Hormonal Contraception for Complex Cases: Family Planning and Beyond

Educational Objectives

The goal of this program is to improve management of contraceptive use for patients with chronic medical conditions. After hearing and assimilating this program, the clinician will be better able to:

1. Utilize the United States Medical Eligibility Criteria for Contraceptive Use when counseling patients.
2. Understand the properties of progestin and estrogen hormones found in methods of contraception.
3. Describe the noncontraceptive benefits of hormonal contraception.

Summary

Menstrual cycle: early rise in follicle-stimulating hormone (FSH) levels recruits primordial follicles for ovulation; the primary follicle secretes estrogen and stimulates release of luteinizing hormone (LH) from the pituitary gland, which triggers ovulation; the corpus luteum secretes progesterone to maintain the endometrial lining (or induce menses with lack of pregnancy); estrogen promotes endometrial proliferation and development of the spiral arteries; estrogen negatively feeds back on FSH, and progesterone negatively feeds back on LH; the progestin component within combined oral contraceptive pills (COCPs) blocks the LH surge, inhibits ovulation, affects tubal transport, and thickens the cervical mucus; estrogen within COCPs decreases FSH, inhibits follicular growth, and maintains the endometrium, leading to cycle irregularity and decreased breakthrough bleeding (BTB)

Progestogens: include natural progesterone and synthetic progestins

Classification of progestins based on subclass: the pregnane subclass includes MPA and cyproterone acetate (unavailable in the United States); the norpregnane subclass includes nomegestrol acetate and segesterone acetate; estranes and gonanes are derived from 19-nortestosterone, though estranes have a methyl group at the 13-carbon and gonanes (eg, LNG, gestodene, etonogestrel, norgestimate) have an ethyl group at the 13-carbon; all estranes are converted to norethindrone (biologically active); dienogest is derived from estranes and pregnanes; DRSP is derived from spironolactone

Classification of progestins based on androgenic properties: LNG and norethindrone have more androgenic activity, while dienogest and DRSP have less androgenic activity and possess antiandrogenic properties; progesterone derivatives (eg, MPA, megestrol acetate) also have glucocorticoid properties and can cross-react with glucocorticoid receptors

Naturally-occurring estrogens: estrone (E1) — primary estrogen in menopause; not very potent; estradiol (E2) — most active during the reproductive years; the most potent naturally-occurring estrogen; secreted by ovarian granulosa cells after androgen aromatization; estriol (E3) — produced by the placenta and rapidly metabolized; estetrol (E4) — a fetal estrogen that is 30 to 35 times less potent than E2; recently synthesized for use in hormonal contraceptives; ethinyl estradiol (EE) — predominant hormone found in contraceptives; created by adding an ethanol group to E2, making it highly potent and resistant to first-pass metabolism; potent inducer of hepatic thrombotic factors and increases risk for venous thromboembolism (VTE) by increasing concentration of procoagulant factors and decreasing concentration of anticoagulant factors

Risk for VTE: Peragallo Urrutia et al (2013) noted 3-fold increased risk for VTE and 2-fold increased risk for ischemic stroke among patients currently using COCPs vs patients not currently using COCPs; risk for VTE is decreased for patients taking newer OCPs containing estradiol valerate (E2V) or E4, substances which raise D-dimer levels to a lesser extent than EE; nonpregnant women who do not use COCPs have an underlying risk for VTE of 1 to 5 per 10,000 woman-yr, compared with risk of 3 to 12 per 10,000 woman-yr among women using COCPs; the risk for VTE among pregnant women is 5 to 20 per 10,000 woman-yr; the risk for VTE among postpartum women is 40 to 65 per 10,000 woman-yr; studies have shown that OCPs containing dienogest, desogestrel, or drospirenone (DRSP) potentially have a 1.5- to 2-fold higher risk for VTE, compared with LNG; no data support that progestin alone increases VTE risk

Combined hormonal contraceptives (CHCs): suppress ovulation; typical-use failure rate is 7%; available as daily pill, weekly transdermal patch, or monthly vaginal ring; when comparing the vaginal ring, the transdermal patch, and a COCP containing 30 μg EE, van den Heuvel et al (2005) found that the transdermal patch produces the highest average serum levels of EE, and the vaginal ring produces the lowest average serum levels of EE; noncontraceptive benefits of CHCs include reducing androgen exposure, risks for endometrial cancer (EC) and ovarian cancer, and functional ovarian cysts, and improving acne, hirsutism, heavy menstrual bleeding (HMB), and premenstrual symptoms and dysphoria

US Centers for Disease Control and Prevention (CDC) contraceptive use recommendations: medical eligibility criteria (MEC) for contraceptive use (Curtis et al, 2016) — a series of guidelines that assess safety of use of contraceptives by patients with various medical conditions or based on select characteristics (eg, age, smoking status); level 1 grading indicates a contraceptive method that can be used without restrictions; level 2 grading indicates that the advantages of the contraceptive method outweigh the risks; level 3 grading indicates that risks usually outweigh advantages; level 4 grading indicates known unacceptable health risks; US selected practice recommendations (Curtis et al, 2016) — provide guidance regarding contraceptive initiation and management of side effects

Prescription of CHCs based on medical condition category: patients with medical conditions in categories 1 or 2 (conditions include, eg, history of gestational diabetes mellitus [GDM], any thyroid disorders, nonmigraine headaches, HIV, benign breast cysts, obesity, depression, adolescents, perimenopausal state) may safely take CHCs; patients with medical conditions in categories 3 or 4 (conditions include, eg, inherited thrombophilia, history of deep vein thrombosis or pulmonary embolism, severe uncontrolled hypertension, longstanding DM with vascular involvement, migraines with aura, smoking in individuals >35 yr old) may experience increased risks for myocardial infarction, cerebrovascular accident, and VTE with prescription of CHC

Polycystic ovarian syndrome (PCOS): characterized by oligomenorrhea, ovulatory dysfunction, hyperinsulinemia, and elevated LH levels (lead to hyperandrogenism); patients may become overweight or obese; patients have a 2- to 6-fold increased risk for EC, and they are also at increased risk for glucose intolerance, T2DM, and hyperlipidemia; risks increase for GDM, preterm birth, pre-eclampsia, stillbirth, and miscarriage; COCs — commonly prescribed for PCOS alongside lifestyle changes; reduce symptoms of hyperandrogenism (through increasing sex hormone-binding globulin [SHBG] levels), protect the endometrium, regulate menstrual cycles, and decrease menstrual abnormalities; choice depends on progestin type, antiandrogenic properties, and estrogen dose and type; COCs containing DRSP may be warranted for patients not receiving benefit from COCs containing an antiandrogenic progestin; a COC with low (≤35 μg) EE is preferable to one with high (50 μg or 100 μg) EE, though low EE formulations increase risk for BTB and decrease impact on SHBG levels; consider a COC containing E2V or E4; consider patient comorbidities and possible contraindications to estrogen, especially severe hypertension (may be associated with PCOS); Fraison et al (2020) showed that COCPs impart greater improvements in hirsutism, acne, and menstrual irregularities than metformin

Progestin-only therapy: recommended for endometrial protection and reduction of risk for EC in patients with contraindications to estrogen; POPs — available in the US as 0.35 mg norethindrone-only pill or 4 mg drospirenone-only pill (DOP); the DOP inhibits ovulation, can be used in a cyclic regimen to improve bleeding irregularities, and has greater efficacy, compared with the norethindrone-only pill (continuously taken; thickens cervical mucus), which has a greater failure rate and can produce BTB; subcutaneous DMPA — 150 mg is administered every 3 mo; suppresses ovulation; has a typical-use failure rate of 4%; benefits include decreased menstrual blood loss (MBL) and the highest rate of amenorrhea among all contraceptive methods; side effects may include weight gain, unpredictable bleeding patterns (especially initially), and prolonged return to fertility after discontinuation

Etonogestrel subdermal implant: approved by the US Food and Drug Administration for 3 yr of use; strongest inhibitor of ovulation and has the lowest typical-use failure rate of all contraceptive methods; irregular bleeding or spotting can occur and are the primary reasons for discontinuation; requires manufacturer certification for placement and removal, decreasing accessibility for some patients; complications are rare

Levonorgestrel IUDs: available in doses of 52 mg (most commonly prescribed; approved for 8 yr of use), 19.5 mg (approved for 5 yr of use) and 13.5 mg (approved for 3 yr of use); may cause unpredictable bleeding and spotting for the first 3 to 6 mo; the 52 mg dose is associated with the highest amenorrhea rates (20% at 1 yr, ≈40% at 3 yr), while other doses cause ongoing light bleeding and spotting

CHCs and comorbidities

Obesity: current US MEC guidelines emphasize safety of contraception in patients with body mass index (BMI) ≥30, though patients with BMI ≥40 may have greater risk for VTE; avoid DMPA injections secondary to glucocorticoid effects; Dinger et al (2011) noted an adjusted hazard ratio of 1.5 for contraceptive failure in women with BMI ≥35; efficacy of DMPA (may induce weight gain), IUDs, or barrier methods do not decrease, though efficacy decreases for the transdermal patch and oral emergency contraception; Zieman et al (2002) noted a significant association between baseline body weight of ≥90 kg and increased risk for pregnancy; consider a COC regimen with fewer placebo days to improve efficacy

Diabetes mellitus: ≥50 μg EE does not affect glucose control in patients with T1DM or T2DM; risks increase for individuals with vasculopathy or complications of microvascular disease (eg, nephropathy, retinopathy, neuropathy), which are considered class 3 or 4 medical conditions

Thyroid disorders: estrogen increases levels of thyroid-binding globulin in a dose-dependent manner in euthyroid individuals, though the resulting changes in free T3 and T4 levels are typically within the normal range and transient; any contraceptive method is considered safe for patients with thyroid disorders; menstrual suppression — consider menstrual suppression in women with thyroid disorders to decrease MBL and spotting; cyclic use of CHCs can result in a 40% to 50% reduction in MBL; DMPA has the highest amenorrhea rate, and the 52 mg LNG-IUD can decrease MBL by ≤90%

Readings

Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. selected practice recommendations for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No. RR-4):1–66. doi:10.15585/mmwr.rr6504a1external icon; Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(No. RR-3):1–104. doi:10.15585/mmwr.rr6503a1external icon; Dinger J, Do Minh T, Buttmann N, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol. 2011;117(1):33-40. doi:10.1097/AOG.0b013e31820095a2; Duijkers IJM, Heger-Mahn D, Drouin D, et al. Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake. Contraception. 2016;93(4):303-309. doi:10.1016/j.contraception.2015.12.007; Fraison E, Kostova E, Moran LJ, et al. Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome. Cochrane Database Syst Rev. 2020;8(8):CD005552. doi:10.1002/14651858.CD005552.pub3; Peragallo Urrutia R, Coeytaux RR, McBroom AJ, et al. Risk of acute thromboembolic events with oral contraceptive use: a systematic review and meta-analysis. Obstet Gynecol. 2013;122(2 Pt 1):380-389. doi:10.1097/AOG.0b013e3182994c43; Pfeifer S, Butts S, Dumesic D, et al. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril. 2017;107(1):43-51. doi:10.1016/j.fertnstert.2016.09.027; Robinson JA, Burke AE. Obesity and hormonal contraceptive efficacy. Womens Health (Lond). 2013;9(5):453-66. doi:10.2217/whe.13.41; Tepper NK, Curtis KM, Cox S, et al. Update to U.S. medical eligibility criteria for contraceptive use, 2016: updated recommendations for the use of contraception among women at high risk for HIV infection. MMWR Morb Mortal Wkly Rep. 2020;69:405–410. doi:10.15585/mmwr.mm6914a3external icon; Tepper NK, Whiteman MK. Clinical considerations for the use of hormonal contraception in obese women. Contraception. 2021:S0010-7824(21)00404-5. doi:10.1016/j.contraception.2021.08.011; van den Heuvel MW, van Bragt AJ, Alnabawy AK, et al. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72(3):168-74. doi:10.1016/j.contraception.2005.03.005; Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77(2 Suppl 2):S13-8. doi:10.1016/s0015-0282(01)03275-7.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Cohen's lecture includes information about the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Cohen was recorded at the Georgia Society of Endocrinology 2023 Annual Meeting, held February 3-4, 2023, in Atlanta, GA, and presented by the Georgia Society of Endocrinology. For information on future CME activities from this sponsor, please visit https://endoconnection.com/home. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

OB701302

Qualifies for:

Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.