception.9 Furthermore, treatment with various dosages of DMPA-IM before surgery for uterine leiomyomas has been shown to reduce menorrhagia and improve hemoglobin levels.10 The LNG-IUS also effectively reduces menorrhagia associated with uterine leiomyomas.11

Cancer and Hyperplasia

Endometrial cancer is diagnosed in approximately 40,000 US women each year, most commonly in those over 60 years of age. Hyperplasia (simple and complex), a thickening of the uterine lining, is a potentially precancerous condition. Unopposed endogenous estrogen stimulation of the endometrium is a predisposing risk factor in many cases of hyperplasia and endometrial cancer.

Use of DMPA-IM for 1 year has been reported to reduce the risk of endometrial cancer by up to 80% for as long as 8 years,12 and prevention of ovarian and endometrial cancer is a recognized benefit of long-term progestin contraception.13 Furthermore, endometrial hyperplasia responds well to treatment with progestins, which may partially explain the preventive effect of progestin-only therapies in endometrial cancer. In addition, nortestosterone progestins are reported to reduce the risk of breast cancer in young women with benign breast disease.14

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OTHER CLINICAL CONDITIONS

Women with iron-deficiency and sickle cell anemia benefit from the reduced menstrual blood loss associated with the use of POCs. A 70% reduction in the number of acute crises has been reported for women with sickle cell disease using DMPA.15

Adenomyosis is characterized by the presence of ectopic endometrial tissue in the myometrium (the muscular layers of the uterus). This condition occurs most commonly in women older than 30 years of age who have had children, and symptoms include prolonged or heavy menstrual bleeding and painful menses with cramping. Treatment generally involves pain medications or hysterectomy in more severe cases. Whereas combination OCs may aggravate symptoms, POCs that lead to amenorrhea (eg, the LNG-IUS, DMPA) may provide relief.

Seizure frequency has been found to decrease in women with epilepsy and high progesterone levels, and to increase when estrogen levels are high. Because DMPA reduces seizure frequency in women with epilepsy or other seizure disorders and is not affected by anticonvulsant medications, it is a particularly suitable therapy for patients with epilepsy who do not wish to become pregnant. 16

Progestin-only injectables may help to prevent pelvic inflammatory disease (PID). A World Health Organization multinational study of 319 women with PID and 638 matched controls found that the risk of acute PID among users of injectable progestin contraception was 50% of that among nonusers.17

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CONCLUSION

Progestin-only contraceptives offer a number of benefits beyond pregnancy prevention, including the amelioration of some menstrual disorders, treatment for endometriotic pain, protection against uterine leiomyomas, and a reduction in the risk of endometrial cancer. Nondaily POCs, in particular, offer convenience, safety, and privacy, and confer noncontraceptive benefits that may enhance long-term compliance.

Prescription of POCs should also take into account their safety profile, as well as patient preferences. Adverse events experienced by women receiving POCs include amenorrhea (which is desirable in some cases), bleeding, spotting, pelvic/lower abdominal pain, weight gain/loss, acne, mood changes, loss of libido, breast tenderness, headache, nausea, and vomiting. Jaundice, thromboembolic disorder, chest pain, and hypertension have also been reported, although with lower frequency. In addition, implanted devices may cause infection at the implantation site, and loss of implant capsules has been noted. Overall, progestins can provide a well tolerated, reliable, and convenient method of contraception and offer a host of additional health benefits, including treatment of common menstrual disorders and prevention of cancerous and precancerous conditions in the endometrium.

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Ronald T. Burkman, MD, is Professor, Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA; and Division of General Obstetrics and Gynecology, Baystate Medical Center, Springfield, MA. Sandra A. Carson, MD, is Professor, Department of Obstetrics and Gynecology, and Director, Division of Reproductive Endocrinology and Infertility, Warren Alpert Medical School of Brown University, Women and Infants’ Hospital of Rhode Island, Providence.

References

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DISCLAIMER
The opinions expressed herein are those of the author and do not necessarily represent the views of the sponsor or the publisher. Please review complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

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