Health Effects of Progestins Contained in Cocs, with A

A PHACTICAL JOURNAL FOR NUHSE PRACTITIONEn5 I i -

1- November 2007 The Official Journal of NPWHj- A 7 .-. Vol. G, No. 11 A Peer-Reviewed Journal &$

Health Effects of Progestins Contained in t COCs, with a -.'P Focus on

Norgestimate- -.-I. 21 ?

NPWH 2007 ' Annual Conference Abstracts HEALTH EFFECTS OF PROLESTINS CONTAINED IN COCs, WITH A FOGUS ON NORGESTIMATE

by Penelope M. Bosarge, MSN, WHNP

ased on interviews with more Nurse practitioners (NPs) and their reproductive-aged than 7600 female adolescents and women aged 15 to 44 patients face numerous challenges, particularly when it years, more than 98% who have comes to choosing a method of birth control. If a combined ever had sexual intercourse have used at least one contraceptive oral contraceptive (COC) is judged to be an appropriate meth~d.~The leading method of contraception in the United choice for a given woman, then her NP will need to select a States in 2002 was the Pill, used particular product from among many that are available. by 11.6 million women, and the second leading method was Among the various COC brands on the market, several female sterilization, used by 10.3 million women.2The condom contain norgestimate (NGM), a progestin introduced in was the third-leading method, 1992. Fvteen years of clinical use of NGM-containing used by about 9 million women and their partners. The condom COCs, as well as continued scientz$c investigations of these is the leading method at first intercourse, but the Pill is the products, support their efficacy, safety, and tolerability leading method among women (ie, these products have minimal androgenic and estrogenic younger than 30 yearse2 effects and provide excellent cycle control). NGM-containing Because COCs are a reversible form of contraception, they are a COCs also ofer a host of noncontraceptive benefits. Of note, good choice for younger women who want to postpone pregnancy NGM is the No. 1 prescribed progestin in COCs when or for women in their 20s or 30s brand-name and generic products are included.' All of these who wish to space their pregnancies a few or several years apart. findings provide the rationalefor this review article on the Unlike most prescription medica- progestins contained in COCs, with a focus on NGM. tions, which are intended for acute or short-term use, COCs may be used for many years or

November 2007 Vol. 6, No. 11 I I even decades. This length of time luteinizing hormone (LH) from dimethisterone, medroxyproges- translates into potential exposure the anterior pituitary gland." In terone acetate, NET or NET to hormone components of 20 to addition, progestins create a thick acetate (NETA), norethynodrel, 30 years or even longer. So, a cervical mucus that slows sperm or norgestrel. Levonorgestrel COC formulation that has proved transport and inhibits capacita- (LNG) was then developed, and to be effective, safe, and well tol- tion (activation of enzymes per- served as the main progestin erated over the long term is likely mitting sperm to penetrate the ingredient in COCs through to be used successfully. ovum) .I1Progestins also affect 1989." By contrast, women are less likely cilia in the Fallopian tubes, Eight Progestins Used in COCs to continue using a COC that is decreasing the intensity and fre- Today-In 2007, eight progestins associated with unwanted side quency of their action. The result with various structures, biologic effects (eg, estrogenic effects may be a slowing effect on the activities, and clinical effects, are such as breast tenderness, nausea, rate of ovum tran~port.'~Finally, used in COC formulations in this and bloating or androgenic side progestins alter the lining of the country (Figure l).l5.I6Seven of effects such as hirsutism and uterus and make it more difficult the eight progestins are 14 acne):" or with a relatively higher for the fertilized egg to implant.12 nortestosterone derivatives classi- rate of unscheduled bleeding fied as first-generation estranes (now the preferred term for BRIEF HISTORY OF PROGESTINS (NET, NETA, and ethynodiol breakthrough bleeding/spotting diacetate) , second-generation [BTB/BTS] or intermenstrual The first synthetic progestins, gonanes (norgestrel and LNG), bleeding) ." Of note, cycle con- norethindrone (NET) and or third-generation gonanes (des- trol is affected not only by estro- norethynodrel, were introduced ogestrel [DSG] and NGM). An gen dose, but also by patient in the 1950s, fueling the emerg- older progestin, norethynodrel, is characteristics and progestin dose ing contraceptive industry. In not commonly prescribed because and type.g 1960, the first COC on the mar- of its high estrogenic activity and ket contained 9.85 mg of pro- Thus, NPs who will be making is not discussed further in this gestin.'"~ the mid-1970s, COCs prescribing decisions need to article. The eighth progestin avail- understand the differences available in the United States able in the United States is among the progestin components contained one of these pro- drospirenone (DRSP) , an analog of COCs to properly assess the gestins: ethynodiol diacetate, of spironolactone, a potassium- risk/benefit ratio for each woman based on her overall health status and her predisposition for certain health-related conditions. NPs also need to continually assess each woman's health, personal needs, and preferences at each office visit to make sure that her COC regimen continues to be a safe and appropriate choice. PROGESTINS' MECHANISM OF ACTION COCs prevent pregnancy primar- ily by inhibiting ovulation through the combined actions of progestin and estrogen.'"The dominant component is progestin, which inhibits ovulation by suppressing the cyclical release of

10 Women's Health Care: A Practical Journal for Nurse Practitioners sparing diuretic. DRSP has a molecular structure and activity TABLE 1. H RELATIVE HORMONAL ACTIVITIES OF SELEC'TEO PROGES'IINS'g~'u profile that differ markedly from those of the other progestins." Progestin Progestational Effects Androgenic Effects Just as an aside, experts in the sci- Estranes entific and healthcare communi- Norethindrone Olt, t, or tt Olt or t ties do not necessarily agree on Norethindrone acetate tt ttt the classification of the different Ethynodiol diacetate tt t progestins by generation (ie, second or third generation) .".'Most Gonanes (Second-Generation) experts base this classification on Norgestrel t or tt tt or ttt the time of the introduction of a Levonorgestrel t t or tt new parent compound, but some base it on structural and physio- Gonanes (Third-Generation) logic differences or efficacy. Desogestrel ttt 01 t Thus, NGM is sometimes classi- Norgestimate Olt Olt fied as a second-generation progestin because it derives most of Spironolactone Derivative its activity from LNG, but it is also Drospirenone 01 t 0 classified as a third-generation progestin because it is relatively 0 = no activity; Olt = low activity; t = medium activity; tt = high activity; ttt = very high activity. newer than other progestins and because it has minimal androgenic effects compared with LNG and norgestrel. predisposed to the development sutism. Also, progestins with of certain disorders.'" greater androgenic activity tend Spectrum of Progestins' to have a relatively more deleteri- Hormonal Activities-Synthetic Androgenic properties. Andro- ous effect on lipid and carbohy- progestins used in COCs differ genicity is determined by the abil- drate metabolism. not only in their hormonal ity of a progestin to bind to potency, but also in their spec- androgen receptors-that is, its Progestins with androgenic prop- trum of hormonal activities.'" androgenic relative binding affin- erties may counteract favorable Beside their progestogenic and ity. Sex hormone-binding globu- ethinyl estradiol (EE)-induced anti-estrogenic effects, contra- lin (SHBG), a glycoprotein, binds changes in lipoprotein metabo- ceptive progestins may exert androgens and prevents expres- lism, but they do not cause ather- estrogenic, androgenic, anti- sion of androgenic activity. osclerosis in the presence of EE.'" androgenic, glucocorticoid Estrogen stimulates SHBG On the other hand, COCs con- and/or antimineralocorticoid release. Some progestins bind to taining androgenic progestogens effects (Tables 1 and 2) .'wo As a SHBG--leaving more androgens that attenuate EE-dependent consequence, progestins may "freen-thereby leading to andro- changes in hemostasis may be affect various metabolic parame- genic side effects. Newer proges- associated with a lower risk of ters and modulate estrogen- tins (eg, NGM, DSG, DRSP), as venous thromboembolic disease induced alterations in lipid compared with older progestins, than are COCs whose progestins metabolism, hemostasis, and vari- compete less for SHBG and are have a less androgenic pr~file.'~ ous other factors. For most therefore less androgenic. Pro- Progestins with androgenic activ- women, the differences in the gestins with higher androgenic ity may also antagonize estrogen- hormonal pattern of progestins activity (eg, NETA, norgestrel) induced alterations in various used in COCs are without clinical are more likely than other pro- other hepatic proteins and modu- consequence, but these differ- gestins to have androgen-related late the effect of EE on growth ences may be relevant for wornen side effects such as acne and hir- factors.'%y contrast, progestins

November 2007 Vol. 6, No. 11 I Progestin Co~nments

Norethindrone NET is a first-generation progestin with low progestational and slight estrogenic activity. NET tends to be less androgenic than the second-generation progestins (LNG and norgestrel) but more androgenic than newer progestins such as DSG and NGM. It is available in monophasic, biphasic, and triphasic formulations. In CDCs containing low doses of EE (40 pg), this progestin improves lipid profiles by raising HDL-C and lowering LDL-C.

Norethindrone acetate Like NET, NETA is a first-generation progestin with low progestational activity and few estrogenic effects. NETA tends to be less androgenic than the second-generation progestins but more androgenic than newer progestins. Estrostep, an NETA-containing CDC, provides increasing levels of estrogen, which may be helpful for women who experience minor estrogenic effects such as nausea, migraine, or fluid retention, and a constant dose of progestin. Loestrin 24 Fe has 24 days of active pills containing NETAIEE and 4 days of inert pills, which may cause fewer hormone fluctuations than other COCs but may not necessarily improve cycle control. OP" Ethynodiol diacetate Ethynodiol diacetate is a first-generation progestin with intermediate progestational activity, minor estrogenic effects, levt and liale androgenic activity. Ethynodiol diacetate is a derivative of NET. Compared with other CDCs, those containing P roi u tel ethynodiol diacetate tend to be associated with a higher rate of unscheduled bleeding events. lack Levonorgestrel LNG is a second-generation progestin with high progestational and androgenic effects. LNG has an adverse effect on rect serum lipoproteins. Several COCs containing low-dose EE and LNG are available. 'The FDA has approved three extended- the1 cycle COCs that use this progestin: Seasonale, Seasonique, and Lybrel. UIlH effe Norgestrel Norgestrel, a second-generation progestin, has high progestational and strong anti-estrogen effects while also being tor high in androgenic activity. Norgestrel may raise LDL-C and lower HDL-C, two potentially harmful effects. clos Pr? Desogestrel DSG is a third-generation progestin with high progestational selectivity, minimizing androgenic effects and estrogenic activity. Relative to older progestins, DSG has a less adverse impact on metabolism, weight gain, and acne, and has Ant favorable effects on lipoproteins, including HDL-C. Clinical trials show a possibly higher risk of nonfatal venous thrombo- Proi e ffe sis with DSG-containing COCs compared with LNG-containing formulations. Mircette, which contains low-dose EEIDSG, toq provides a shorter placebo interval, which may be helpful for women with migraines, dysmenorrhea, or other adverse con events during the HFI. Cyclessa, which contains triphasic DSG, is one of two COC formulations that contain EE 25 lg. era1 Norgestimate NGM, a third-generation progestin, has high progestational activity, few estrogenic effects, and minimal androgenicity. aldc NGM has minimal effect on serum lipoproteins or carbohydrate metabolism. With its low androgenicity, an NGM-contain- tion ing product (Ortho Tri-Cyclen) was the first COC approved to treat acne. Ortho Tri-Cyclen Lo, which contains triphasic Am1 NGM, is one of two COC formulations containing EE 25 pg. Compared with COCs that contain other doses of EE, this COC Des formulation may find the "sweet spot" between avoiding estrogenic side effects and maintaining cycle control. accc the! Drospirenone DRSP, the only progestin derived from the potassium-sparing diuretic spironolactone, has antiandrogenic and antiminer- to tl alocorticoid effects. Use of DRSP may cause higher potassium levels, so women with kidney, liver, or adrenal disease mor should not use it. The brand YAZ has 24 days of active pills and 4 days of inert pills, which may cause fewer hormone low1 fluctuations than other COCs but may not necessarily improve cycle control. YAZ has also been FDA approved to help achr treat PMDD and to treat acne in females aged 14years or older. tion bipl NET = norethindrone; LNG = levonorgestrel; OSG = desogestrel; NGM = norgestimate; COC = combined oral contraceptive; EE = ethinyl estradiol; HDL-C = high-density lipoprotein cholesterol; end LDL-C = low-density lipoprotein cholesterol; NETA = norethindrone acetate; FDA = Food and Drug Administration; HFI = hormone-free interval; DRSP = drospirenone; PMOD = premenstrual gest dysphoric disorder. ing user

12 Women's Health Care: A Practical Journal for Nurse Practitioners Nove with anti-androgenic activity may effects. Virtually every COC on with the positive metabolic enhance the beneficial effect of the market contains the same syn- actions of estrogens, notably the EE in women with hyperandro- thetic estrogen-EE-at a dose estrogen-induced increase in genic manifestations.'" ranging from 20 pg to 50 pg per high-density lipoprotein choles- pill. (A few products contain mes- terol (HDLC) levels." COCs con- Progestational effects. Proges- tranol, the first estrogen used in taining NGM/EE increase the tational effects depend on a pro- COCs, but they are not discussed serum concentration of SHBG gestin's ability to stimulate in this article.) The amount and threefold, thereby augmenting progesterone receptors, thereby the dosing schedule of EE affect helping to prevent ovulation and the binding of circulating testos- the adverse-event profile and tol- lessen menstrual bleeding. A sim- terone and reducing free testos- erability of a COC too, but these ilar term is progestational selec- terone levels by 50%.24As a differing effects are also beyond tivity, which is the degree to consequence, COCs with NGM the scope of this article. Table 3 which progestational effects are are therapeutic for hyperandro- lists a broad variety of COCs cur- maximized and androgenic genic symptoms such as acne, hir- rently on the market. effects are minimized. Thus, an sutism, and alopecia.242" optimal COC achieves a high Progestational Effects-Like level of progestational selectivity. DSG, another third-generation Progestins with high affinity for The chemical structure (Figure progestin, NGM has a higher uterine progestin receptors and a 2),".22biologic activity, and phar- affinity for progesterone recep- lack of affinity for androgen macokinetics of NGM and its tors than do their predecessor^.^^ receptors are desirable because metabolite norelgestromin distin- Therefore, only a low dose of they are associated with fewer guish them from other proges- NGM is required in COCs to unwanted androgenic side tins. NGM is a 19-nortesterone effectively inhibit ovulation and effects. High progesterone recep- derivative of the gonane family.25 control uterine bleeding.2"n tor selectivity confers activity Norelgestromin, NGM's major triphasic (tri-)NGM/EE formula- closely resembling that of natural metabolite, is responsible for tions, the total monthly load of progesterone. most of its progestogenic activ- progestin is only 4.5 mg.24 ity.20Norelgestromin reaches Antimineralocorticoid activity. Effects on Lipid and Carbo- mean peak concentrations within Progestins with glucocorticoid hydrate Metabolism-Like DSG, 1.5 hours and has a half-life effects may increase procoagula- NGM is neutral in terms of its exceeding 24 hours.24A small tory activity in the vessel wall. By effects on lipid and carbohydrate percentage of NGM is metabo- contrast, progestins with antimin- metabolism.2w27In general, pro- eralocorticoid activity may reduce lized to norge~trel.~~NGM is gestins can induce two types of aldosterone-induced water-reten- highly bioavailable when adminis- adverse effects: changes in lipid tion in some women.16 tered orally. metabolism and bleeding irregu- Amount of Progestin and Dosing Lack of Androgenic Effects- laritie~.'~The newer compounds Design-COCs vary not only NGM has a low androgenic such as NGM and DSG seem to according to the type of progestin impact and does not interfere have overcome the first of these they contain, but also according to the amount of progestin. he more selective a progestin is, the lower the dose that is required to achieve the desired progesta- Only a low dose of NGM is required tional effects. In addition, a biphasic or triphasic design COCs to effectively inhibit ovulation enables a lower amount of progestin to be used overall, decreas- and control uterine bleeding. ing the likelihood that a COC user will experience androgenic

November 2007 Vol. 6. No. 11 13 TABLE 3.1SELECTED COMBINED ORAl CONTRACEPTIVE FORMUlATI[INS

Brand Name EE Dose (pg) Progestin and Dose (mg) Dosing Days* EE 50/Monophasic Progestin Ovral, Ogestrel 0.5150 50 Norgestrel0.5 2117 Ovcon-50 50 Norethindrone 1 2117 Demulen 1/50, Zovia 1150E 50 Ethynodiol diacetate 1 2117 Monophasic or Biphasic EE 30 or 35lMonophasic Progestin Apri, Desogen, Ortho-Cept 30 Desogestrel0.15 2117 Demulen 1/35, Zovia 1135E 35 Ethynodiol diacetate 1 2117 Levlen, Levora, Nordette-21, Portia 30 Levonorgestrel0.15 2117 Seasonale 30 Levonorgestrel 0.15 8417 Seasonique 30110 Levonorgestrel0.15 8417' LoIOvral, Low-Ogestrel, Cryselle 30 Norgestrel0.3 2117 Loestrin Fe 1.5130, Junel Fe 1.5130, Microgestin Fe 1.5130 30 Norethindrone acetate 1.5 2117 Necon 1/35, Norinyl 1 t 35, Nortrel 1/35, Ortho-Novum 1/35 35 Norethindrone 1 2117 Ortho-Cyclen, MonoNessa, Sprintec 35 Norgestimate 0.25 2117 Brevicon, Modicon, Nortrel 0.5135 35 Norethindrone 0.5 2117 Ovcon-35, Femcon Fe, Balziva 35 Norethindrone 0.4 2117 Yasmin 30 Drospirenone 3 2117 Monophasic or Biphasic EE 20lMonophasic Progestin Alesse, Aviane, Lessina, Levlite 20 Levonorgestrel0.1 2117 Mircette, Kariva 20110 Desogestrel0.15 211512' Loestrin Fe 1/20, Microgestin Fe 1/20, Junel Fe 1/20, Loestrin 21 1/20 20 Norethindrone acetate 1 2117 Loestrin 24 Fe 20 Norethindrone acetate 1 2414 YAZ 20 Drospirenone 3 2414 Lybrel 20 Levonorgestrel0.09 36510 Monophasic EE 35lBiphasic Progestin Necon 10/11, Ortho-Novum 10111 35 Norethindrone 0.5 on days 1-10 and 1 on days 11-21 10/11/7 Monophasic, Biphasic, or Triphasic EEflriphasic Progestin Ortho Tri-Cyclen Lo 25 Noryestimate 0.18 on days 1-7,0.215 on days 8-14,0.25 on days 15-21 7/7/7/7 Ortho Tri-Cyclen, Tri-Previfem, TriNessa, Tri-Sprintec 35 Norgestimate 0.18 on days 1-7,0.215 on days 8-14,0.25 on days 15-21 7/7/7/7 Ortho-Novum 71717, Necon 71717 35 Norethindrone 0.5 on days 1-7,0.75 on days 8-14,l on days 15-21 7171717 Tri-Norinyl 35 Norethindrone 0.5 on days 1-7,l on days 8-16,0.5 on days 17-21 7191517 Enpresse, Tri-Levlen, Trivora, Triphasil 30 on days 1-6,40 on days Levonorgestrel0.05on days 1-6,0.075 on days 7-11, 7-11,30 on days 12-21 0.125 on days 12-21 6/5/10/7 Estrostep 21, Estrostep Fe 20 on days 1-5,30 on days Norethindrone 1 51611 017 6-12,35 on days 13-21 Cyclessa 25 Desogestrel0.1 on days 1-7,0.125 on days 7171717 8-14,0.15 on days 15-21

'Active pillslinert pills or no pills.'EE 10 pg only for days 85-91 of cycle;'EE 10pg on days 22.26 of cycle, inert pills on days 27 and 28 of cycle. EE = ethinyl estradiol.

14 Women's Health Care A Practical Journal for Nurse Pract~t~oners

-- - - - adverse effects; they are less likely to alter lipid and carbohydrate metab~lism."~~'In addition, proper cycle control can be achieved by adding EE-in just the "right" amount (see section on Con~parativeStudies of Efficacy, Safety, and Cycle Control in the far right-hand column). Antimineralocorticoid Effects- DRSP, the newest progestin available in COCs, is an antimineralocorticoid steroid with no androgenic effect and a partial antiandrogenic effe~t.'~The antimineralocorticoid property leads to decreased salt and water retention and an antihypertensive effect." In theory, the use of DRSP-containing COCs could indexes were 0.55 and 0.37, pg and in 3/43 (7%) women on lead to h~perkalemia.~~However, respectively. In a much larger NGM 180/215/250 pg/EE 35 pg. studies have not demonstrated an study, Runnebaum et a1 assessed Comparative Studies of Efficacy, increased incidence of electrolyte the efficacy of monophasic Safety, and Cycle Control- problems in users, and concern NGM/EE in 59,701 women over Results of comparative studies for this issue is likely reserved for 342,348 menstrual cycles; 42,022 evaluating the efficacy, safety, and women with unique and easily women completed the planned cycle control of various COC regi- identifiable health conditions treatment regimen of 6 cycles." A mens have indicated that similar (eg, chronic use of nonsteroidal use-efficacy (overall) Pearl index efficacy, better cycle control, and anti-inflammatory drugs, renal of 0.25 pregnancies per 100 similar side effects can be disease) that would preclude the woman-years was calculated based achieved with NGM/EE regimens use of any estrogen-containing on 342,348 cycles. contraceptive." versus other progestin/EE regi- More recently, LaGuardia et al mens.33,.1114 For example, Contraceptive Efficacy of NGM conducted a randomized, multi- Hampton et a1 compared two When Combined with EE- center, parallel-group study of COCs, NGM 180/215/250 pg/EE Results of efficacy studies of five NGM/EE-containing regi- 25 pg (Ortho Tri-Cyclen Lo; n = NGM/EE-containing COCs have mens, including NGM 1723) and NETA 1 mg/EE 20 pg shown that this hormone combi- 180/215/250 pg/EE 35 pg (the (Loestrin Fe 1/20; n = 1171), nation provides excellent contra- formulation contained in Ortho with respect to these outcomes." ceptive efficacy for women Tri-Cyclen), NGM 180/215/250 Women were treated for up to desiring reversible contracep- pg/EE 25 pg (the formulation 13 cycles. Contraceptive efficacy tion.""' For example, Gauthier et contained in Ortho Tri-Cyclen and safety were similar for the a1 evaluated the efficacy of tri- Lo), and three other cyclophasic two COCs. The overall and NGM/EE over 12 months in 661 regimens." Ovulation suppression method failure probabilities of women; 2 pregnancies ascribed to was similar among all five regi- pregnancy through 13 cycles were product failure occurred in a total mens. Presumed ovulation 1.9% and 1.5%.respectively, with of 651 1 treatment cycle^.^' The (serum progesterone levels 23 tri-NGM/EE 25 pg and 2.6% and life-table predicted pregnancy rate ng/rnL during days 19-21 of cycle 2.4%, respectively, with NETA was 0.57 per 100 woman-years of 3) occurred in 0/41 (0%)women 1 mg/EE 20 pg. However, BTB/ use. Overall and theoretical Pearl on NGM 180/215/250 pg/EE 25 BTS was reported by a significantly

Id November 2007 Vol. 6, No. 11 lower proportion of tri-NGM/EE 25 users than NETA 1 mg/EE 20 to users. At cycles 1, 3, 6, 9, and 13, fin BTB/BTS rates were 16.3%, be 11.5%, 10.3%, 7.9%, and 7.7%, hi1 respectively, 1 the: tri 'EE C( 25 group an 34.9%, COI . 22.2%, 15.9%, and 13.1%, respec- C( tively, in the N 'ETA 1 mg/EE 20 N( group (Figure 3) .,' m Unscheduled bleeding is a com- fac mon problem for COC users, although few randomized con- WO trolled trials have compared the bo1: different COC formulations in dis this regard.45A recent review con- US( cluded that ultra-low-dose EE (20 CP pg)-containing COCs conlpared He

less favorably with higher-dose EE- 2 Uf - -0 containing COCs, both in terms COI of unscheduled bleeding and other effects. But the choice some studies, COCs containing CUI amen~rrhea.~Theinvestigators should also reflect the impact NGM have been associated with a va5 also concluded that different that the formulation nlay have on low risk or no increased risk.49In 2 brt types of progestins, along with the the woman's current health status other studies, NGM-containing no! EE dose, could contribute to and risk factors for certain dis- COCs have been associated with lar these finding~.~Wfinterest, even eases. Because the progestins in less VTE risk than that linked to ti01 a modest increase in EE dose (ie, different COCs vary in terms of COCs containing progestins such he1 the 25-pg dose used in Ortho Tri- their potential effects on certain as DSG0.51 or they have been asso- ha\ Cyclen Lo) may lead to improved health parameters, NPs need to ciated with indeterminate risk.4' P ra cycle control, as seen in the afore- consider the risk/benefit ratio Still other studies have demon- ind mentioned study by Hanlpton et when choosing an appropriate strated an increased WE risk bea al.ll As mentioned earlier, COC for each woman. linked to NGM-containing easl unscheduled bleeding is a leading COCs," which may be related to Effects on Venous Thrombo- Hei cause of COC di~continuation."~ acquired APC resi~tance.~'~~' embolism (VTE) Risk and Better cycle control can increase CV Hemostasis-Although the estro- In the study by Jick et al, which NP! users' satisfaction and success with gen component of COCs is was based on 281 newly diagnosed their COC, and ultimately lead to Pot largely responsible for the ele- idiopathic cases of VTE and 1055 effe more consistent use and better vated risk of VTE associated with controls, the incidence rates of contraceptive efficacy. Pee use of these products," progestins WE were 30.6, 53.5, and 27.1 per pre, may also increase WE Gsk. The 100,000 woman-years for users of In r PO'TEN'I'IAL EFFECTS OF PROGESTINS, reported increased risk associated NGM-, DSG and LNGcontaining birt INCLLI[IING NGM, [IN HEALTH with some second- and third-gen- COCs, re~pectively.'~Incidence intr PARAME'TERS eration progestins remains con- rate ratios for NGM/EE and tin- troversial, and study results are DSG/EE versus LNG/EE were 1.1 to I Choosing a specific COC formu- inconsistent and conflicting (eg, and 2.0, respectively. Thus, the use lation for a given wonlan is based use of these agents may be associ- risk of nonfatal WE in DSG/EE wi tl partly on what an NP knows ated with an increased WE risk users was significantly elevated iscl about the product's estrogenic, but a reduced risk of myocardial compared with that in LNG/EE of I progestational, androgenic, and infarction [MI] and stroke).4Vn users, and the risk of nonfatal ]OM

16 -Women's Health Care: A Practical Journal for Nurse Practitioners Nov VTE in NGM/EE users was similar taining one of the newer proges- low-dose COCs, one containing to that of LNG/EE users. These tins, including NGM.48,"NPs tri-NGM/EE 35 pg (Ortho Tri- findings are of particular interest should note that CVD occurs Cyclen) and one containing because the amount of EE was mainly among COC users who monophasic NETA/EE 20 pg higher in the NGM-containing smoke or have predisposing fac- (Loestrin Fe 1/20) ." Tri- COCs (35 pg) than in the DSG tors such as age >35 years, over- NGM/EE, compared with containing or LNGcontaining weight/obesity, diabetes, and/or NETA/EE, had a significantly COCs (30 pg). hyperten~ion.~',~' more beneficial effect on HDL-C (median change from baseline to NGM has been found to exert Stroke." Studies evaluating COCs cycle 6, +4.5% vs -4.0%; P1.OO1). minimal effects on coagulation and stroke are difficult to inter- Although the LDL-C/HDLC factors." Nevertheless, the pack- pret because they are generally ratio increased in both groups, a age inserts for COCs state that small, do not differentiate smaller increase was noted in the women with a history of throm- between hemorrhagic and throm- tri-NGM/EE group than the bophlebitis or thromboernbolic boembolic stroke, and do not NETA/EE group (6.7% vs 14.3%; disorders are not candidates for include controls for major risk P<.001). use of these medications. factors. Most evidence suggests no CardiovascuIar/Cerebrovascular increased risk for stroke among NPs should keep in mind that a Health-According to COC pack- ever or current users of COCs, beneficial or deleterious effect of age inserts, the use of COCs is with the exception of smokers, a progestin on lipids does not contraindicated in women with a and, possibly, women with necessarily translate into a similar current or past history of cardio- migraines with aura. Risk factors effect on CVD or cerebrovascular vascular disease (CVD) or cere- such as hypertension and diabetes disease risk." But if research even- brovascular disease. COCs should contribute far more significantly tually supports a connection not be used in women with valvu- to stroke risk than does COC use. between an improved lipid profile lar heart disease with complica- Although the risk of stroke with and a reduced vascular disease tions. But the story does not end COC use is low, it is not zero. risk, then even a small perturba- here, because certain COCs may Women who develop persistent tion of vascular disease risk in have beneficial effects on lipid severe headaches or other possi- either direction (as a result of profiles, although no evidence ble signs of stroke while taking long-term COC use) would have indicates that this benefit has any COCs should discontinue them epidemiologic consequences, bearing on future vascular dis- and see their NP immediately for given that more women die of ease risk. further evaluation. Women who CVD than all cancers or any other have a his tory of migraine with single cause ~ombined.~" Heart disease. For women with aura should be carefully evaluated CVD or an increased risk of CVD, Blood pressure. COC use is asso- before COC use. NPs must consider not only the ciated with the development and potential adverse cardiovascular Lipid profile. A progestin's exacerbation of hypertensi~n.~'~~~ effects of COCs, but also the androgenicity is responsible for No studies indicate that one type potential adverse effects that its effects on lipids and is directly of COC formulation is any more pregnancy can have on the heart. associated with a decrease in or less harmful in this regard. In many of these cases, a better HDL-C, an increase in low-density Thus, NPs should monitor blood birth-control choice is an lipoprotein cholesterol (LDL-C), pressure on a regular basis in all intrauterine device or a proges- and an increase in triglycerides. COC users. tin-only contraceptive. According In other words, the more andro- Carbohydrate Metabolism and to package inserts for COCs, the genic a progestin, the more Diabetes--In theory, COCs may use of these agents is associated harmful effects it has on a impair carbohydrate metabolisnl with an increased risk of MI and woman's lipid profile. Sulak et a1 and glucose tolerance.ll In prac- ischemic stroke. However, the risk led a six-cycle, multicenter, open- tice, however, several studies have of MI or ischemic stroke may be label, randomized study compar- shown that COCs have little, if lower with the use of COCs con- ing the clinical effects of two any, effect on carbohydrate

November 2007 Vol. 6, No. 11 PROGESTINS - FOCUS ON NORGESTIMATE

use. Among studies that provided data on nulliparous and parous melower the EE dose and the less women separately, COC use was androgenic the progestin, the smaller associated with breast cancer risk in both parous (OR, 1.29) and effect the formulation will have on nulliparous (OR, 1.24) women. Longer duration of COC use did carbohydrate metabolism. not substantially alter risk in nulliparous women (OR, l .29). Among parous women, the associ- ol ation was stronger when OCs br metabolism and that they do not persons with diabetes at year 10 were used before first full-term hi differ significa~ltlyfrom each was small (n = 17). pregnancy (FFTP; OR, 1.44) than tll other in this regard."" In gen- Breast Cancer-COC use does after the FFTP (OK, 1.15). The wil eral, the lower the EE dose and not appear to increase the risk of association between COC use and br the less androgenic the progestin, breast cancer significantly- breast cancer risk was greatest for Mir the smaller effect the formulation regardless of the dose, duration parous women who used OCs 4 ca will have on this ~arameter.'~ of use, or female's age- at use- or nlore vears before the FFTP as! Although COCs can be used in even in women with a family his- (OR, 1.52). In an editorial in women with diabetes, they should tory of breast cancer." Breast accompanying the study by wa be used with caution. The cancer risk is reasonably expected Kahlenborn et al, Mayo Clinic in1 American College of Obstetri- to be lower in users of COC for- epidemiologist James Cerhan sig mulations that contain relatively re! cians and Gynecologists recorn- pointed out that although the L mends that use of COCs in lower doses of estrogen and rela- link between COC use and early ! lo1 women with diabetes be limited tively less androgenic progestins breast cancer appears real, the 1 at1 such as NGM. Because of conflict- to those who do not smoke, are risk is still quite small." i th younger than 35 years, and are ing reports over the decades that 11t otherwise healthy (ie, those show- COCs have been studied, most, if > Marchbanks et a1 conducted a fil ing no evidence of hypertension, not all, COC package inserts cau- population-based, case-control ca nephropathy, retinopathy, or tion that the risk of having breast study to determine the risk of other vascular diseases) ." In the cancer diagnosed may be slightly breast cancer among former and CARDIA (Coronary Artery Risk increased among current and current u5ers of COCs (Table 4) .'' Development in Young Adults) recent COC users, but that this The investigators interviewed study, researchers studied the excess risk appears to decline women aged 35 to 64 years: a associations between current use over time after the COC is discon- total of 4575 women had breast of COCs and glucose levels, tinued. By 10 years after cessa- cancer and 4682 served as con- insulin levels, and diabetes in tion, this excess risk disappears. A trols. The relative risk (RR) of 1940 African American and descriptioil of several recent stud- having breast cancer was 1.0 for Caucasian wornen aged 18 to 30 ies shows the status of scientific current COC users and 0.9 for years.'" After adjustrrlent for evidence to date: past COC users. The RR did not covariates, current use of COCs * Kahlenborn et a1 pel-formed a rise consistently with longer peri- was associated with lower fasting rneta-analysis of case-control ods of use or with higher EE glucose levels (-1.8 mg/dL) and studies addressing whether past doses. Results were similar among a lower odds of developing dia- COC use is associated with pre- white women and black women. betes (odds ratio [OR], 0.56), but menopausal breast cancer.j2The Use of COCs by women with a higher insulin levels (0.12 researchers found that COC use fanlily history of breast cancer iiU/mL). No association existed was associated with an increased was not associated with an between pattern of COC use and risk of premenopausal breast can- increased risk of breast cancer, incident diabetes at year 10, cer in general (OR, 1.19) and nor was the initiation of COC use although the total number of new across various patterns of COC at a young age.

Women's Health Care: A Practical Journal for Nurse Practitioners B- Silvera et a1 analyzed the asso- tically significant. These data cancer, with risk reductions of ciation between COC use and raise the possibility that relatively 50% to 60%. As with ovarian can- breast cancer risk in 27,318 long duration of COC use may be cer, the benefit appears to women in the Canadian National inversely associated with breast increase with duration of use." Breast Screening Study who cancer risk in women with a film- This protective effect has been reported a family history of breast ily history of the disease. shown to continue for 20 years or more after COC cessation." cancer on enrollment into the Gynecologic Cancers and Overall COCs have also been shown to st~idy."Duringa mean of 16.0 Cancer-One of the most irnpor- protect users against colorectal years of follow-up, the researchers tant benefits of COC use is a observed 1707 incident cases of cancer risk.'" . . reduction of ovarian cancer breast cancer in women with any risk.l,A~~~~~ cOc users, the A 2007 large British cohort study history of breast cancer: 795 of overall risk for developing. - ovar- evaluated the absolute risks or these cases occurred in women ian cancer is 40% to 80% lower benefits on gynecologic cancers with a first-degree relative with than that among nonusers." This and any cancers associated with breast cancer. Among women protective effect appears to COC use." The main data set with any family history of breast increase with longer duration of contained -339,000 woman-years cancer, ever use of COCs was COC use and continues for at of observation for never users associated with a 12% reduction least 15 years after COC discon- and -744,000 woman-years for in breast cancer risk, and there tinuation.'' Although some bene- ever users. Compared with never was an inverse trend with increas- fit may accrue to women taking users, ever users had significantly ing diiration of use of borderline COCs for as little as 3 to 6 lower rates of colorectal cancer, significance. Although the months, at least 3 years of use uterine body cancer, and ovarian researchers also observed a 25% has been found to be needed for cancer; small, statistically non-sig- lower risk of breast cancer associ- significant protection. Endo- nificant increases in cancers of ated with COC use of greater metrial cancer, though not as the lung, cervix, and central ner- ! than 84 months' duration versus often fatal, is much more com- vous system or pituitary; and no never use among women with a mon than ovarian cancer. Studies material difference in the rate of first-degree relative with breast have demonstrated a protective the most common cancer-breast cancer, this finding was not statis- effect of COCs in endometrial cancer. Taken together, there was

TABLE 4.1"OCS AND BREAST CANCER WOMEN'S CARE" CASE-CONIROL S'IUOY"

DESIGN

b Population-based, case-control study conducted by researchers at the Centers for Disease Control and Prevention

4575 cases and 4682 controls (women aged 35-64 years) were interviewed

RESULTS

b 77% of the cases and 79% of the controls had used combined oral contraceptives (COCs).

b Breast cancer risk in women who had ever used COCs versus those who had never used COCs was 0.9 195% confidence interval, 0.8-1.0).

b No increase in risk for longer periods of use or higher doses of estrogen was observed.

b Initiation of COC use at a young age was not associated with an increased risk of breast cancer.

b Among women aged 35-64 years, current or former COC use was not associated with increased breast cancer risk.

I November 2007 Vol. 6, No. 11 a 29% reduced risk of the main to be effective in decreasing bone of NGM/EE in treating ad gynecologic cancers combined. turnover in osteopenic pre- or clarified the mechanism of too The estimated absolute rate menopausal women with hypo- action of this regimemg" P" reduction of any cancer among thalamic arnen~rrhea."~~Wowever, use More recently, YAZ and Estrostep ever users was 45 per 100,000 another study did not show a ben- CC have been approved to treat woman-years. efit of NGM/EE on BMD in ado- an( acne."'" These COCs, as well as lescents with an~rexia.'~ ma Although no studies have singled the tri-NGM/EE formulation tro ' Acne-Many COCs improve acne approved to treat acne, are ideal out NGM-containing COCs in ha1 terms of their effects on cancer symptoms-both in terms of for females with acne who are COI risk, a population-based case-con- lesion severity and lesion co~nt.'~ seeking a birth-control method COI trol study, which enrolled 745 In 1996, NGM 180/215/250 and for those who are not candi- women with incident, histologi- pg/EE 35 pg received the first dates for, or who have not cally confirmed epithelial ovarian noncontraceptive indication for a responded to, oral antibiotics or carcinoma and 943 controls, COC-for the treatment of mod- isotretin~in.~~ erate acneegoThe following year, demonstrated that, when com- Polycystic Ovary Syndrome- aw in a multicenter, randomized, pared with nonusers, users of COCs are the mainstay of treat- an( double-blind, placebo-controlled COCs with low-dose EE (135 pg) ment for hirsutism and acne in rep and low-dose progestin (equiva- trial in which 160 women women with PCOS.looA key deter- are lent to <0.3 mg of norgestrel) received this COC formulation or minant in the choice of a specific t mi content were at significantly placebo for 6 months, active COC is the type of progestin con- the reduced risk of ovarian carci- treatment led to significant tained in the compound. Each dor noma (OR, 0.19) .7Withregard improvement on all efficacy mea- progestin varies in its suppressive Altl to concern about the increased sures: facial acne lesion count, effect on SHBG levels and in its dor risk of cervical cancer in COC investigator's global assessment, androgenic potential. Ethynodiol of; users, Burkman and Shulman subject's self-assessment, and an diacetate has a relatively low nu; have ascribed this phenomenon analysis of within-cycle variation androgenic potential, whereas t EE. (cycle 6) in lesion count.g' For not to an intrinsic effect of the progestins such as NET, llg) hormones but, rather, to the fact the COC and placebo groups, norgestrel, and LNG are particu- cyc1 that more women are having respectively, the mean decrease in larly androgenic. NGM and DSG lihc unprotected intercourse and, as a inflammatory lesion count from are virtually non-androgenic and Pill result, are more likely to be baseline to cycle 6 was 11.8 are considered the progestins of rig1 exposed to human papillo- (62.0%) versus 7.6 (38.6%) (P= choice in the treatment of stri, mavirus, the primary cause of cer- .0001) and the mean decrease in women with PCOS. More bili vical cancer.'" As a precaution, total lesion count was 29.1 recently, DRSP, in combination these authors recommend that (53.1%) versus 14.1 (26.8%) (P= with EE, has shown promise in on COCs users involved in non- .0001). In the investigator's global the treatment of women with CO monogamous situations add a assessment, 93.7% of tri-NGM/EE PCOS. ma barrier method such as a condom recipients versus 65.4% of nee when having sex. placebo recipients were rated as improved at the end of the study A FINAL WORD ABOUT CYCLE C[IN'IROl con Bone Mineral Density-COC use (P<.001). Six of the seven sec- Unscheduled bleeding is a lead- tior has been associated with an ondary efficacy measures (total ing cause of COC discontinua- and increase in BMD in some stud- comedones, open comedones, tion. Better cycle control call Chi iesRaR4and a decrease in BMD in closed comedones, papules, pus- increase women's satisfaction and gesl other^,^"^^ although the decrease tules, and women's self-assess- success with their COC, and ulti- and in BMD associated with use of ment of study treatment) were mately lead to more consistent alth COCs containing ultra-low-dose also significantly more favorable use and better contraceptive effi- Pro EE is likely reversible when the in the COC group than in the cacy. Although the amount of EE anc Pill is stopped." NGGM/EE-con- placebo group. Many additional in a COC is a major determinant full taining regimens have been shown studies have affirmed the efficacy of the level of cycle control of s

20 Women's Health Care: A Practical Journal for Nurse Practitioners Nov~