Gonadotropin-releasing hormone agonists (GnRHa) are an effective treatment of endometriosis-associated pelvic pain. The use of hormonal add-back therapy can alleviate the hypoestrogenic symptoms associated with GnRHa therapy, while preserving therapeutic efficacy. Norethindrone acetate (NETA) is a unique progestin that has both estrogenic and androgenic properties and is effective as an add-back regimen without estrogen supplementation. Through its estrogenic activity, NETA exerts beneficial effects on bone mineral density and vasomotor symptoms in women treated with GnRHa. In addition, NETA exhibits strong endometrial antiproliferative effects, which may result in further benefits for the endometriosis patient population. However, NETA add-back may be associated with progestogenic side effects and may lower high-density lipoprotein due to androgenic activity. These effects must be balanced with the overall benefits of NETA add-back therapy.
European Society of Human Reproduction and Embryology. ESHRE guideline for the diagnosis and treatment of endometriosis. 2010; http://guidelines.endometriosis.org/index.html. Accessed July 27, 2010.
2.
GamboneJCMittmanBSMunroMGScialliARWinkelCA. Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril. 2002;78(5):961–972.
3.
OliveDL. Gonadotropin-releasing hormone agonists for endometriosis. N Engl J Med. 2008;359(11):1136–1142.
4.
SurreyES. Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show?Curr Opin Obstet Gynecol. 2010;22(4):283–288.
5.
AgorastosTVaitsiVPaschopoulosMProlonged use of gonadotropin-releasing hormone agonist and tibolone as add-back therapy for the treatment of endometrial hyperplasia. Maturitas. 2004;48(2):125–132.
6.
OliveDL. The role of add-back therapy in the United States. Drugs Today (Barc). 2005;41(suppl A):23–26.
7.
SurreyES. The role of progestins in treating the pain of endometriosis. J Minim Invasive Gynecol. 2006;13(6):528–534.
8.
SurreyES. Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group. Fertil Steril. 1999;71(3):420–424.
9.
HornsteinMDSurreyESWeisbergGWCasinoLA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91(1):16–24.
10.
FalconeTLebovicDI. Clinical management of endometriosis. Obstet Gynecol. 2011;118(3):691–705.
11.
MounseyALWilgusASlawsonDC. Diagnosis and management of endometriosis. Am Fam Physician. 2006;74(4):594–600.
FuldeoreMJMarxSEChwaliszKSmeedingJEBrookRA. Add-back therapy use and its impact on LA persistence in patients with endometriosis. Curr Med Res Opin. 2010; 26(3):729–736.
14.
StanczykFZ. Structure–function relationships, pharmacokinetics, and potency of orally and parenterally administered progestogens intervention. In: LoboRA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 3rd ed. Burlington, MA: Academic Press; 2007:779–798.
15.
WiegratzIKuhlH. Progestogen therapies: differences in clinical effects?Trends Endocrinol Metab. 2004;15(6):277–285.
16.
KenemansPSperoffL. Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group. Maturitas. 2005;51(1):21–28.
17.
AlbertazziPBottazziMSteelSA. Bone mineral density and depot medroxyprogesterone acetate. Contraception. 2006;73(6):577–583.
18.
MeierCBrauchliYBJickSSKraenzlinMEMeierCR. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab. 2010;95(11):4909–4916.
19.
SchindlerAECampagnoliCDruckmannRClassification and pharmacology of progestins. Maturitas. 2003;46(suppl 1):S7–S16.
20.
BackDJBreckenridgeAMCrawfordFEKinetics of norethindrone in women. I. Radioimmunoassay and concentrations during multiple dosing. Clin Pharmacol Ther. 1978;24(4):439–447.
21.
BackDJBreckenridgeAMCrawfordFEKinetics of norethindrone in women. II. Single-dose kinetics. Clin Pharmacol Ther. 1978;24(4):448–453.
22.
StanczykFZRoyS. Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception. 1990;42(1):67–96.
23.
KuhnzWHeunerAHumpelMSeifertWMichaelisK. In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women. Contraception. 1997;56(6):379–385.
24.
ChuMCZhangXGentzscheinEStanczykFZLoboRA. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92(6):2205–2207.
25.
BurkmanRTFisherACWanGJBarnowskiCELaGuardiaKD. Association between efficacy and body weight or body mass index for two low-dose oral contraceptives. Contraception. 2009;79(6):424–427.
26.
BarbieriRL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166(2):740–745.
27.
SmithCLO'MalleyBW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25(1):45–71.
28.
SmithCLNawazZO'MalleyBW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol. 1997;11(6):657–666.
29.
ChwaliszKPerezMCDemannoDWinkelCSchubertGElgerW. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev. 2005;26(3):423–438.
30.
KeHZChenHKSimmonsHAComparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model. Bone. 1997;20(1):31–39.
31.
WeissSREllmanHDolkerM. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol. 1999;94(3):330–336.
32.
GenantHKLucasJWeissSLow-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med. 1997;157(22):2609–2615.
33.
MashchakCALoboRADozono-TakanoRComparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. 1982;144(5):511–518.
34.
PriorJC. Progesterone as a bone-trophic hormone. Endocr Rev. 1990;11(2):386–398.
35.
RickardDJIwaniecUTEvansGBone growth and turnover in progesterone receptor knockout mice. Endocrinology. 2008;149(5):2383–2390.
36.
WellsGTugwellPSheaBMeta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):529–539.
37.
GallagherJCKableWTGoldgarD. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med. 1991;90(2):171–178.
38.
ThijssenJH. Long-term effects of progestins on bone quality and fractures. Gynecol Endocrinol. 2007;23(suppl 1):45–52.
39.
KawanoHSatoTYamadaTSuppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A. 2003;100(16):9416–9421.
40.
SouleSGConwayGPrelevicGMPrenticeMGinsburgJJacobsHS. Osteopenia as a feature of the androgen insensitivity syndrome. Clin Endocrinol (Oxf). 1995;43(6):671–675.
41.
SmithEPBoydJFrankGREstrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994;331(16):1056–1061.
42.
AbdallaHIHartDMLindsayRLeggateIHookeA. Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol. 1985;66(6):789–792.
43.
MooreRA. Livial: a review of clinical studies. Br J Obstet Gynaecol. 1999;106(suppl 19):1–21.
44.
HorowitzMWishartJNeedAGMorrisHPhilcoxJNordinBE. Treatment of postmenopausal hyperparathyroidism with norethindrone. Effects on biochemistry and forearm mineral density. Arch Intern Med. 1987;147(4):681–685.
45.
JohansenJSJensenSBRiisBJChristiansenC. Time-dependent variations in bone turnover parameters during 2 months' cyclic treatment with different doses of combined estrogen and progestogen in postmenopausal women. Metabolism. 1990;39(11):1122–1126.
46.
EikenPKolthoffNNielsenSP. Effect of 10 years' hormone replacement therapy on bone mineral content in postmenopausal women. Bone. 1996;19(5 suppl):191S–193S.
47.
Pors NielsenSBarenholdtOHermansenFMunk-JensenN. Magnitude and pattern of skeletal response to long term continuous and cyclic sequential oestrogen/progestin treatment. Br J Obstet Gynaecol. 1994;101(4):319–324.
48.
CrosignaniPOliveDBergqvistALucianoA. Advances in the management of endometriosis: an update for clinicians. Hum Reprod Update. 2006;12(2):179–189.
49.
CrosignaniPGLucianoARayABergqvistA. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21(1):248–256.
50.
FernandezHLucasCHedonBMeyerJLMayengaJMRouxC. One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial. Hum Reprod. 2004;19(6):1465–1471.
51.
RouxCLucasCBriotKKoltaSFechtenbaumJFernandezH. 3 year-follow-up of bone mineral density after a randomised trial of 12-month treatment with a GnRH agonist (leuprorelin 3.75 mg) associated with 2 options of steroidal "Add-Back" regimens in patients with endometriosis. Paper presented at: Conference title: 27th Annual Meeting of the American-Society-for-Bone-and-Mineral- Research, September 23-27, 2005, Nashville, TN, USA, Sponsor: Amer Soc Bone & Mineral Res. 2005.
52.
UtianWHShoupeDBachmannGPinkertonJVPickarJH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75(6):1065–1079.
53.
GoodwinJWGreenSJMoinpourCMPhase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: Southwest Oncology Group Study 9626. J Clin Oncol. 2008;26(10):1650–1656.
54.
LoprinziCLMichalakJCQuellaSKMegestrol acetate for the prevention of hot flashes. N Engl J Med. 1994;331(6):347–352.
55.
KuhlH. Mechanisms of sex steroids. Future developments. Maturitas. 2004;47(4):285–291.
56.
FraserDIParsonsAWhiteheadMIWordsworthJStuartGPryse-DaviesJ. The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study. Fertil Steril. 1990;53(3):460–468.
57.
Activella [package insert]. Princeton, NJ: Novo Nordisk; 2006.
58.
ClarkeRB. Steroid receptors and proliferation in the human breast. Steroids. 2003;68(10-13):789–794.
59.
SoderqvistGIsakssonEvon SchoultzBCarlstromKTaniESkoogL. Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol. 1997;176(1 pt 1):123–128.
60.
LundstromEWilczekBvon PalffyZSoderqvistGvon SchoultzB. Mammographic breast density during hormone replacement therapy: differences according to treatment. Am J Obstet Gynecol. 1999;181(2):348–352.
61.
ConnerPSvaneGAzavedoEMammographic breast density, hormones, and growth factors during continuous combined hormone therapy. Fertil Steril. 2004;81(6):1617–1623.
62.
RossouwJEAndersonGLPrenticeRLRisks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.
63.
BeralV. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419–427.
64.
ChlebowskiRTAndersonGLGassMEstrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304(15):1684–1692.
65.
LyytinenHDybaTPukkalaEYlikorkalaO. Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: national-wide case-control study from Finland. Int J Cancer. 2010;127(1):185–189.
66.
StuedalAMaHBjorndalHUrsinG. Postmenopausal hormone therapy with estradiol and norethisterone acetate and mammographic density: findings from a cross-sectional study among Norwegian women. Climacteric. 2009;12(3):248–258.
SperoffLDarneyPD, eds. A Clinical Guide for Contraception. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
69.
Breast cancer and hormonal contraceptives: further results. Collaborative Group on Hormonal Factors in Breast Cancer. Contraception. 1996;54(3 suppl):1S–106S.
70.
RosenbergLPalmerJRClarkeEAShapiroS. A case-control study of the risk of breast cancer in relation to oral contraceptive use. Am J Epidemiol. 1992;136(12):1437–1444.
71.
Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1996;347(9017):1713–1727.
72.
Plu-BureauGLeMGSitruk-WareRThalabardJCMauvais-JarvisP. Progestogen use and decreased risk of breast cancer in a cohort study of premenopausal women with benign breast disease. Br J Cancer. 1994;70(2):270–277.
73.
RossouwJEPrenticeRLMansonJEPostmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465–1477.
74.
BernsteinPPohostG. Progesterone, progestins, and the heart. Rev Cardiovasc Med. 2010;11(4):228–236.
75.
CrewsJKKhalilRA. Antagonistic effects of 17 beta-estradiol, progesterone, and testosterone on Ca2+ entry mechanisms of coronary vasoconstriction. Arterioscler Thromb Vasc Biol. 1999;19(4):1034–1040.
76.
EarlPLSugiuraWMontefioriDCImmunogenicity and protective efficacy of oligomeric human immunodeficiency virus type 1 gp140. J Virol. 2001;75(2):645–653.
77.
JiangCWSarrelPMLindsayDCPoole-WilsonPACollinsP. Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro. Eur J Pharmacol. 1992;211(2):163–167.
78.
MinshallRDPavcnikDBrowneDLHermsmeyerK. Nongenomic vasodilator action of progesterone on primate coronary arteries. J Appl Physiol. 2002;92(2):701–708.
79.
PedersenSHPedersenNGDalsgaardTLundCONilasLOttesenB. Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand White rabbit. Climacteric. 2004;7(1):12–22.
80.
RosanoGMWebbCMChierchiaSNatural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000;36(7):2154–2159.
81.
GodslandIF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril. 2001;75(5):898–915.
82.
KuhlH. Effects of progestogens on haemostasis. Maturitas. 1996;24(1-2):1–19.
83.
HerkertOKuhlHSandowJBusseRSchini-KerthVB. Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression: role of the glucocorticoid receptor. Circulation. 2001;104(23):2826–2831.
