- Email: [email protected]
Hepatic Adenomas in Adolescents and Young Women with Endometriosis Treated with Norethindrone Acetate
Accepted Manuscript Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate P.C. Brady, S.A. Missmer, M.R. Laufer PII:
S1083-3188(16)30232-7
DOI:
10.1016/j.jpag.2016.12.002
Reference:
PEDADO 2077
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 20 October 2016 Revised Date:
8 December 2016
Accepted Date: 12 December 2016
Please cite this article as: Brady P, Missmer S, Laufer M, Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate, Journal of Pediatric and Adolescent Gynecology (2017), doi: 10.1016/j.jpag.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate
RI PT
Brady PC1,2,4 Missmer SA3,4,5,6, Laufer MR1,2,4
1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics,
Gynecology, and Reproductive Biology; Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115 USA
SC
2 Division of Gynecology, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115 USA
M AN U
3 Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115 USA 4 Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women’s Hospital, Boston, MA, 02115 USA
5 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115 USA
TE D
6 Department of Obstetrics, Gynecology, and Reproductive Biology; College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
Requests for reprints
EP
Paula C. Brady, M.D.
AC C
Brigham and Women’s Hospital 75 Francis St., ASBI-3 Boston, MA 02115
Phone: 617-732-4648 Fax: 617-566-7752
Email: [email protected]
No sources of financial support. The authors have no conflicts of interest to disclose.
1
ACCEPTED MANUSCRIPT
Abstract
Background: Endometriosis—ectopic implantation of endometrial-like tissue—affects 10% of
RI PT
female adolescents and adults. First-line treatment includes progesterone-only (such as norethindrone acetate, NET-A) or combined estrogen/progestin oral contraceptive pills. Estrogen-containing contraceptives confer increased risk of hepatic adenomas, while the
SC
association with NET-A is very rarely reported.
M AN U
Case: Three adolescents with Stage I-II endometriosis managed with NET-A (up to 15 mg/day for 28-78 months) were diagnosed with hepatic adenomas at ages 17-22 years. They previously received estrogen-containing medications, which were stopped > 24 months before diagnosis of
TE D
hepatic adenoma.
Summary and Conclusion: NET-A in a dose above 10 mg per day may be associated with increased risk for hepatic adenomas, likely due to peripheral conversion to ethinyl estradiol. Use
AC C
EP
of NET-A may not be advisable in patients with known hepatic adenomas.
2
ACCEPTED MANUSCRIPT
Introduction
Endometriosis is defined by endometrial-like tissue that is thriving outside of the uterus,
RI PT
affecting approximately 10% of female adolescents and adults of reproductive age.1 Currently, definitive diagnosis of endometriosis is by surgical visualization, and the extent of disease is categorized as stage I to IV – although stage correlates poorly to patients’ symptoms.2,3 While
SC
patients may be asymptomatic, endometriosis often presents with dysmenorrhea, dyspareunia,
M AN U
chronic pelvic pain and infertility.4
Maintenance therapy for suspected or confirmed endometriosis commonly involves analgesics and hormonal medications, including progestin-only (such as norethindrone acetate, NET-A) and combined estrogen/progestin oral contraceptive pills, progestin-only injections, implants or
TE D
intrauterine devices, aromatase inhibitors, or gonadotropin-releasing hormone agonists. Progesterone-only or combined estrogen/progestin oral contraceptive pills are often the first step in management.4 Patients with recurrent or refractory pain may require surgical ablation or
EP
excision of endometriosis.4
AC C
Estrogen-containing contraceptives are associated with an increased risk of hepatic adenomas (34 per 100,000), which can cause life-threatening hemorrhage.5 The risk of developing hepatic adenomas is closely correlated with the duration of use of estrogen-containing contraceptives, and with the potency of the estrogen component.5 Conversely, the association of NET-A and hepatic adenoma has been rarely reported and only in specific populations taking NET-A for
3
ACCEPTED MANUSCRIPT
menstrual suppression such as patients undergoing dialysis or those with congenital platelet disorders.6,7
RI PT
Herein is reported a series of three young women with endometriosis who developed hepatic adenomas after being treated with maximum-dose NET-A (15 mg/day). NET-A is a widely-used medication in the management of endometriosis; this case series alerts clinicians to a potentially
SC
highly morbid complication in patients receiving NET-A for the treatment of endometriosis.
M AN U
Case
Three adolescents and young women with surgically-diagnosed endometriosis were managed with NET-A (Table 1); two patients were diagnosed with stage I endometriosis, while the third
TE D
had stage II endometriosis. The first patient has a past medical history of asthma; the second reports palpitations and migraines, while the third patient had an immature ovarian teratoma and
EP
underwent unilateral oophorectomy at age 11 years with no evidence of recurrence.
The patients initiated NET-A at ages 15-19 years and received the medication for a period of 28-
AC C
78 months prior to the diagnosis of hepatic adenoma. The dose of NET-A varied over that time period, as the dose was titrated according to symptoms; the patients were exposed to the maximum dose of 15 mg/day of NET-A for a period of 12-30 months.
All three patients had previously been exposed to estrogen-containing medications, either combined oral contraceptive pills or conjugated equine estrogen as part of add-back therapy
4
ACCEPTED MANUSCRIPT
during treatment with leuprolide acetate. The patients were exposed to estrogen-containing medications for a range of 13-31 months. These medications were stopped more than 24 months
RI PT
before the hepatic adenomas were diagnosed.
The patients were diagnosed with hepatic adenomas after presenting with abdominal pain and/or nausea and emesis. Abdominal computed tomography (CT) scans were performed in all patients
SC
for diagnosis; two patients also underwent magnetic resonance imaging (MRI) to confirm the diagnosis (Figure 1). The number of adenomas ranged from 3-15, with largest diameters of 2.2-
M AN U
7.3 cm. Only the patient who had both the most numerous adenomas and largest adenoma (15 adenomas, the largest of which was 7.3 cm in diameter) also had mildly elevated liver function tests at the time of presentation.
TE D
The two patients with more limited hepatic disease continued on progestins (one on NET-A, the other on norethindrone 0.35 mg per day), as repeat imaging revealed stability of the lesions. The third patient with the most extensive disease underwent wedge biopsies and stopped all hormonal
EP
medications, after which the lesions significantly reduced in size; eighteen months later, the
AC C
largest lesion was just 2.5 cm in diameter.
Summary and Conclusion
The pathogenesis of hepatic adenoma development due to estrogen exposure is unknown, but the association between the two is well established. Hepatic adenomas are more common in women than in men, and in obese patients, which is relevant as adipose tissue is a peripheral source of
5
ACCEPTED MANUSCRIPT
estrogen production.8 Hepatic adenomas are also associated with combined estrogen/progestin oral contraceptive use; the risk of developing hepatic adenomas is greatest in women over 30 years taking “high potency” (not defined) combined oral contraceptives for more than 25
RI PT
months.5 Of note, combined oral contraceptives have utilized progressively lower doses of
estrogen over time, associated with a decreased incidence of hepatic adenomas among those exposed to combined oral contraceptives.8 Reported only in case reports and small series,
SC
following cessation of estrogen-containing contraceptives, regression of hepatic adenomas
M AN U
(which does not occur in all patients) has been documented in as little as nine months.9
The development of hepatic adenoma in patients receiving NET-A is likely due to peripheral conversion to ethinyl estradiol. Metabolism of NET-A to ethinyl estradiol has been demonstrated to result in serum levels comparable to levels in patients ingesting ethinyl estradiol primarily.10
TE D
A daily dose of 10-20 mg of NET-A results in serum estradiol levels commensurate with ingestion of 20-30 µg of ethinyl estradiol per day.10
EP
This is the first case series to report development of hepatic adenomas in patients receiving NETA for the treatment of endometriosis. Existing reports of the association of NET-A with hepatic
AC C
adenomas are limited to six patients.6,7 These patients received between 10-20 mg per day of NET-A for the indication of menstrual suppression in the setting of dialysis (2 patients) and congenital platelet disorders (4 patients); these patients presented with intra-abdominal hemorrhage (5 patients) or infection (1 patient). Prior exposure to estrogen-containing medication was not reported in these series. This current series represents an important addition
6
ACCEPTED MANUSCRIPT
of three patients who developed hepatic adenomas after being treated with NET-A for a separate indication (endometriosis) and who presented with milder, relatively non-specific symptoms.
RI PT
The development of multiple adenomas in the third patient is notable as she also had the shortest duration of exposure to NET-A (28 months). As obesity is a known risk factor for the
development of hepatic adenomas, the clinical course of this patient may theoretically be
SC
associated with her elevated body mass index (29 kg/m2), possibly due to the peripheral
production of estrogen in adipose tissue.8 However, this is only speculation, as the pathogenesis
M AN U
of hepatic adenomas is not well understood.
The patients in this series had been exposed to estrogen-containing medications in the past, and contribution of these medications to the development of hepatic adenomas cannot be definitively
TE D
excluded. A majority of patients with symptomatic endometriosis, however, will have been exposed to estrogen-containing medications during their treatment. As a result, these three cases are notable above and beyond the background risk of hepatic adenomas in this population.
EP
Furthermore, in these three patients, estrogen-containing medications had been discontinued at least two years prior to the diagnosis of hepatic adenomas, theoretically leaving ample time for
AC C
resolution of adenomas associated with primary estrogen ingestion. The patients also had no symptoms suggestive of hepatic adenomas while consuming estrogen-containing medications, and only became symptomatic following initiation of NET-A. Finally, given the peripheral conversion of NET-A to ethinyl estradiol, biologic plausibility exists for NET-A driving the development of these hepatic adenomas.
7
ACCEPTED MANUSCRIPT
NET-A is approved by the U.S. Food and Drug Administration for use of up to 15 mg per day for the treatment of endometriosis.11 Use of more than 10 mg per day of NET-A, however, may not be advisable in patients with known hepatic adenomas. Furthermore, patients receiving NET-
RI PT
A who report abdominal pain, nausea and/or emesis should undergo imaging to assess for hepatic lesions.
SC
References
M AN U
1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789-99.
2. The American Fertility Society. Classification of endometriosis. Fertil Steril. 1979;32:633-4. 3. Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol. 1990;162:568-9.
TE D
4. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101:927-35. 5. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW Jr.
1979;242:644.
EP
Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA.
AC C
6. Crosnier H, Thibaud E, Duflos C, Polak M. Norethisterone-induced hepatic adenomas can cause life-threatening bleeding in girls with inhereted platelet disorders. Fertil Steril. 2010;94:2329.e1-3.
7. Kalra PA, Guthrie JA, Dibble JB, Turney JH, Brownjohn AM. Hepatic adenomas induced by norethisterone in patients receiving renal dialysis. Br Med J (Clin Res Ed). 1987;294:808.
8
ACCEPTED MANUSCRIPT
8. Agrawal S, Agarwal S, Arnason T, Saini S, Belghiti J. Management of Hepatocellular Adenoma: Recent Advances. Clin Gastroenterol Hepatol. 2015;13:1221-30. 9. Aseni P, Sansalone CV, Sammartino C, Benedetto FD, Carrafiello G, Giacomoni A, et al.
RI PT
Rapid disappearance of hepatic adenoma after contraceptive withdrawal. J Clin Gastroenterol. 2001;33:234-6.
10. Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA. Formation of ethinyl estradiol in
SC
women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92:2205-7. 11. Aygestin label. U.S. Food and Drug Administration website.
AC C
EP
TE D
2007. Accessed April 1, 2016.
M AN U
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf. Updated July
9
ACCEPTED MANUSCRIPT
Legends:
Table 1. Adolescents diagnosed with hepatic adenomas while receiving norethindrone
RI PT
acetate (NET-A) for the treatment of endometriosis. NET-A = norethindrone acetate; cm = centimeter; CT = computed tomography; MRI = magnetic resonance imaging
SC
Figure 1. Abdominal MRI of hepatic adenomas. T2-weighted image of the upper abdomen in Patient 3 (Table 1) at presentation with the largest and most numerous hepatic adenomas. The
AC C
EP
TE D
M AN U
largest adenoma, 7.3 cm in diameter, is indicated with an arrow.
10
ACCEPTED MANUSCRIPT
Table 1. Adolescents diagnosed with hepatic adenomas while receiving norethindrone acetate (NET-A) for the treatment of endometriosis Age at NET-A initiation (years)
NET-A Duration of dose at NET-A at diagnosis diagnosis (mg/day) (months)
22
22
19
15
46
2
22
25
16
10
78
3
17
29
15
15
28
Abdominal pain Abdominal pain, nausea Nausea, emesis
CT scan
3
2.2
CT scan, MRI
3
2.5
CT scan, MRI
15
7.3
AC C
EP
TE D
M AN U
SC
1
Symptoms
Greatest Diagnostic Number of adenoma imaging adenomas diameter (cm)
RI PT
Age at BMI at Patient diagnosis diagnosis (years)
Treatment Continued NET-A Switched to norethindrone 0.35 mg/day Wedge biopsy, cessation of hormones
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1083-3188(16)30232-7
DOI:
10.1016/j.jpag.2016.12.002
Reference:
PEDADO 2077
To appear in:
Journal of Pediatric and Adolescent Gynecology
Received Date: 20 October 2016 Revised Date:
8 December 2016
Accepted Date: 12 December 2016
Please cite this article as: Brady P, Missmer S, Laufer M, Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate, Journal of Pediatric and Adolescent Gynecology (2017), doi: 10.1016/j.jpag.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate
RI PT
Brady PC1,2,4 Missmer SA3,4,5,6, Laufer MR1,2,4
1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics,
Gynecology, and Reproductive Biology; Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115 USA
SC
2 Division of Gynecology, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115 USA
M AN U
3 Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115 USA 4 Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women’s Hospital, Boston, MA, 02115 USA
5 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115 USA
TE D
6 Department of Obstetrics, Gynecology, and Reproductive Biology; College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
Requests for reprints
EP
Paula C. Brady, M.D.
AC C
Brigham and Women’s Hospital 75 Francis St., ASBI-3 Boston, MA 02115
Phone: 617-732-4648 Fax: 617-566-7752
Email: [email protected]
No sources of financial support. The authors have no conflicts of interest to disclose.
1
ACCEPTED MANUSCRIPT
Abstract
Background: Endometriosis—ectopic implantation of endometrial-like tissue—affects 10% of
RI PT
female adolescents and adults. First-line treatment includes progesterone-only (such as norethindrone acetate, NET-A) or combined estrogen/progestin oral contraceptive pills. Estrogen-containing contraceptives confer increased risk of hepatic adenomas, while the
SC
association with NET-A is very rarely reported.
M AN U
Case: Three adolescents with Stage I-II endometriosis managed with NET-A (up to 15 mg/day for 28-78 months) were diagnosed with hepatic adenomas at ages 17-22 years. They previously received estrogen-containing medications, which were stopped > 24 months before diagnosis of
TE D
hepatic adenoma.
Summary and Conclusion: NET-A in a dose above 10 mg per day may be associated with increased risk for hepatic adenomas, likely due to peripheral conversion to ethinyl estradiol. Use
AC C
EP
of NET-A may not be advisable in patients with known hepatic adenomas.
2
ACCEPTED MANUSCRIPT
Introduction
Endometriosis is defined by endometrial-like tissue that is thriving outside of the uterus,
RI PT
affecting approximately 10% of female adolescents and adults of reproductive age.1 Currently, definitive diagnosis of endometriosis is by surgical visualization, and the extent of disease is categorized as stage I to IV – although stage correlates poorly to patients’ symptoms.2,3 While
SC
patients may be asymptomatic, endometriosis often presents with dysmenorrhea, dyspareunia,
M AN U
chronic pelvic pain and infertility.4
Maintenance therapy for suspected or confirmed endometriosis commonly involves analgesics and hormonal medications, including progestin-only (such as norethindrone acetate, NET-A) and combined estrogen/progestin oral contraceptive pills, progestin-only injections, implants or
TE D
intrauterine devices, aromatase inhibitors, or gonadotropin-releasing hormone agonists. Progesterone-only or combined estrogen/progestin oral contraceptive pills are often the first step in management.4 Patients with recurrent or refractory pain may require surgical ablation or
EP
excision of endometriosis.4
AC C
Estrogen-containing contraceptives are associated with an increased risk of hepatic adenomas (34 per 100,000), which can cause life-threatening hemorrhage.5 The risk of developing hepatic adenomas is closely correlated with the duration of use of estrogen-containing contraceptives, and with the potency of the estrogen component.5 Conversely, the association of NET-A and hepatic adenoma has been rarely reported and only in specific populations taking NET-A for
3
ACCEPTED MANUSCRIPT
menstrual suppression such as patients undergoing dialysis or those with congenital platelet disorders.6,7
RI PT
Herein is reported a series of three young women with endometriosis who developed hepatic adenomas after being treated with maximum-dose NET-A (15 mg/day). NET-A is a widely-used medication in the management of endometriosis; this case series alerts clinicians to a potentially
SC
highly morbid complication in patients receiving NET-A for the treatment of endometriosis.
M AN U
Case
Three adolescents and young women with surgically-diagnosed endometriosis were managed with NET-A (Table 1); two patients were diagnosed with stage I endometriosis, while the third
TE D
had stage II endometriosis. The first patient has a past medical history of asthma; the second reports palpitations and migraines, while the third patient had an immature ovarian teratoma and
EP
underwent unilateral oophorectomy at age 11 years with no evidence of recurrence.
The patients initiated NET-A at ages 15-19 years and received the medication for a period of 28-
AC C
78 months prior to the diagnosis of hepatic adenoma. The dose of NET-A varied over that time period, as the dose was titrated according to symptoms; the patients were exposed to the maximum dose of 15 mg/day of NET-A for a period of 12-30 months.
All three patients had previously been exposed to estrogen-containing medications, either combined oral contraceptive pills or conjugated equine estrogen as part of add-back therapy
4
ACCEPTED MANUSCRIPT
during treatment with leuprolide acetate. The patients were exposed to estrogen-containing medications for a range of 13-31 months. These medications were stopped more than 24 months
RI PT
before the hepatic adenomas were diagnosed.
The patients were diagnosed with hepatic adenomas after presenting with abdominal pain and/or nausea and emesis. Abdominal computed tomography (CT) scans were performed in all patients
SC
for diagnosis; two patients also underwent magnetic resonance imaging (MRI) to confirm the diagnosis (Figure 1). The number of adenomas ranged from 3-15, with largest diameters of 2.2-
M AN U
7.3 cm. Only the patient who had both the most numerous adenomas and largest adenoma (15 adenomas, the largest of which was 7.3 cm in diameter) also had mildly elevated liver function tests at the time of presentation.
TE D
The two patients with more limited hepatic disease continued on progestins (one on NET-A, the other on norethindrone 0.35 mg per day), as repeat imaging revealed stability of the lesions. The third patient with the most extensive disease underwent wedge biopsies and stopped all hormonal
EP
medications, after which the lesions significantly reduced in size; eighteen months later, the
AC C
largest lesion was just 2.5 cm in diameter.
Summary and Conclusion
The pathogenesis of hepatic adenoma development due to estrogen exposure is unknown, but the association between the two is well established. Hepatic adenomas are more common in women than in men, and in obese patients, which is relevant as adipose tissue is a peripheral source of
5
ACCEPTED MANUSCRIPT
estrogen production.8 Hepatic adenomas are also associated with combined estrogen/progestin oral contraceptive use; the risk of developing hepatic adenomas is greatest in women over 30 years taking “high potency” (not defined) combined oral contraceptives for more than 25
RI PT
months.5 Of note, combined oral contraceptives have utilized progressively lower doses of
estrogen over time, associated with a decreased incidence of hepatic adenomas among those exposed to combined oral contraceptives.8 Reported only in case reports and small series,
SC
following cessation of estrogen-containing contraceptives, regression of hepatic adenomas
M AN U
(which does not occur in all patients) has been documented in as little as nine months.9
The development of hepatic adenoma in patients receiving NET-A is likely due to peripheral conversion to ethinyl estradiol. Metabolism of NET-A to ethinyl estradiol has been demonstrated to result in serum levels comparable to levels in patients ingesting ethinyl estradiol primarily.10
TE D
A daily dose of 10-20 mg of NET-A results in serum estradiol levels commensurate with ingestion of 20-30 µg of ethinyl estradiol per day.10
EP
This is the first case series to report development of hepatic adenomas in patients receiving NETA for the treatment of endometriosis. Existing reports of the association of NET-A with hepatic
AC C
adenomas are limited to six patients.6,7 These patients received between 10-20 mg per day of NET-A for the indication of menstrual suppression in the setting of dialysis (2 patients) and congenital platelet disorders (4 patients); these patients presented with intra-abdominal hemorrhage (5 patients) or infection (1 patient). Prior exposure to estrogen-containing medication was not reported in these series. This current series represents an important addition
6
ACCEPTED MANUSCRIPT
of three patients who developed hepatic adenomas after being treated with NET-A for a separate indication (endometriosis) and who presented with milder, relatively non-specific symptoms.
RI PT
The development of multiple adenomas in the third patient is notable as she also had the shortest duration of exposure to NET-A (28 months). As obesity is a known risk factor for the
development of hepatic adenomas, the clinical course of this patient may theoretically be
SC
associated with her elevated body mass index (29 kg/m2), possibly due to the peripheral
production of estrogen in adipose tissue.8 However, this is only speculation, as the pathogenesis
M AN U
of hepatic adenomas is not well understood.
The patients in this series had been exposed to estrogen-containing medications in the past, and contribution of these medications to the development of hepatic adenomas cannot be definitively
TE D
excluded. A majority of patients with symptomatic endometriosis, however, will have been exposed to estrogen-containing medications during their treatment. As a result, these three cases are notable above and beyond the background risk of hepatic adenomas in this population.
EP
Furthermore, in these three patients, estrogen-containing medications had been discontinued at least two years prior to the diagnosis of hepatic adenomas, theoretically leaving ample time for
AC C
resolution of adenomas associated with primary estrogen ingestion. The patients also had no symptoms suggestive of hepatic adenomas while consuming estrogen-containing medications, and only became symptomatic following initiation of NET-A. Finally, given the peripheral conversion of NET-A to ethinyl estradiol, biologic plausibility exists for NET-A driving the development of these hepatic adenomas.
7
ACCEPTED MANUSCRIPT
NET-A is approved by the U.S. Food and Drug Administration for use of up to 15 mg per day for the treatment of endometriosis.11 Use of more than 10 mg per day of NET-A, however, may not be advisable in patients with known hepatic adenomas. Furthermore, patients receiving NET-
RI PT
A who report abdominal pain, nausea and/or emesis should undergo imaging to assess for hepatic lesions.
SC
References
M AN U
1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789-99.
2. The American Fertility Society. Classification of endometriosis. Fertil Steril. 1979;32:633-4. 3. Adamson GD. Diagnosis and clinical presentation of endometriosis. Am J Obstet Gynecol. 1990;162:568-9.
TE D
4. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101:927-35. 5. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW Jr.
1979;242:644.
EP
Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA.
AC C
6. Crosnier H, Thibaud E, Duflos C, Polak M. Norethisterone-induced hepatic adenomas can cause life-threatening bleeding in girls with inhereted platelet disorders. Fertil Steril. 2010;94:2329.e1-3.
7. Kalra PA, Guthrie JA, Dibble JB, Turney JH, Brownjohn AM. Hepatic adenomas induced by norethisterone in patients receiving renal dialysis. Br Med J (Clin Res Ed). 1987;294:808.
8
ACCEPTED MANUSCRIPT
8. Agrawal S, Agarwal S, Arnason T, Saini S, Belghiti J. Management of Hepatocellular Adenoma: Recent Advances. Clin Gastroenterol Hepatol. 2015;13:1221-30. 9. Aseni P, Sansalone CV, Sammartino C, Benedetto FD, Carrafiello G, Giacomoni A, et al.
RI PT
Rapid disappearance of hepatic adenoma after contraceptive withdrawal. J Clin Gastroenterol. 2001;33:234-6.
10. Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA. Formation of ethinyl estradiol in
SC
women during treatment with norethindrone acetate. J Clin Endocrinol Metab. 2007;92:2205-7. 11. Aygestin label. U.S. Food and Drug Administration website.
AC C
EP
TE D
2007. Accessed April 1, 2016.
M AN U
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf. Updated July
9
ACCEPTED MANUSCRIPT
Legends:
Table 1. Adolescents diagnosed with hepatic adenomas while receiving norethindrone
RI PT
acetate (NET-A) for the treatment of endometriosis. NET-A = norethindrone acetate; cm = centimeter; CT = computed tomography; MRI = magnetic resonance imaging
SC
Figure 1. Abdominal MRI of hepatic adenomas. T2-weighted image of the upper abdomen in Patient 3 (Table 1) at presentation with the largest and most numerous hepatic adenomas. The
AC C
EP
TE D
M AN U
largest adenoma, 7.3 cm in diameter, is indicated with an arrow.
10
ACCEPTED MANUSCRIPT
Table 1. Adolescents diagnosed with hepatic adenomas while receiving norethindrone acetate (NET-A) for the treatment of endometriosis Age at NET-A initiation (years)
NET-A Duration of dose at NET-A at diagnosis diagnosis (mg/day) (months)
22
22
19
15
46
2
22
25
16
10
78
3
17
29
15
15
28
Abdominal pain Abdominal pain, nausea Nausea, emesis
CT scan
3
2.2
CT scan, MRI
3
2.5
CT scan, MRI
15
7.3
AC C
EP
TE D
M AN U
SC
1
Symptoms
Greatest Diagnostic Number of adenoma imaging adenomas diameter (cm)
RI PT
Age at BMI at Patient diagnosis diagnosis (years)
Treatment Continued NET-A Switched to norethindrone 0.35 mg/day Wedge biopsy, cessation of hormones
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT