Beyond Birth Control: Noncontraceptive Benefits of Hormonal Methods and Their Key Role in the General Medical Care of Women

Abstract

Contraceptives that contain estrogen and/or progestins are used by millions of women around the world to prevent pregnancy. Owing to their unique physiological mechanism of action, many of these medications can also be used to prevent cancer and treat multiple general medical conditions that are common in women. We performed a comprehensive literature search. This article will describe the specific mechanisms of action and summarize the available data documenting how hormonal contraceptives can prevent ovarian and uterine cancer and be used to treat women with a variety of gynecological and nongynecological conditions such as endometriosis, uterine fibroids, heavy menstrual bleeding, polycystic ovary syndrome, acne, and migraines. Contraceptive methods containing estrogen and progestin can be used for a wide variety of medical issues in women.

Introduction

Pharmaceutical methods of contraception provide effective protection from pregnancy and are used by millions of women each year.¹ In 2014, >40% of all women using contraception were using some type of hormonal contraception (pills, vaginal ring, injectable progestin, progestin implant, or progestin intrauterine device [IUD]).² In addition to their important role in pregnancy prevention, the physiological actions of the estrogens and progestogens that make up the various preparations also provide important noncontraceptive benefits, including cancer prevention, treatment of common gynecological and nongynecological medical conditions, and are a key part of health care especially for women with chronic medical conditions.³ The purpose of this article is to review the common hormonal contraceptive methods and provide an overview of their central role in the general medical care of women.

Overview of Hormonal Contraceptive Methods

Contraceptive methods can be broadly classified into two groups: those containing both estrogens and progestins, and those containing only progestins (Table 1). Within each group there are various methods of delivery, each associated with different physiological effects locally and systemically and, therefore, with different benefits and risks.

Table 1.

Classes of Hormonal Contraceptive Preparations

Type	Formulations and delivery
Combined hormonal contraceptives	Oral (monophasic, multiphasic, continuous)
	Transdermal patch (monophasic)
	Vaginal ring (monophasic)
Progestin-only methods	Oral “mini pill”
	Depot-medroxyprogesterone acetate injection
	Levonorgesterol intrauterine system (LARC)
	Subdermal implant (LARC)

LARC, long acting reversible contraception.

Combined hormonal contraceptives

There are several contraceptive preparations that include both estrogen and progestin. The most commonly used are combined oral contraceptive (COC) pills. The contraceptive patch and vaginal ring dispense similar hormones, but use a different delivery system. Combination contraception has a variety of physiological effects, from both estrogen and progestin. The estrogen inhibits ovulation by inhibiting follicle-stimulating hormone (FSH), but it also provides stability of the endometrium leading to regular bleeding patterns. Common doses of estrogen (mostly as ethinyl estradiol [EE]) in modern combined contraceptives range from 20 to 35 μg. The progestin component contributes to the ovulation suppression by inhibiting the luteinizing hormone (LH) surge, but also has local effects on the endometrium. The continuous administration of low-dose progestin contributes to thinning of the endometrial lining, leading to a lighter menstrual flow as well as a theoretical decrease in local prostaglandins.

Most progestins available in the United States used in combination contraception are derived from 19-nortestosterone, with the exception of drosperinone, which is derived from spironolactone. Progestins are classified by generation, and a recent systematic review by the American Society for Reproductive Medicine found “fair” evidence that thromboembolic risk associated with drospirenone or third-generation progestins (desogestrel and gestodene) is slightly higher when compared with norethindrone or Levonorgestrel (second generation).⁴ The androgenic action of the various preparations also differ and can be tailored to the individual when used to manage symptoms or polycystic ovary syndrome (PCOS), acne, and hirsutism.

Progestin-only methods

Progestogens (progesterone and other progestins) work through a complex interplay of hormonal upregulation and suppression. The progesterone-only pills work by thickening cervical mucus to inhibit sperm migration, thinning the endometrium, suppressing ovulation, lowering the midcycle peaks of FSH and LH, and slowing movement of an egg through the fallopian tubes. The effects on cervical mucus and endometrium are the critical factors in prevention of conception in most patients.^5,6 Levonorgestrel (LNG) IUDs result in a local thinning of the endometrium and thickened cervical mucus, but fewer systemic effects. Available formulations of progestogen-only contraception include some LNG-IUDs, the progestin-only pill or “mini-pill,” the injectable depot medroxyprogesterone acetate (DMPA), and the subdermal implant.

Intrauterine devices

Progestin IUDs (LNG-IUD) are one of the long-acting reversible methods of contraception. They are inserted by a clinician and remain in place for 3–7 years.⁷ LNG-IUD are an excellent form of contraception due to their high level of effectiveness. They induce endometrial atrophy due to a local effect of the progestin, which is slowly released from the IUD. They are also commonly prescribed for use by women for whom pregnancy would carry a high risk of maternal morbidity and mortality and are also an excellent treatment for many common medical and gynecological conditions as discussed hereunder.

Beyond Birth Control

Pharmaceutical products typically considering to be “contraceptives” play an important role in the general medical care of women. As depicted in Table 2, their use covers a broad range of purposes, including both prevention and management of both common and uncommon medical concerns.

Table 2.

Combined Hormones and Women's Health Care

Cancer prevention	Ovarian
Cancer prevention	Endometrial
Gynecological conditions	Endometriosis
	Uterine fibroids
	Heavy menstrual bleeding
General medical conditions	Bleeding disorders
	Polycystic ovary syndrome
	Acne
	Hirsutism
	Migraine headache
	Relative energy deficiency of sport (RED-S, formerly Female Athlete Triad)⁸
Preconception health and pregnancy planning for optimal outcomes	Pregnancy prevention for women with acute and chronic medical conditions
	Optimal pregnancy timing
	Prevention of birth defects during treatment with teratogenic medications or infection exposure

Cancer prevention

There is an overall reduction in cancer risk associated with use of hormonal contraceptives, in particular COCs and the LNG-IUD.⁹ The greatest and most consistent benefit has been shown for ovarian and endometrial cancers. There have been weak benefits shown in some studies for prevention of colorectal, kidney, bladder, and pancreatic cancers as well as lymphoma.^9,10 Although the CDC recommends against the use of hormonal contraception in women with known breast cancer, some observational studies find a weak association between COCs and the risk of breast cancer. However, the clinical implications of this finding are unclear due to potential biases in the studies. Notably, most population data about contemporary hormonal contraceptives have also not demonstrated an increased risk of breast cancers with either COCs or LNG-IUD use.^11,12

Ovarian cancer

The use of combined hormonal contraceptives (CHCs) decreases the occurrence of ovarian cancer. The mechanism of action is not completely clear, but it is hypothesized that as COCs inhibit ovulation and reduced cancer rates are due to reduction in cell proliferation. Studies using more current formulations of COCs have demonstrated a 21%–40% reduction in ovarian cancer with both short- and long-term use.^11,13 Longer-term use of COCs (>10 years) provides a larger effect.¹³ The protective benefit of hormonal contraceptives seems to be greatest when use begins before age 35 years, and risk reduction appears to persist for up to 25 years after pill use has stopped.^13,14 The evidence that LNG-IUD reduces risk of ovarian cancer is not as robust; findings from population range from no benefit to a 47% reduction in ovarian cancer.^12,13

Endometrial cancer

The use of hormonal contraceptives has also been shown to reduce the occurrence of endometrial cancers. The largest reduction in risk has been shown with the use of the LNG-IUD, which may reduce the risk of endometrial cancer by 78%.¹² With regard to COCs, long-term (>10 years) use has been shown to have the largest impact, with a risk reduction of up to 34%, however, short-term use of COCs has also shown benefit.¹¹ The risk reduction is greater among users who have additional risk factors for endometrial cancer, including a history of tobacco use, obesity, and sedentary lifestyle. However, the risk of COC treatment in these higher risk populations must be weighed.¹¹ A systematic review suggests that the LNG-IUD may be an adequate treatment for women with endometrial hyperplasia without atypia.¹⁵

Management of gynecological conditions

Endometriosis

Endometriosis is an estrogen-dependent inflammatory disorder characterized by the presence of endometrial tissue outside of the uterus. The two main complications are pelvic pain and infertility. Laparoscopic surgery and destruction of endometriosis lesions improves fertility.¹⁶ There is no evidence that medical treatment affects the long-term outcomes for women with endometriosis and infertility, but is commonly used for symptom management.¹⁶ Hormonal contraception is a mainstay of long-term therapy for women with endometriosis-related dysmenorrhea and pelvic pain due to its ease of use and relative lack of side effects. CHCs, progestin-only contraception (i.e., progestin-only pills, etonogestrel implants, and DMPA injections), as well as LNG-IUD have all demonstrated efficacy in primary treatment of endometriosis-related pain as well as reduction of disease progression after surgical interventions.^17

–21 A recent randomized clinical trial found that both LNG-intrauterine system (IUS) and the progestin implant reduced dysmenorrhea and pelvic pain and improved health-related quality of life.²² Mechanism of actions include decreased circulating prostaglandins, which consequently decreases inflammation (LNG-IUD) and inhibition of ovulation (COCs). Monophasic COCs are used in a continuous manner, as opposed to cyclically, with withdrawal bleeds limited to every 3 or more months.²³

Although the evidence for use of CHCs to improve pain in women with endometriosis is rated as low quality,^18,24 the potential side effects are relatively minimal as compared with GnRH agonists, which is the other medical therapy used in women with endometriosis-related pain.

Uterine fibroids

Uterine leiomyomas (also called fibroids) are the most common solid pelvic tumor in women and are reported in 70% of white women and >80% of black women by age 50 years. Typical symptoms of uterine fibroids include abnormal uterine bleeding and/or pelvic pain/pressure, making leiomyomas the most common indication for hysterectomy.^25,26 Evidence-based reviews show a lack of randomized trial data showing effectiveness of medical therapies in management of symptomatic fibroids, with most therapies offering only short-term relief with a high rate of conversion to surgical therapies.^27,28

CHCs and progestin-only contraceptives are commonly prescribed to improve heavy uterine bleeding commonly associated with uterine fibroids via the mechanism of endometrial atrophy and are an important option for women with fibroids who desire contraception before proceeding to more invasive therapies. CHCs and progestins do not appear to be effective in decreasing bulk symptoms related to large uterine fibroids, thus most symptomatic leiomyomas are still managed surgically.²⁷

There is some evidence from cohort studies that progestin-only agents, including DMPA, are associated with a decreased risk of leiomyoma formation and may decrease uterine and fibroid volumes after 6 months of therapy.^29

–33

Observational studies and systematic reviews have shown a reduction in uterine volume and bleeding, and an increase in hematocrit after placement of the LNG-IUD.^33

–38 A randomized controlled trial comparing COCs with a LNG-IUS for the treatment of fibroids showed the superiority of the LNG-IUD, but the COC still demonstrated a reduction in menstrual blood loss but no significant change in the volume of the tumors.³⁸

Heavy menstrual bleeding

Heavy menstrual bleeding (HMB), defined in research protocols as >80 mL of menstrual blood per cycle, is common, affecting up to 30% of women and directly related to 15% of all gynecology referrals.³⁹ Practically, it is difficult to measure amount of blood loss, so clinical parameters are measured instead, including length of bleeding (>7 days), interference in daily activities, and quality of life measures.⁴⁰ Specific etiology of HMB may not be identified in almost half of all women. Medical therapies are desirable to avoid unnecessary surgery.

Hormonal contraceptives have been used to manage HMB for many years.⁴¹ The best (and only FDA approved) hormonal method to control bleeding is the LNG-IUD.^39,42,43 The LNG-IUD works by local effect of progestin to induce thinning and atrophy of the endometrium. The LNG-IUD decreased HMB more than progestin-only methods or COCs, but not quite as much as endometrial ablation.^42,44 In studies, the LNG-IUD not only decreased bleeding but led to improved iron stores and quality of life.⁴⁴ Limited research has looked at progestin-only methods with other delivery systems.³⁹

COCs are also effective in decreasing blood loss in HMB but are inferior to LNG-IUD.³⁹ Different types of pills may have varying effects in managing HMB^18,45 possibly related to estrogen dose. Tranexamic acid is also FDA approved for treatment of HMB.

Management of general medical conditions

Bleeding disorders

Bleeding disorders are a relatively uncommon cause of HMB. A systematic review found that among women presenting with HMB, the average prevalence of von Willebrand disease was 13% (prevalence in individual studies ranged from 5% to 24%).⁴⁶ Good data suggest that LNG-IUD and COCs may be effective methods of treating HMB in this population.⁴⁷ Progestin-only contraceptives can also be used, but there are few studies looking at their effectiveness.⁴⁷

Acquired bleeding disorders, for example, cancer therapy that causes thrombocytopenia, can lead to significant HMB. Both combined hormonal methods as well as the use of the LNG-IUD are used to manage heavy bleeding and prevent the development of anemia.⁴⁷

Polycystic ovary syndrome

PCOS is a heterogeneous disorder of hormonal imbalance characterized by hyperandrogenism and multisystem metabolic dysfunction. It is the most common endocrinopathy among women of reproductive age and affects between 5% and 16% of the world's population. Although the exact interplay of hormonal dysregulation is poorly understood, insulin resistance appears to be a key feature contributing to many of the known comorbidities of PCOS. Hyperandrogenism (and possibly hyperestrogenism) causes the dermatological manifestations and contributes to anovulation.

CHCs are considered first-line medications in the management of menstrual abnormalities and dermatological manifestations (hirsutism, acne) of PCOS. They accomplish this through decreasing androgen levels via various mechanisms. Estrogen promotes synthesis of sex hormone binding globulin in the liver, which itself binds circulating androgens thereby decreasing bioavailable androgens in the bloodstream. Progestogens suppress LH and subsequently decrease ovarian androgen production. In addition, some progestogens have antagonistic effects on androgen receptors and may also inhibit 5α-reductase, preventing conversion of testosterone to dihydrotestosterone (a more potent androgen).

Although recent studies show that all COCs appear to have equal efficacy for PCOS,⁴⁸ characteristics of particular estrogens and progestogens lend themselves to PCOS treatment. Among available forms, EE, particularly doses of 20–35 μg daily, increases sex hormone binding globulin (SHBG) levels significantly more than alternative formulations or EE at lower doses.⁴⁹ Some progestogens (cyproterone, drosperinone, and chlormadinone) have antiandrogenic effects. The choice of monophasic, biphasic, or triphasic pill does not have an effect on androgen production and patient preference should be taken into account when choosing a formulation.

Addition of antiandrogens has been found to have little treatment benefit when added to CHCs in treatment of PCOS. However, antiandrogens such as spironolactone, flutamide, finasteride, or cyproterone may have a role as adjuvant treatments when used with progestogen-only contraceptives (including nonoral options) or nonhormonal contraceptives in women who cannot use CHCs.⁴⁹ Nonhormonal treatments such as metformin are also a mainstay of treatment for PCOS.

Acne

Acne is one of the most common skin conditions requiring medical treatment affecting 40–50 million people in the United States annually.⁵⁰ Acne is largely thought to be related to an increased rate of sebum production, which is predominantly controlled by androgenic sex hormones.^51,52 Hormonal therapies such as COCs are useful in the treatment of acne. Estrogens increase the binding of free testosterone by increasing the production of sex hormone binding globulin and decrease androgen levels via inhibition of ovulation to reduce sebum production. At the same time, progestins have antiandrogenic properties through competitive inhibition and minimize the risk of endometrial cancer associated with the use of unopposed estrogens.^53,54

A Cochrane review, including 31 trials with 12,579 participants, showed that COCs reduced acne lesion counts, severity grades, and self-assessed acne compared with placebo for a period of 3–4 months.⁵⁵

In the United States, three COCs have been approved by the Food and Drug Administration for treating moderate acne that contain the progestins norethindrone, norgestimate, and drospirenone combined with EE.⁵⁶

Acne is a commonly reported adverse effect of progesterone-only contraceptives that is related to progestin dose. Most women using the subdermal implant report either no change or an improvement in acne with just 10%–14% of users experience a worsening of symptoms.⁵⁷

DMPA can make acne worse, although it is uncertain if LNG-IUDs have the same effect.

COCs are rarely used as monotherapy for acne. In most instances, patients are already taking a combination therapy of topical retinoids, topical benzoyl peroxide, and antibiotics. In particular, COCs used in conjunction with spironolactone can be beneficial for acne in addition to decreasing the side effects of spironolactone, such as dysmenorrhea, irregular menses, and breast tenderness. In addition, adequate contraception is recommended during spironolactone therapy, as studies in rats have demonstrated feminization of male fetuses. Oral contraceptives can also reduce the acne flare ups that may occur related to menstrual cycles.⁵⁸

Proper contraceptive counseling is also imperative for pregnancy prevention when using isotretinoin in females of childbearing potential as the FDA-mandated iPLEDGE program stipulates that any female of childbearing potential must use two forms of highly effective contraception.⁵⁸

Migraines

Migraine is a disabling headache, characterized by moderate to severe head pain often with associated symptoms, including nausea, photophobia, phonophobia, and osmophobia. About 30% of migraine attacks are preceded by transient focal neurological symptoms called aura. Most commonly, auras consist of visual symptoms such as flashing lights, zigzag lines, or blind spots in visual fields.⁵⁹

Migraine affects ∼18% of women and 6% of men in the United States and Western Europe, and its cumulative lifetime prevalence is 43% in women and 18% in men.⁶⁰ Migraine tends to be most active during the fertile period of a female's life with a peak of prevalence in their 20s and 30s.⁶⁰ During these reproductive years, hormonal contraception of any kind (hormone-containing pills, patches, ring, shots, implants, or IUDs) is used by ∼43% of U.S. women who are using any type⁶¹ of birth control.

COCs may be used in majority of women with headache and migraine but do carry a small but significant vascular risk in patients that experience migraine with aura.⁶² The WHO medical eligibility criteria categorizes estrogen-containing contraception as contraindicated in women who have migraine with aura. All other forms of contraception are acceptable.⁶³

In women who experience migraine without aura, there may also be an increase in vascular risk in those women who have additional stroke risks, including smoking, hypertension, diabetes, hyperlipidemia, and thrombophilia, or age >35 years.^64,65 For women with these risk guidelines recommend progestogen-only contraception as an alternative safer option because it does not seem to be associated with an increased risk of venous thromboembolism and ischemic stroke. There is general consensus that progesterone-only contraceptives (including progesterone-only pills, implants, IUDs, and injectables) are safe for use in women who have migraine with aura, even in the presence of other risk factors for stroke.^57,62,66

Preconception health and pregnancy planning for the prevention of maternal morbidity and birth defects

Preconception care is an important health care strategy designed to help optimize a woman's health before conception to improve birth outcomes. In general, preconception care includes discussions about a woman's reproductive life plan, screening for health risks, optimizing health behaviors, updating immunizations, and recommendations for folic acid supplementation.⁶⁷ For women with chronic medical conditions, receipt of preconception health care is critical and should be integrated into their general health care especially for those treated with potentially teratogenic medications. Safe and effective contraceptive methods enable women to better time or avoid pregnancies, reduce exposure to teratogenic medications or viruses when conceiving, and receive treatment with teratogenic medications while avoiding potential exposure during pregnancy.⁶⁵ Although a detailed review of these complex medical settings is beyond the scope of this article, a few examples are mentioned as follows to highlight this important area.

Pregnancy timing or avoidance

Women diagnosed with serious medical conditions such as diabetes, cancer, collagen vascular diseases (such as systemic lupus erythematosus or rheumatoid arthritis), and others can time their pregnancies to begin during a period when their underlying condition is optimally controlled and thereby reduce maternal and fetal risk.^68
–70 For women with very high-risk health conditions, highly effective pregnancy prevention can be lifesaving. For example, some women with complex cardiac disease may have a high risk of mortality and pregnancy avoidance may be recommended.⁷¹ Women undergoing cancer treatment may also require effective contraception to prevent both potential risk of anomalies as well as avoid potential need for treatment delay and the associated increased risk to the mother.⁶⁹ Women who have had organ transplants require reliable contraception due to potential toxicity of medications⁷² prescribed to prevent rejection. It is usually recommended that they wait at least 1–2 years after the transplant to attempt pregnancy.⁷³

Use of highly effective methods, such as the LNG-IUD, copper IUD, or implant, provides safe contraception that enables women to avoid surgical sterilization. There is robust data to show that conception at a time of good glycemic control decreases the risk of fetal anomalies in women with diabetes.⁷⁴ Similarly, the tailoring of medications before conception can also reduce risk the risk of anomalies. For instance, women using antidepressants or antiepileptic drugs should review and tailor their medications before conception to minimize potential teratogenicity.^75,76

Teratogenic medications or viruses

Highly effective contraception enables women and their providers to balance of risk and benefit of some treatments for serious medical conditions that typically present during the reproductive years.³ For example, women with rheumatological disorders benefit greatly by the use of disease-modifying agents that require highly effective contraception during treatment.⁷⁰ Similarly, the use of isotretinoin to treat acne requires highly effective pregnancy avoidance although abstinence or the use of two contraceptive methods.⁷⁷ Another important use is to protect women during periods of exposure to potentially teratogenic viruses as in the recent public health response to the 2016/2017 Zika epidemic.⁷⁸

Conclusions

The availability of contraceptive methods containing estrogens and progestins are key to providing high-quality evidence-based general health care of women. In their role in cancer prevention, to managing both medical and gynecological conditions, to avoiding potentially devastating teratogenicity in women with chronic medical disorders and on high-risk medications, these hormonal medications play a key role in women's health. Access to hormonal contraceptive methods is crucial in taking care of women, and barriers to their use put the health outcomes of both women and infants at risk.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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