Menstrual suppression: current perspectives.

Menstrual suppression to provide relief of menstrual-related symptoms or to manage medical conditions associated with menstrual morbidity or menstrual exacerbation has been used clinically since the development of steroid hormonal therapies. Options range from the extended or continuous use of combined hormonal oral contraceptives, to the use of combined hormonal patches and rings, progestins given in a variety of formulations from intramuscular injection to oral therapies to intrauterine devices, and other agents such as gonadotropin-releasing hormone (GnRH) antagonists. The agents used for menstrual suppression have variable rates of success in inducing amenorrhea, but typically have increasing rates of amenorrhea over time. Therapy may be limited by side effects, most commonly irregular, unscheduled bleeding. These therapies can benefit women's quality of life, and by stabilizing the hormonal milieu, potentially improve the course of underlying medical conditions such as diabetes or a seizure disorder. This review addresses situations in which menstrual suppression may be of benefit, and lists options which have been successful in inducing medical amenorrhea.

Background

Suppression of menstrual periods to provide relief of menstrual-related symptoms has been used in a variety of medical conditions since the availability of steroid hormone therapy. This option has gained legitimacy through its use in treating symptoms, but is now being used more frequently by women for personal preference. A recent Cochrane review of trials comparing 28-day and extended cycles found comparable contraceptive efficacy and safety.1 The review found overall discontinuation rates and discontinuation for bleeding problems to be similar. Extended cycling resulted in improved headaches, genital irritation, tiredness, bloating, and menstrual pain.1

The term “therapeutic amenorrhea” was first used in the mid-1960s to describe the suppression of menstrual bleeding in women with hematologic disorders and coagulation defects leading to heavy menstrual bleeding.2,3 A small randomized trial in 1971 in the US compared a high-dose combination oral contraceptive pill, given continuously, with depot medroxyprogesterone acetate (DMPA) or DMPA plus daily conjugated estrogens.3 The differences among these regimens were not significant.

When oral contraceptives containing a synthetic estrogen and a progestin were initially developed, an arbitrary regimen comprising 21 days of hormonally active pills followed by 7 days of placebo or a hormone-free interval were devised to mimic the natural menstrual cycle (“the Pill”). It was even the belief of one of the original developers of oral contraceptives, John Rock, MD, that this cycling would provide a regimen that was acceptable to the Pope, as he reasoned that the Pill was simply a natural variant of the rhythm method of contraception.4 Pope Pius XII had approved the Pill in 1958 for the treatment of medical conditions such as menstrual pain, given that its contraceptive actions were an “indirect” effect. John Rock’s argument that the Pill was natural, by virtue of mimicking the normal menstrual cycle,4 was ultimately rejected by Pope Paul VI in 1968.5

Clinicians have used hormonal therapy to suppress menstruation since combination birth control pills were initially developed. Continuous hormonal therapy has been used when menstrual bleeding is medically problematic or even life-threatening, such as in patients with aplastic anemia or in bleeding disorders such as thrombocytopenia or severe Von Willebrand disease. Pelvic pain and dysmenorrhea in conditions such as endometriosis or uterine leiomyomata have been managed historically with menstrual suppression as well.6 Medical conditions that may benefit from menstrual suppression are listed in Table 1.

Table 1

Medical conditions that may benefit from menstrual suppression

Gynecologic conditions

Chronic pelvic pain32

Dysmenorrhea33

Endometriosis34,35

Heavy menstrual bleeding30,32

Uterine leiomyomata

Anemia due to heavy menstrual bleeding

Irregular bleeding/anovulation

Polycystic ovary syndrome (PCOS)36

Perimenopausal symptoms32

Premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD)37–39

Pre-procedure

Obstructing utero-vaginal anomalies pending definitive surgery40

Pre-operative endometrial thinning prior to endometrial ablation41

Menstrual molimina42

Breast pain

Headaches

Nausea/cyclic vomiting

Hematologic conditions

Anticoagulation43

Malignancy requiring chemotherapy/BMT44

Inherited anemia/bleeding disorders45,46

Sickle cell disease47

Thalassemias

Fanconi anemia

Von Willebrand disease48

Hemophilia, clotting factor deficiencies

Other hematologic conditions

ITP/thrombocytopenia49

Mental retardation/developmental delay50,51

Behavioral issues/PMS symptoms

Contraception

Hygiene/inability to manage menstrual products

Neurologic disease

Migraine headaches52,53

Menstrual migraines

Menstrual-associated migraines

Seizure disorders54–56

Catamenial seizures

Other conditions associated with menstrual exacerbation57,58

Anaphylactoid reactions59

Asthma60,61

Catamenial pneumothorax62

Diabetes mellitus63

Irritable bowel syndrome64,65

Pancreatitis66

Rheumatoid arthritis

Skin conditions

Acne60

Other

Deployed military personnel67

Female athletes32

Physical difficulty with managing menstrual hygiene

Cerebral palsy

Rheumatoid arthritis

Abbreviations: BMT, bone marrow transplant; ITP, idiopathic thrombocytopenic purpura; PMS, premenstrual syndrome.

The question “Is menstruation obsolete?” was raised by Coutinho and Segal in a popular press book of this name, published in 1999.6 These authors cited a variety of symptoms, including dysmenorrhea, bloating, breast tenderness, premenstrual syndrome (PMS), nausea, and edema, as well as medical conditions including migraine headaches, endometriosis, epilepsy, and anemia, that could be improved by menstrual suppression.

Sulak et al reported that extending the duration of hormonally active pills improved menstrual symptoms including dysmenorrhea, menorrhagia, premenstrual-type symptoms, and menstrual migraines.7 Investigators have asked, “Should monthly menstruation be optional for women?” and have described extended-cycle oral contraceptives as “menstrual nirvana”.8,9 Women’s autonomy and the right to choose and regulate their cycles for whatever reason has been a focus of publications and debate.10,11

In 2003, an oral contraceptive pill formulation was approved by the US Food and Drug Administration (FDA) with packaging for a dosing regimen that provided 82 days of hormonally active pills, followed by 7 days of placebo. In 2007, a pill providing continuous combined hormonal therapy, 365 days/year, was approved by the FDA. The availability of these specific combined oral contraceptive regimens led to greater use of hormonal therapy to reduce the frequency of menstruation, or attempts to eliminate it. Prior to this dedicated packaging or an extended regimen, clinicians described to women how to use the traditionally packaged pill formulations by discarding the placebo pills and tailoring the dosing regimen.

While there are many medical conditions that are improved with menstrual suppression, healthy women who were prescribed oral contraceptive pills in the traditional fashion have learned that their cycles could be manipulated. Prior to the advent of the specifically packaged extended cycle regimens, women would occasionally extend their cycles by a few days to a week to allow for planning special events, vacations, or athletic events. The availability of extended cycle regimens led to more discussion of this option. The acceptability of extended cycles has generally been good, with irregular bleeding or spotting being the most common side effect; bleeding tends to decrease in successive cycles.12–15 Irregular, unscheduled bleeding with an extended regimen may be unacceptable to some women, leading to discontinuation.

A number of polls have cited women’s opinions about the frequency of preferred menstrual bleeding. Some polls suggest that up to half of women may prefer a menstrual frequency of “never”, although the acceptability of amenorrhea has cultural determinants and varies widely.16,17 An international study involving women in Nigeria, South Africa, Scotland, and the People’s Republic of China found that most women dislike menstruation, and in all of the countries studied except the People’s Republic of China, most women expressed a willingness to try a contraceptive method that induced amenorrhea.18

There remain women who believe it’s unnatural or not normal to suppress menses.19 Studies in the US and in other countries including Germany and Brazil have found that many women consider monthly bleeding as reassurance that they are not pregnant.16,20

The efficacy and safety of menstrual suppression has been supported by a number of studies and is recognized in a Cochrane Database Systematic Review.1 The Cochrane review cites possible improved compliance, greater satisfaction, fewer menstrual symptoms, and less menstruation-related absenteeism from work or school. While no studies have shown differences in the contraceptive efficacy of traditional pill packaging versus extended cycling, the greater suppression of follicular development that has been demonstrated with extending cycling would suggest a theoretical edge in favor of less likelihood of development of a follicle and thus lower risk of ovulation, leading to greater efficacy.21 Greater ovarian and endometrial suppression with continuous use has been shown in a randomized trial of continuous versus cyclical oral contraceptives.22

The lack of excessive endometrial proliferation has been described,23 and is reassuring. However, the Society for Menstrual Cycle Research maintains a 2007 position statement stating that “menstruation is not a disease, and that further research on the potential health risks and long-term safety of cycle-stopping contraception is still needed”.24

This review addresses the many medical conditions that may be improved by menstrual suppression, as well as the benefits and potential side effects of various options for the medical suppression of menstruation.

While more studies and reviews have focused on the potential benefits of menstrual suppression with the use of combined oral contraceptive pills, other combined estrogen and progestin hormonal delivery systems (patches and rings) have also been used in a continuous fashion, and likely confer similar benefits.25–28 New formulations and delivery systems are in development, and some of these options may prove to have similar benefits for menstrual suppression when additional studies are performed to assess non-contraceptive benefits.29

Treatment options for menstrual suppression

A variety of medications have been used to induce therapeutic amenorrhea, including: extended cycle or continuous use of oral combined contraceptives; various progestin delivery systems (depot medroxyprogesterone acetate administered intramuscularly [IM] or subcutaneously, oral progestins, intrauterine systems); gonadotropin-releasing hormone (GnRH) analogs, and older drugs such as danazol.30 Table 2 summarizes the formulations that have been used in this manner, along with their dosing regimens, limitations, and efficacy in inducing amenorrhea, as well as potential advantages and disadvantages. Some of these therapies represent unlabeled use of an FDA-approved medication, and clinicians should review the data supporting their use for a specific clinical indication; such use is not precluded by the FDA, and clinicians frequently use drugs for such unlabeled indications when supported by evidence and clinical judgment.31

Table 2

Options for inducing therapeutic amenorrhea

Medication	Dosing	Frequency	Limitations	Amenorrhea	Advantages	Disadvantages
Continuous combined oral contraceptives (COCs)	Multiple formulations; monophasic formulations discarding placebo pills or dedicated packaging for extended cycle	Daily	BTB; other hormonal side effects;28 risk of VTE68	~70% at 1 year with continuous use;69 extended cycle use	Long history and clinical experience with both cyclic and extended use	Daily compliance required; variable duration of menstrual suppression before BTB
Transdermal combination contraceptives	Patch used continuously or extended cycle	Weekly	Similar to COCs;28 skin reaction; possible increased risk VTE cf with COC70	Extended 84/7 cycle fewer days of BTB than monthly use25	Weekly compliance easier than daily COCs	Risks of VTE; little data regarding continuous use
Vaginal contraceptive ring	Ring used continuously or extended cycle	Monthly	Similar to other combined methods	Rates of spotting not reduced with extended or continuous use compared with monthly use71	Monthly compliance easier than daily or weekly	Higher discontinuation rates because of BTB with both extended and continuous regimen
Depot medroxyprogesterone acetate (DMPA)	150 mg IM 104 mg sub-Q	Every 12 weeks	BTB; progestin related side effects; weight gain; reversible impact on bone density with prolonged use (>2 years)72	50%–60% at one year; ~70% at 2 years73	Every 12 weeks administration	Weight gain; potential impact on bone density (reversible)
Oral progestins	Varies by progestin, eg, norethindrone acetate 5 mg bid–tid; medroxyprogesterone acetate; megestrol up to 80 mg/d	Daily	Irregular bleeding; progestin-related side effects; adverse impact on lipids	Up to 76% with high dose progestins at two years74	May be useful if estrogens are contraindicated; oral dosing is adjustable compared to DMPA	Inconsistent achievement of amenorrhea; more expensive than COCs; need for consistent and strict compliance
GnRH analogs	Formulation-dependent: IM, subdermal implants, intranasal	Formulation-dependent: daily or more, to every 12 weeks	GnRH agonists have an initial stimulatory effect and bleeding prior to suppression; menopausal symptoms; impact on bone density with prolonged use	High rates	May provide ovarian protection from chemotoxic effects of chemotherapy44,75,76	Menopausal effects limit therapy but may be given with hormonal “addback” to minimize these side effects; very expensive; potential impact on bone density
Progestin-containing intrauterine system	Levonorgestrel release 20 μg per day	Five years	Initial BTB and possible hormonal effects improve with time	50% at 1 year;77 60% at 5 years78	Top tier contraceptive efficacy, with benefits demonstrated for medical conditions including heavy menstrual bleeding, endometriosis, adenomyosis, fibroids30,79–81	Initial expense and insertion-related pain/discomfort
Danazol	Typically 400–800 mg po per day82	Daily	Dose related: menopausal symptoms, weight gain, and androgenic side effects limit therapy71,83	High rates		More side effects than progestins; expensive

Abbreviations: BTB, breakthrough bleeding; cf, compare; po, orally; GnRH, gonadotropin-releasing hormone; IM, intramuscular; bid, twice daily; tid, three times daily; sub-Q, subcutaneous; VTE, venous thromboembolism.

The primary clinical limitation in virtually all regimens is the inability to perfectly suppress menses from the time of initial dosing. This relates in part to initiation of therapy at varying times in the menstrual cycle, and in varying clinical settings in which the endometrium may have proliferative or secretory histology, and the hypothalamic–pituitary–ovarian axis may be supporting ovulatory or anovulatory cycles. Most therapeutic options have similar efficacy in menstrual suppression at the end of one year of use, but most also have considerable rates of irregular, unpredictable, or unscheduled bleeding in the initial few months after initiation. Rates of amenorrhea reflect amenorrhea in individuals who continued the hormonal method; irregular, unscheduled bleeding may have resulted in discontinuation, thus artificially raising the reported rates of amenorrhea. This limitation is of variable acceptability to women, and must be described fully with instructions to patients in order to provide a truly informed consent process, and in an effort to prevent premature discontinuation of the therapy. The author’s sample instructions to patients are provided in Table 3. Sample instructions to patients are provided in Table 3. Factors that play a part in the selection of an option for menstrual suppression include the route of administration, frequency of use which impacts compliance and satisfaction, the presence of uncomfortable side effects, other effects of administration such as an improvement in acne, and factors such as cost or insurance coverage. Clinicians are challenged to work with their individual patients to find a therapy that will be efficacious in suppressing menstrual bleeding when clinical symptoms or medical conditions warrant an attempted induction of therapeutic amenorrhea.

Table 3

Instructions to patients

1. No method of menstrual suppression is perfect. Irregular, unpredictable bleeding or spotting occurs in the initial months of treatment with all therapies. While this can be bothersome, it is usually not medically worrisome, doesn’t mean that the treatment isn’t working for birth control or that it won’t eventually cause bleeding to stop.

2. Write down or record electronically all bleeding (with a menstrual-tracking application for smartphone or tablet) so that you and your clinician can discuss management at a follow-up visit.

3. Irregular bleeding and spotting almost always get better after the first 1–3 months of treatment, although it may take up to a year (or occasionally longer for some people) for most bleeding to stop.

4. Not all irregular bleeding is due to the effects of hormones, especially if your initial irregular bleeding has stopped. Sometimes bleeding can signal a sexually transmitted infection (STI) or other cause (such as polyps, or uterine growths like fibroids). Talk with your clinician and be tested for STIs if you are at risk.

Summary

Menstrual suppression can have considerable benefits in improving quality of life, and in ameliorating menstrual cycle-related exacerbations of menstrual symptoms/molimina as well as underlying catamenial worsening of underlying medical conditions. The most common factor limiting the use of therapeutic measures to effect menstrual suppression is breakthrough bleeding and imperfect rates of amenorrhea, although the experience of other side effects can also be problematic if this has not been adequately explained prior to initiating the therapy. In the past, clinicians have reserved the recommendation of menstrual suppression for severe symptoms or significant disease. With the advent of marketing of extended cycle regimens of combination oral contraceptives directly to consumers, women have become aware of the option to choose menstrual suppression or extended cycles based on their own preferences and experiences of uncomfortable or painful menstrual symptoms. The realities of menstrual suppression and, in particular, the relatively high initial rates of irregular and unscheduled spotting or bleeding need to be understood by both clinicians and by women who may be choosing this option. However, over time, high rates of amenorrhea can typically be achieved, and those who do not achieve complete amenorrhea with medical therapies can often benefit from a marked reduction in menstrual volume. Surgical therapies can often be avoided, particularly in younger women who wish to preserve child-bearing capabilities.