EDITORIAL 3 cases of hormone therapy optimized to match the patient problem There are 5 different dose combinations of ethinyl estradiol and norethindrone acetate, ranging from 2.5 µg to 30 µg of ethinyl estradiol, and a 6th option is norethindrone acetate monotherapy Robert L. Barbieri, MD Chair Emeritus, Department of Obstetrics and Gynecology Interim Chief, Obstetrics Brigham and Women’s Hospital Kate Macy Ladd Distinguished Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School Boston, Massachusetts here are dozens of medica- spontaneous menses in the past year thereby reducing ovarian produc- tions containing combinations and bothersome facial hair and acne. tion of testosterone, and ethinyl T of estrogen and progestin. I Her total testosterone concentration is estradiol increases hepatic secre- am often confused by the bewildering at the upper limit of normal (0.46 ng/mL) tion of SHBG, reducing bioavailable proliferation of generic brand names and her sex hormone binding globulin testosterone. These two goals are used to describe the same estrogen- (SHBG) concentration is at the lower best accomplished with an oral progestin (E-P) regimen. For exam- limit of normal (35 nM). For treatment of E-P hormone medication contain- ple, the combination medication the patient’s menstrual disorder, what ing ethinyl estradiol doses of 20 µg containing ethinyl estradiol 20 µg plus is an optimal E-P combination? to 30 µg per pill. An E-P hormone norethindrone acetate (NEA) 1 mg medication containing pills with is available under at least 5 different Prioritize the use of an an ethinyl estradiol dose ≤ 10 µg names: Lo Estrin 1/20 (Warner Chil- estrogen-dominant medication daily may stimulate less hepatic cot), Junel 1/20 (Teva Pharmaceu- Based on the Rotterdam criteria production of SHBG than a pill with ticals), Microgestin Fe 1/20 (Mayne this woman has polycystic ovary an ethinyl estradiol dose of 20 µg or Pharma), Gildess 1/20 (Qualitest syndrome (PCOS).1 In women with 30 µg daily.4,5 In addition, E-P pills Pharmaceuticals), and Larin 1/20 PCOS, luteinizing hormone (LH) containing levonorgestrel suppress (Novast Laboratories). To reduce the secretion is increased, stimulat- SHBG hormone secretion compared confusion, it is often useful to select ing excessive ovarian production with E-P pills with other progestins.6 a single preferred estrogen and pro- of testosterone.2 In addition, many Therefore, levonorgestrel-containing gestin and use the dose combinations women with PCOS have decreased E-P pills should not be prioritized for that are available to treat a wide range hepatic secretion of SHBG, a bind- use in women with PCOS because of gynecology problems (TABLE, page ing protein that prevents testoster- the estrogen-induced increase in 13). In this editorial I focus on using one from entering cells, resulting SHBG will be blunted by levonor- various dose combinations of ethinyl in excessive bioavailable testoster- gestrel. estradiol and NEA to treat 3 common one.3 The Endocrine Society rec- gynecologic problems. ommends that women with PCOS CASE 2 Moderate to severe pelvic who have menstrual dysfunction or pain caused by endometriosis CASE 1 Polycystic ovary syndrome hirsutism be treated initially with a A 25-year-old woman (G0) with se- A 19-year-old woman reports 4 combination E-P hormone medica- vere dysmenorrhea had a laparoscopy tion.1 Combination E-P medications showing endometriosis lesions in the doi: 10.12788/obgm.0114 suppress pituitary secretion of LH, cul-de-sac and a peritoneal window CONTINUED ON PAGE 13 mdedge.com/obgyn Vol. 33 No. 7 | July 2021 | OBG Management 9 EDITORIAL CONTINUED FROM PAGE 9 of norethindrone 0.35 mg daily for TABLE Estrogen-progestin pills with a wide dose range of the treatment of pelvic pain caused a ethinyl estradiol by endometriosis. Ethinyl Norethindrone Patients commonly ask if NEA Examples of generic estradiol acetate (NEA) Brand name brand names dosage dosage 5 mg daily has contraceptive effi- cacy. Although it is not approved Aygestin (Duramed Norethindrone Acetate 0 5 mg NEA Pharmaceuticals) at this dosage by the US Food and FemHRT (Allergan) Jevantique Lo 2.5 µg 0.5 mg NEA Drug Administration as a contracep- tive,8 norethindrone 0.35 mg daily is FemHRT Jinteli (Teva Pharmaceuti- 5.0 µg 1.0 mg NEA cals), Jevantique (Watson approved as a progestin-only con- Pharma) traceptive.9 Norethindrone acetate is Lo LoEstrin Fe No generic available 10 µg 1.0 mg NEA rapidly and completely deacetylated (Allergan) to norethindrone and the disposition Lo Estrin 1/20 Junel Fe 1/20 (Teva Phar- 20 µg 1.0 mg NEA of oral NEA is indistinguishable from (Warner Chilcot) maceuticals) that of norethindrone (which is the Lo Estrin 1.5/30 Junel 1.5/30 (Teva Pharma- 30 µg 1.5 mg NEA FDA-approved dosage mentioned (Warner Chilcot) ceuticals) above). Since norethindrone 0.35 mg aPills containing ethinyl estradiol ≤ 5 µg per pill are progestin dominant. daily is approved as a contraceptive, it is highly likely that NEA 5 mg daily has contraceptive efficacy, especially near the left uterosacral ligament. Bi- treatment but, following the insur- if there is good adherence with the opsy showed endometriosis. Postop- ance denial of the prescription, an daily medication. eratively, the patient was treated with alternative treatment for moder- an E-P pill containing 30 µg ethinyl ate or severe pelvic pain caused by CASE 3 Perimenopausal AUB estradiol and 0.15 mg desogestrel per endometriosis would be a proges- A 45-year-old woman reports vary- pill using a continuous-dosing proto- tin-dominant hormone medica- ing menstrual cycle lengths from 24 to col. During the year following the lap- tion (for example, NEA 5 mg daily). 60 days with very heavy menses in aroscopy, her pelvic pain symptoms Norethindrone acetate 5 mg daily some cycles. Pelvic ultrasonography gradually increased until they became may be associated with bothersome shows no abnormality. Endometrial severe, preventing her from perform- adverse effects including weight gain biopsy shows a proliferative endome- ing daily activities on multiple days per (16% of patients; mean weight gain, trium. Her serum progesterone level, month. She was prescribed elagolix 3.1 kg), acne (10%), mood lability obtained 1 week before the onset of but her insurance did not approve the (9%), hot flashes (8%), depression menses, is < 3 ng/mL. She has no past treatment. What alternative treatment (6%), scalp hair loss (4%), headache history of heavy menses, easy bruising, would you prescribe? (4%), nausea (3%), and deepening of excessive bleeding with procedures, or the voice (1%).7 a family history of bleeding problems. Use progestin-dominant pills I sometimes see women with She also reports occasional hot flashes to treat pelvic pain moderate to severe pelvic pain that wake her from sleep. Cellular activity in endometriosis caused by endometriosis being lesions is stimulated by estradiol treated with norethindrone 0.35 mg Use an estrogen step- and inhibited by a high concentra- daily. This dose of norethindrone down regimen to manage tion of androgenic progestins or is suboptimal for pain treatment postmenopause transition androgens. This simplified endo- because it does not reliably suppress This patient is likely in the perimeno- crine paradigm explains the effec- ovarian production of estradiol. In pause transition, and the abnormal tiveness of hormonal treatments that addition, the cells in endometrio- uterine bleeding (AUB) is caused, in suppress ovarian estradiol produc- sis lesions are often resistant to the part, by oligo- or anovulation. Peri- tion, including leuprolide, elagolix, effects of progesterone, requiring menopausal women with AUB may medroxyprogesterone acetate, and higher dosages to produce secretory have cycles characterized by above NEA. For the woman in the above or decidual changes. In most situa- normal ovarian estradiol produc- case, I would advocate for elagolix tions, I recommend against the use tion and below normal progesterone mdedge.com/obgyn Vol. 33 No. 7 | July 2021 | OBG Management 13 EDITORIAL production, or frank anovulation.10 covering the transition into post- hepatic SHBG production. For endo- Elevated ovarian estrogen and low menopause. Once the woman is in the metriosis, if a GnRH antagonist is not progesterone production sets the stage postmenopause, treatment with trans- available to the patient, a high-dose for heavy bleeding in the perimeno- dermal estradiol and oral micronized progestin, such as NEA 5 mg, may pause, regardless of the presence of progesterone is an option to treat be an effective treatment. During uterine pathology such as fibroids. menopausal vasomotor symptoms. the perimenopause transition in a For perimenopausal women, woman with AUB, a treatment plan one option for treatment of AUB using a sequential E-P step-down due to anovulation is to prescribe Optimize estrogen and program might control symptoms an estrogen step-down regimen. For progestin treatment for and help smoothly glide the patient the 45-year-old woman in this case, your patients into the postmenopause. l initiating treatment with an E-P pill Many gynecologic problems are containing ethinyl estradiol 10 µg effectively treated by estrogen and/or and NEA 1 mg will likely control the progestin steroids. The dose of estro- 11 AUB and her occasional hot flash. gen and progestin should be tailored [email protected] As the woman ages, the ethinyl estra- to the specific problem. For PCOS, diol dose can be decreased to pills the estrogen dose selected should Dr. Barbieri reports no financial rela- containing 5 µg and then 2.5 µg, be sufficient to safely stimulate tionships relevant to this article. References 1. Legro RS, Arslanian SA, Ehrmann DA, et al. Diag- tive vs. ethinyl estradiol and drospirenone 21/7 Adolesc Gynecol. 2012;25:105-108. doi: 10.1016/j.