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Therapeutic amenorrhea is not always easy to initiate or to maintain. But anticipating prolonged, heavy bleeding in patients with certain medical problems--and managing it prophylactically--is far better than trying to stop potentially life-threatening bleeding once it's begun.
|Jump to:||Choose article section... Therapeutic amenorrhea for hematologic conditions Let every woman choose fewer periodsor none? Studies on extended menstrual suppression Traditional hormonal approaches for the mentally retarded GnRH agonists and ideal timing DMPA takes its time in inducing amenorrhea Danazol is a less attractive choice When progestins cause breakthrough bleeding Controlling acute bleeding in thrombocytopenic patients The levonorgestrel IUS Working with oncologists and hematologists Conclusions Key points|
Therapeutic amenorrhea is not always easy to initiate or to maintain. But anticipating prolonged, heavy bleeding in patients with certain medical problemsand managing it prophylacticallyis far better than trying to stop potentially life-threatening bleeding once it's begun.
Prolonged or heavy menstrual bleeding can be problematic, medically risky, or even life threatening to adolescent girls and women with certain medical conditions. Among those at risk who'll need to be proactively managed are females undergoing chemotherapy, including bone marrow transplant (BMT), and those with aplastic anemias, thrombocytopenia, or other bleeding disorders. It's far better to anticipate heavy or prolonged bleeding and manage it prophylactically than to attempt to stop the bleeding once it has begun.
Clinicians have long recognized the challenge of identifying the best way to stop menstruation. My goal in this article is to discuss the advantages of reducing or eliminating menstruation in patients who require it and to describe the various therapeutic regimens for doing so.
The term therapeutic amenorrhea was first coined in the mid 1960s.1 Clinicians have used a variety of hormonal regimens to achieve this end, even though no large-scale studies have compared regimens. In 1971, investigators described a randomized study of 29 patients with hematologic disorders and coagulation defects leading to menorrhagia who were treated with one of three regimens to manage these disorders and defects: (1) a high-dose estrogen-progestin combination oral contraceptive on a continuous basis; (2) depot-medroxyprogesterone acetate (DMPA); or (3) DMPA plus daily conjugated estrogens.2 Although this small study found a trend toward less bleeding in patients treated with a combination of estrogens and progestins compared to progestins alone, the findings were not statistically significant.
Inherited bleeding disorders such as Von Willebrand disease can devastate a patient's quality of life, with hysterectomy a last resort for some women with uncontrolled bleeding.3 The pharmacologic effects of OCs on clotting factors suggest that the use of continuous OCs to improve menorrhagia makes sense and would improve overall quality of life for these women. The continuous administration of combination estrogen-progestin OCs is still commonly used to induce amenorrhea in patients undergoing BMT, even though no clear consensus exists as to the most appropriate regimen.
Subsequent investigators described the use of continuous progestins or combination OCs to produce prolonged amenorrhea, which results from progressive endometrial atrophy. In a 1959 study, continuous combined OCs given to treat endometriosis-induced pelvic pain had a secondary effect of producing amenorrhea.4 Researchers have also used continuous OCs to manage hematologic disorders ranging from afibrinogenemia to von Willebrand disease.5,6
Investigators have recently proposed reducing the frequency of menstruationor eliminating it altogethereven for women with no hematologic problems. Some investigators ask, "Is menstruation obsolete?" or point out the menstrual-related problems that improve with continuous OCs.7,8 These problems range from dysmenorrhea, bloating, breast tenderness, premenstrual syndrome, nausea/vomiting, and edema, to more medically disabling conditions like migraines, endometriosis, epilepsy, and anemia. Perhaps as many as 75% to 85% of menstruating women experience some degree of premenstrual or menstrual symptoms, with up to one third having it interfere with daily activities.9,10
Sulak and her colleagues have shown that extending the duration of hormonally active pills was well tolerated and improved quality-of-life symptoms.11 Other indications for therapeutically inducing amenorrhea include wartime use for mobilized female military personnel or the use of various therapeutic measures to induce an atrophic endometrium before hysteroscopic or thermal endometrial ablative procedures (Table 1).12,13
Researchers have recently focused on menstrual suppression using continuous OCs.14-17 The current regimen for almost all combination OC pills consists of 21 days of hormonally active pills, followed by 7 days of placebo, which results in regular withdrawal bleeding for almost all users. When this regimen was first designed, however, it was intended to be more "natural" by providing a planned menses every 28 days. Withdrawal bleeding can be postponed by various time intervals. A handful of trials using trimonthly regimens suggests reasonable acceptability, with irregular bleeding or spotting being the most common side effect, although bleeding did decrease in successive cycles.18-21
One study did not find significantly more days of spotting in extended users, and reported significantly fewer overall bleeding episodes and days, with the resulting use of fewer menstrual hygiene products compared to standard regimen users.22 Another study gauged the annual savings on sanitary products and found that for the average OC user, it was less than the costs associated with using more packages of pills.23
One formulation of combination OCs could be commercially available within the next year or so; this pill will be sold in 3-month packs of 84 days of hormonally active pills with 7 days of placebo. Preliminary results are in from a trial that studied two different dosage formulations (EE 30 µg/ levonorgestrel 150 µg or EE 20 µg/ levonorgestrel 100 µg) in a trimonthly or traditional regimen. These suggest high efficacy, but with more discontinuations for "unacceptable" bleeding in the 20-µg extended regimen.24
Another study examined a similar regimen using an EE 30 µg/levonorgestrel 150-µg formulation and found that 71% discontinued the trimonthly regimen in the first year, with half citing breakthrough bleeding (BTB) as the reason.25 The urgency and severity of the need to suppress menses may well dictate the acceptability of such a regimen. Women who consider their symptoms mild may be unwilling to continue such a regimen, while those with medical conditions that are severe or life threatening may be more willing to do so. A number of therapeutic options exist to induce amenorrhea (Table 2).
|Medication||Dosing||Frequency||Limitations||Efficacy in inducing amenorrhea||Contraceptive effect||Advantages||Disadvantages|
|Continuous combined oral contraceptives (COCs) estrogen dose||Multiple formulations available with varying and progestin type; continuous extended use, skipping placebo pills||Daily||Breakthrough bleeding or nuisance side effects; consider contraindications to estrogen use||Good||Yes||Long clinical experience; relatively inexpensive||Duration of individual sustainable amenorrhea varies; breakthrough bleeding; daily compliance required|
|Depot medroxypro- gesterone acetate (DMPA)||150 mg||IM every 12 weeks||Prolonged irregular bleeding; progestin- related side effects; weight gain; osteopenia||50% amenorrhea at 1 year||Yes||Relatively inexpensive; some specific advantages (eg., seizure disorders)||Progestin-related side effects; delay to induction of amenorrhea; inconsistent achievement of amenorrhea|
|GnRH agonists||Formulation- dependent: IM, implants, nasal||Formulation- dependent: daily or more to every 12 weeks||Menopausal symptoms; osteopenia, dependent on duration of therapy||Good||No||May provide ovarian protection from chromotoxic effects||Initial dose requires attention to timing in menstrual cycle; expense; potential impact on bone density|
|Oral progestins||Varies by progestin, e.g., norethisterone acetate 5 mg daily three times per day||Daily or multiple x/day (varies)||Irregular bleeding; progestin- related side effects||Good||Dose- dependent||Dose adjustable compared with DMPA||Inconsistent achievement of amenorrhea; more expensive than COCs; strict daily compliance required|
|Danazol||Up to 800 mg/day||Daily||Androgenic side effects; menopausal symptoms||Good||No||May have disease- specific benefits||Treatment-limiting side effects|
|Transdermal combination contraceptives||Patch used continuously||Weekly||Similar to combination OCs; skin reactions||Theoretically similar to combination OCs; few data to support||Yes; contraceptive efficacy lower in women >90 kg (198 lb)||Weekly rather than daily dosing; parenteral administration||Few data to support this use|
|Vaginal contraceptive ring||Vaginal ring used continuously||Every 3-4 weeks||Similar to combination OCs; vaginal route may not be acceptable to some||Theoretically similar to combination OCs; few data to support||Yes||Less frequent administration||Few data to support this use|
|Progestin- containing intrauterine system||Levonorgestrel release 20 µg/day||5 years||Limited to appropriate candidates for IUD||Up to 50% at 1 year||Yes||Long-lasting; cost-effective for long-term use||Inconsistent achievement of amenorrhea|
|GnRH antagonists||Varies||Few data for this indication||Potential for use in the future||No||Theoretical advantage over agonists with more rapid down-regulation|
Ob/gyns have long recognized the value of using hormonal medications to induce therapeutic amenorrhea in mentally retarded women. Clinicians continue to do so today because the drugs address issues relating to hygiene, behavior, caretakers' comfort with menses, the spread of blood-borne infections like hepatitis and HIV, and nonconsensual intercourse. Parents, guardians, and caretakers may decide on this course for a variety of reasons.26,27
Early Scandinavian research has shown that the nortestosterone derivative lynestrenol, an oral progestin, induces therapeutic amenorrhea in institutionalized mentally retarded women.28-30 Adverse hepatic effects associated with this agent include elevated hepatic enzymes, adverse effects on serum lipids, and the development of venoocclusive disease after BMT.28-31 These adverse effects appear to be dose-related, so also keep that principle in mind when prescribing combination OCs that contain estrogen.28,32
Clinicians have used norethindrone acetate to suppress and control menses with both parenteral and oral dosing (5 mg one to three times a day) for women with mental retardation, menorrhagia, dysmenorrhea, endometriosis, anemia, PMS, and menstrual migraines.33-37 A Cochrane Review comparing progestins versus estrogens and progestins for irregular bleeding called for further research, noting a paucity of studies.38 Drawbacks of norethindrone include irregular bleeding as well as progestin-related side effects, such as bloating or mood changes. The oral dosing is more costly than extended combination OC use.
The advantages of using combination OCs to induce therapeutic amenorrhea include their overall safety and low cost, while problems with patient compliance are among the drawbacks. Success may be especially challenging for women undergoing chemotherapy who have mucositis and nausea, for patients with severe GI toxicity who may be unable to absorb the drug, for women having altered pharmacokinetics due to drug interactions, and those experiencing BTB related to the above factors.39
More recent studies have reported on GnRH agonist therapy for abnormal bleeding, including hematologic disorders and bone marrow transplantation.39-41 Limitations to the use of GnRH agonists (side effects and cost) may also apply to the use of steroid hormones to induce amenorrhea. Because these drugs require approximately 2 to 4 weeks to induce amenorrhea, their effectiveness for acute treatment is understandably limited. GnRH agonists are expensive. They can be given as an intramuscular injection, as a depot formulation, IV, or intranasally. You must also consider the effects of GnRHa on bone mineral density, although the effects of short-term (3 to 6 months) use are often judged to be acceptable.
GnRH therapy may protect the ovary from the toxic effects of chemotherapy, thereby helping to preserve fertility.42,43 Controlled research remains to be done, however, to provide definitive evidence. GnRH therapy interrupts the hypothalamic-pituitary-ovarian axis, transiently suppressing gametogenesis. Animal studies that looked at the effect of these drugs on rat gonads have yielded mixed results, while limited data suggest benefit in monkeys.44-46 A clinical trial of men receiving chemotherapy for germ cell tumors failed to demonstrate protection.47 Ovarian function was preserved in 12/12 adolescent girls treated with GnRHa before polychemotherapy, compared with 0/4 who did not receive GnRHa.48 GnRH therapy seems to benefit women receiving chemotherapy for systemic lupus erythematosus and other autoimmune nonmalignant, as well as malignant conditions such as lymphoma.43,49
The timing of administering amenorrhea-inducing medications in relationship to the menstrual period is important. Internists or medical subspecialists who see these women sometimes fail to obtainor recordinformation about menstrual cyclicity. In addition, the adolescent or adult woman often cannot accurately recall when she had her last period, although knowing that information is important to the success of the regimen chosen to suppress menses. Evidence suggests that administering GnRH agonist during the midluteal phase of the cycle (compared to the early proliferative phase) more promptly suppresses estrogen secretion and follicular development.50 However, a heavy initial bleeding episode may result in either case. Ghalie reported that significant menstrual bleeding was more likely to occur if a GnRH agonist were given less than 2 weeks before the development of thrombocytopenia.39
Clinicians often use DMPA to attempt to induce amenorrhea in women with medical problems. Amenorrhea is uncommon in the first few months of use, but becomes progressively more likely with time; at the end of 1 year, approximately 50% of women are amenorrheic.51 Obviously then, DMPA is not the best choice when attempting to quickly induce therapeutic amenorrhea. But oncologists or other medical specialists may be unaware of the fact that most women who receive an initial dose of this drug will have irregular and unpredictable bleeding. They may mistakenly believe that amenorrhea will reliably and consistently follow the initial dose.
The timing of menstrual cycle intervention is also important with DMPA. When given beyond day 10 to 13 of a menstrual cycle, you can't count on DMPA to reliably inhibit ovulation or menstruation.52 Similarly, starting OCs after day 7 or 8 of the menstrual cycle may result in some follicular development and possible ovulation.53,54 When attempting to achieve amenorrhea through endometrial suppression and atrophy, take into consideration the stimulation of the endometrium that results from follicular development and estrogen production.
During therapy and attempts to induce therapeutic amenorrhea with progestins, an excessively atrophic endometrium can sometimes cause irregular breakthrough bleeding. Therapeutic options include estrogens alone or combination OCs,34,51,55 although experienced clinicians rarely treat hormonally.34 Most prefer to rely on prophylactic educational guidance about the likelihood of irregular bleeding coupled with ongoing support and follow-up.34 Some women with hematologic problems such as thrombocytopenia or pancytopenia may actually need a transfusion as a result of BTB. Thus, there's a real tendency to prescribe acute hormonal managementeven to the point of using multiple therapies that compound the clinical picture and possibly cause more bleeding when hormonal therapy is withdrawn.
Clinicians have used this drug to suppress menses in women with endometriosis and menorrhagia. In most clinical situations, however, its lack of contraceptive effect, relative cost, and frequent treatment-limiting androgenic and hypoestrogenic side effects make it a much less attractive option, when compared to the alternatives described above.56 Clinicians have used danazol to induce amenorrhea in women with idiopathic thrombocytopenic purpura and other hematologic conditions.57-59 We do not yet know of any additional benefits or mechanisms of action that would lead clinicians to recommend its use for specific conditions over other amenorrhea-inducing drugs.
At times, physicians try to manage BTB in patients on progestin-only contraceptives by using high-dose (qid) estrogen-progestin combination OCs. This approach is ill-advised. This approach may be indicated for anovulatory dysfunctional bleeding, which results from an excessively proliferative endometrium with irregular shedding. But in contrast, BTB due to a progestin-induced atrophic endometrium usually responds to low-dose estrogens.
The proliferative effect of the high-dose estrogens results in endometrial growth that will be shed as soon as estrogen therapy is stopped. Avoid using multiple hormonal therapieseither concurrently or consecutively for patients on progestin-only therapiesas they can cloud the clinical picture. Alternating therapies of high-dose estrogen and progestins have opposing effects of endometrial proliferation and atrophy, making it difficult to predict the effect on the end-organ, the endometrium. Progestogen-related BTB is associated with morphologic and functional endometrial changes, chiefly due to a patchy capillary origin for the bleeding.60
The adverse effects of high-dose steroid hormones can confound attempts at management. A case in point involved two patients who were undergoing stem-cell transplants. Cholestatic jaundice was temporally associated withand likely caused byhigh-dose OC regimens (Ovral qid), as part of attempts to induce amenorrhea with various hormone regimens.61 There are many hypotheses about the mechanism by which the estrogen component of OCs decreases hepatic excretory function, resulting in intrahepatic cholestasis. As this is an uncommon effect, some researchers suggest that it represents an idiosyncratic reaction that may be dose-dependent. I've discussed the problems associated with multiple therapeutic regimens to induce therapeutic amenorrhea and manage BTB elsewhere.62
How do you control acute bleeding in patients with thrombocytopenia or pancytopenia? One therapeutic option would be a dilation and curettage to remove the superficial endometrium, leaving the endometrial basalis layer as a fresh "background" for subsequent hormonal therapy or normal regrowth. While this works at first, the results don't last beyond the first menstrual period.63 It is not recommended as first-line therapy. Patients with heavy uncontrolled bleeding complicated by thrombocytopenia may develop hematometra. Clots within the uterus then impede the effect of uterine contractions that normally aid in controlling the bleeding (similar to the mechanism of continued bleeding with postpartum uterine atony).64 While this rarely occurs, pelvic ultrasound will demonstrate the presence of hematometra, which may require uterine evacuation using suction curettage to evacuate clots and allow myometrial contractions to be effective.
The effect on the endometrium of a levonorgestrel-containing intrauterine system is characterized by pseudodecidualization, atrophy, and inflammation. The longer it's in place, the more menstrual blood loss will decrease. Thus, these IUDs have been effective in treating menorrhagia.65 During the first year of use, 17% of women reported amenorrhea lasting at least 3 months.66 With continued use, amenorrhea rates rose to 60% by 12 years.67 While you can't extrapolate these rates of amenorrhea to all women with severe hematologic problems, others may benefit from this option, particularly if they need contraception, don't require complete menstrual suppression, and "therapeutic hypomenorrhea" is sufficient. Of course, you need to determine for which patients an IUD is best suited; clearly, this is an inappropriate method for suppressing menses in an adolescent, who may be at risk for STDs when her acute illness has resolved.
Before you can rationally use these drugs to induce amenorrhea, however, you must understand two things: the effects that timing and the dose of estrogen and progestin have on the endometrium. Your best chance at successfully inducing therapeutic amenorrhea depends on collaboration with hematologists, oncologists, and other medical subspecialists.
Before a patient undergoes a bone marrow transplant, her oncologist should recommend a consultation with a gynecologist. This may allow hormonal manipulation to successfully induce amenorrhea before chemotherapy. Practically speaking, of course, it's not always possible to have sufficient time to establish amenorrhea, or to give attention to appropriate timing in the menstrual cycle. Nevertheless, a preventive focus is always preferable to an urgent consultation triggered by the need to stop the problematic acute bleeding of a patient with thrombocytopenia or severe anemia.
While you must pay careful attention to the probable endometrial effects of various hormonal therapies in attempts to achieve therapeutic amenorrhea and to manage potential BTB, it's often difficult to achieve therapeutic amenorrhea. The ideal regimen for suppression is not yet clearly defined. In my view, a GnRH agonist is the most predictable and useful agent for patients who are also concerned about preserving ovarian function and fertility. However, you must start this therapy as early as possible before chemotherapy is begun. By accomplishing this, you can minimize the use of hormonal regimens with potentially toxic effects at high doses.
Continuous or trimonthly regimens of OCs are the best way to manage other medical conditions. Some patients with continuing severe disease will require active, ongoing suppression, while others may need only periodic suppression. With continuing use of DMPA or a levonorgestrel-containing intrauterine system, a patient with less acute disease but other factors that make amenorrhea desirable can benefit from the likelihood of eventual amenorrhea. Examples would be women with moderate-to-severe or profound mental retardation.
If you're considering inducing therapeutic amenorrhea in girls and women with significant medical problems, discuss this issue with your colleagues who care for women with chronic diseases. Clinicians in other fields may be unaware of therapeutic options for menstrual suppression that can improve the quality of life of their female patients by preventing severe episodes of menstrual bleeding. While the induction of therapeutic amenorrhea is not always easy to initiate or to maintain, it can be good preventive medicine. h
Dr. Hillard is a paid consultant for Procter & Gamble, has received grants and research support from Berlex and Wyeth-Ayerst, and is on the Speakers Bureaus of Wyeth-Ayerst, Berlex, 3-M Pharmaceuticals, Pfizer, Organon, and Ortho-McNeil.
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Paula Hillard. Cover Story: When should you induce amenorrhea?.
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