Author's response to reviews Title:Primary Amenorrhea in the Physician's Office: Normal Coitus or Not? Always Take a Look. Authors: Flora Bacopoulou (bacopouf@hotmail.com) George Creatsas (geocre@aretaieio.uoa.gr) George P Chrousos (chrousog@mail.nih.gov) Nikoleta Papanikolaou (nikol.papanikolaou@hotmail.com) Efthimios Deligeoroglou (edeligeo@aretaieio.uoa.gr) Version:6Date:27 January 2014 Author's response to reviews: We would like to thank the reviewers for giving us the opportunity to submit a revised version of our manuscript. We appreciate the reviewers insight and we hope that we accommodated most of their suggestions in the revised manuscript. We provide detailed responses to each of the reviewers' comments and we hope that we explain satisfactorily why we think that some comments are invalid. Reviewer: Tarek Shokeir Reviewer's report: This paper describes a case report which does not make a contribution to medical knowledge and does not have educational value or highlight the need for a change in clinical practice or diagnostic/prognostic approaches. This paper describes two cases of the very rare sexual phenomenon of urethral coitus, which is not a common medical knowledge. The aim of this report is to emphasize that a careful assessment of the external genitalia and vagina patency must always be performed in case of primary amenorrhea even if normal sexual activity is assumed and highlights the need for a change in clinical practice, as many pediatricians do not perform gynecologic examination in their current practice setting, according to a recent Clinical Report of the American Academy of Pediatrics (Braverman PK, Breech L and The Committee on Adolescence: Gynecologic examination for adolescents in the pediatric office setting. Pediatrics 2010, 126:583-590). Comment 1: Case reports should include relevant positive and negative findings from history, clinical examination, and investigations. There are a lot of publications and many case reports concerning the issue of primary amenorrhea in adolescents caused by Mayer-Rokitansky-Klister-Hauser syndrome (MRKH-Type II) and associated
with urethral intercourse. Coexistance with pituitary adenoma (micro or macro) is not a novel [Eom KS et al. (J Clin Neurosci, 2009)]. We also include relevant positive and negative findings in the description of our cases. There are a lot of publications concerning the issue of primary amenorrhea caused by Müllerian agenesis as the syndrome accounts for approximately 10% of cases of primary amenorrhea. However, urethral coitus, is a very rare sexual phenomenon; to the best of our knowledge 31 cases in the literature have been described, in women with Müllerian agenesis, as well as with other vaginal abnormalities (Sakinci M, Kokcu A, Malatyalioglu E. Satisfactory urethral coitus in a patient with vaginal stenosis: case report. Int Urogynecol J 2012;23:237-9), hymenal variations (Di Donato V, Manci N, Palaia I, Bellati F, Perniola G, Panici PB: Urethral coitus in a patient with a microperforate hymen. J Minim Invasive Gynecol 2008, 15:642-643), paraplegia, or even with an intact vagina (Ayan S, Gökçe G, Kiliçarslan H, Kaya K, Gültekin EY: An unusual cause of incontinence: urethral coitus. Scand J Urol Nephrol 2001, 35:254). We agree with the reviewer that coexistance of type II with pituitary adenoma (micro or macro) is not a novel. Therefore we have modified the first and fifth paragraphs of the Conclusion section of the manuscript as following: Urethral coitus, is a very rare sexual phenomenon; 31 cases in the literature have been described, most commonly in women with vaginal abnormalities and only in four adolescents. To the best of our knowledge, Case 1 also represents the second reported case of pituitary prolactinoma in association with Müllerian agenesis. Although both conditions are rare, most likely the concurrence is coincidental. When the defective genes for Müllerian agenesis are known, a possible conjecture may be then formulated. Comment 2 - For Case 1: -How did the family physician report 'normal' results on screening with Pap smears in a case with absent vagina and cervix? The family physician was obtaining Pap smears from the dilated urethra and screening was performed on the epithelium of the urethra. Along the urethra there is pseudostratified columnar and stratified columnar epithelium as well as stratified squamous cells near the external urethral orifice. There are small mucus-secreting urethral glands, that help protect the epithelium from the corrosive urine. -What were the tumor markers performed for this case? The tumor markers performed were lactate dehydrogenase (LDH), human
chorionic gonadotropin (HCG), alpha-fetoprotein (AFP) and cancer antigen (CA 125). They have been added in the manuscript. -What was the initial size of the microadenoma at first presentation? The initial size of the microadenoma at presentation was 9.5mm (lateral oblique diameter) and 7.1mm ((longitudinal diameter). Under Case 1 presentation the size of the microadenoma has been added: lateral oblique diameter of 9.5mm and longitudinal diameter of 7.1mm. -What was the dose and course of quinagolide given?. how was the progress with the treatment going on? Quinagolide was administered according to the British National Formulary: the adolescent was commenced 25 micrograms per day at bedtime for the first 3 days, followed by 50 micrograms/day for a further 3 days. From day 7 onwards, the maintenance dose was 75 micrograms/day. In a recent MRI of the pituitary, 2 years after initial investigation, the adenoma is undetectable and serum prolactin has reverted to normal levels 9 ng/ml. The following have been included in the revised manuscript under Case 1: She was started on oral quinagolide aiming for full cure of her prolactinoma. After two years the pituitary adenoma is undetectable on MRI and serum prolactin has reverted to normal. -A supplementation with a laparoscopic picture for the herniated inguinal gonad rather than a picture for dilated urethra would be very appreciated. Inadvertently such photos were not obtained at the time of the operation. Comment 3 - For Case 2: -We think that it is difficult to consider gradual vaginal dilatation as a first line treatment option for a case with total vaginal aplasia with no any pre-existing small vaginal pouch. We thank the reviewer for highlighting this oversight. The adolescent had indeed a vaginal dimple and this has been added in the manuscript. Our patient expressed the desire for nonsurgical management and therefore she was advised to manually place successive dilators on the vaginal dimple for 30 minutes to 2 hours per day. Nonsurgical creation of the vagina is the appropriate first-line approach in most patients as per ACOG Committee Opinion No. 562 (Müllerian agenesis: diagnosis, management, and treatment. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:1134-7). The above have been clarified in the manuscript under Case 2 section: The diagnosis of Müllerian agenesis was made and the adolescent expressed
the desire for nonsurgical management; she was advised to manually place successive dilators on the vaginal dimple for 30 minutes to 2 hours per day. Reviewer: David Klein Major Compulsory Revisions: Comment 4: Conclusion section: Be cautious about stating that our cases highlight the need for careful assessment of external genitalia in all girls external genitalia examination can easily appear to be normal in patients with Mullerian agenesis since the distal vagina can be preserved. Similar comment with the last sentence in the conclusion regarding need for early identification of Mullerian agenesis. Are the authors also recommending a first-line bimanual or speculum exam for all adolescents with primary amenorrhea. This would be very controversial. According to AAP (Braverman PK, Breech L and The Committee on Adolescence: Gynecologic examination for adolescents in the pediatric office setting. Pediatrics 2010, 126:583-590) amenorrhea is an indication for a complete pelvic examination. However, many pediatricians do not have the skills and equipment in their current practice setting to perform a pelvic examination and the adolescent may be fearful, anxious, may experience pain or discomfort with a bimanual or speculum exam. Therefore, we recommend that in adolescents with primary amenorrhea, at a minimum, during assessment of external genitalia, the patency of the vagina should also be checked with gentle insertion of a saline-soaked cotton swab. We have amended the Conclusion section in the revised version of our paper as following: Our cases highlight the need for careful assessment of the external genitalia and vagina patency in all girls with amenorrhea, even if they report normal vaginal sexual activity. The American Academy of Pediatrics promotes the inclusion of the external gynecologic examination in the primary care setting as part of the annual comprehensive physical examination of children and adolescents of all ages and a complete pelvic examination for adolescents with amenorrhea. However, many pediatricians do not have the skills and equipment in their current practice setting to perform a pelvic examination and the adolescent may be fearful, anxious, may experience pain or discomfort with a bimanual or speculum exam. Therefore, we recommend that in adolescents with primary amenorrhea, at a minimum, during assessment of external genitalia, the patency of the vagina should also be checked with gentle insertion of a saline-soaked cotton swab. Despite potential negative implications (loss of patient rapport, practical barriers i.e. need for chaperone) the primary care office of the clinician who has established trust and a comfort level with the patient and often is the first to address her gynecologic issues, is the best setting to perform a gynecologic examination.
Comment 5: In the conclusion sections, it is difficult to tell if the authors are suggesting that the microprolactinoma and MRKH syndrome are related ( associated - i.e. syndromic) or unrelated (e.g. the microprolactinoma was incidentally found in the process of this work up, but unrelated to her presenting symptoms). Prolactinomas have an estimated prevalence of 1 per 10,000 population (Colao A, Lombardi G: Growth hormone and prolactin excess. Lancet 1998; 352: 1455-1461) whereas Müllerian agenesis occurs in 1 of every 4,000-10,000 females (Müllerian agenesis: diagnosis, management, and treatment. Committee Opinion No. 562. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013; 121:1134-7). The following has been included in the revised manuscript under the Conclusion section: Although both conditions are rare, most likely the concurrence is coincidental. When the defective genes for Müllerian agenesis are known, a possible conjecture may be then formulated. Comment 6: Although the authors correctly reference the AAP recommendation, it is important to acknowledge some negative outcomes from universal GU examination: a. Potential loss of rapport thus undermining the most revealing assessment of the asymptomatic adolescent the psychosocial history. b. Decreased usefulness -- with less need for cervical cytology, alternative methods for STI testing, etc. c. Issues with test sensitivity - as stated above, Mullerian agenesis can easily be missed on simple external GU examination d. Time finding chaperone and conducting the exam - universal GU exam takes valuable time away from psychosocial screening 4) Similarly, clarify that the AAP recommendation is for external exam, not pelvic/speculum exam (for which their table 1 gives specific indications). Stating gynecologic exam in the second sentence of that paragraph might be confusing to some readers. We thank the reviewer for the comment. Indeed we have to acknowledge some negative outcomes from universal GU examination. We have amended the Conclusion section in the revised manuscript as following: Our cases highlight the need for careful assessment of the external genitalia and vagina patency in all girls with amenorrhea, even if they report normal vaginal
sexual activity. The American Academy of Pediatrics promotes the inclusion of the external gynecologic examination in the primary care setting as part of the annual comprehensive physical examination of children and adolescents of all ages and a complete pelvic examination for adolescents with amenorrhea. However, many pediatricians do not have the skills and equipment in their current practice setting to perform a pelvic examination and the adolescent may be fearful, anxious, may experience pain or discomfort with a bimanual or speculum exam. Therefore, we recommend that in adolescents with primary amenorrhea, at a minimum, during assessment of external genitalia, the patency of the vagina should also be checked with gentle insertion of a saline-soaked cotton swab. Despite potential negative implications (loss of patient rapport, practical barriers i.e. need for chaperone) the primary care office of the clinician who has established trust and a comfort level with the patient and often is the first to address her gynecologic issues, is the best setting to perform a gynecologic examination. Minor Essential Revisions: Comment 7: Under background, second sentence: please add a pregnancy test as a first line test in primary (and secondary) amenorrhea. Pregnancy test has been added as first line test for primary amenorrhea in the Background section of the manuscript. Comment 8: Under case presentation, Case 1 (and conclusion): please change Papanicolaou smear to Papanicolaou test Papanicolaou smear has been changed to Papanicolaou test in Case 1 and Conclusion sections of the manuscript. Comment 9: Under case presentation, Case 1: please characterize the microadenoma (at least in size); and clarify the indications for treatment (size vs gonadal dysfunction vs fertility issues) as opposed to simply monitoring it over time. Also clarify marked improvement after treatment is this only in size/prolactin level or in patient oriented outcomes as well (patient feeling better, etc.). For asymptomatic patients with small lesions, size/prolactin level improvement is less important. Under Case 1 presentation the size of the microadenoma has been added: lateral oblique diameter of 9.5mm and longitudinal diameter of 7.1mm. We elected to treat the prolactinoma aiming for full cure, as per endocrine protocol of our hospital. In a recent MRI of the pituitary, 2 years after initial
investigation, the adenoma is undetectable and serum prolactin has reverted to normal levels 9 ng/ml. These latest results have been included in the manuscript under Case 1 presentation: She was started on oral quinagolide aiming for full cure of her prolactinoma. After two years the pituitary adenoma is undetectable on MRI and serum prolactin has reverted to normal. Comment 10: Under conclusion, both first and second paragraphs state very rare sexual phenomenon change the wording on one of the two. The phrase very rare sexual phenomenon has been deleted from the second paragraph. Comment 11: For case 2: please clarify the vaginal dilator recommendation clearly there must have been some vaginal tissue present; the reported physical exam and imaging results seem to indicate a complete absence of vaginal tissue. What did bimanual exam show? Will dilators work for this patient? We thank the reviewer for highlighting this oversight. The adolescent had indeed a vaginal dimple and this has been added in the manuscript. Rectal examination did not reveal any evidence of cervix or uterus. Our patient expressed the desire for nonsurgical management and therefore she was advised to manually place successive dilators on the vaginal dimple for 30 minutes to 2 hours per day as per ACOG Committee Opinion No. 562 (Müllerian agenesis: diagnosis, management, and treatment. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:1134-7). Nonsurgical creation of the vagina is the appropriate first-line approach in most patients. According to reported data, 90-95% of a series of patients with müllerian agenesis were able to achieve anatomic and functional success by vaginal dilation (Roberts CP, Haber MJ, Rock JA. Vaginal creation for mullerian agenesis. Am J Obstet Gynecol 2001;185:1349 52; discussion 1352 3; Edmonds DK, Rose GL, Lipton MG, Quek J. Mayer-Rokitansky-Kuster-Hauser syndrome: a review of 245 consecutive cases managed by a multidisciplinary approach with vaginal dilators. Fertil Steril 2012;97:686-90). The vaginal dilator recommendation has been clarified in the manuscript under Case 2 section: The diagnosis of Müllerian agenesis was made and the adolescent expressed the desire for nonsurgical management; she was advised to manually place successive dilators on the vaginal dimple for 30 minutes to 2 hours per day. Discretionary Revisions: Comment 12:
Abstract and throughout text: To be consistent with reference 1 (which is commonly cited for articles on amenorrhea); the authors should consider using Mullerian Agenesis instead of MRKH syndrome, although both terms are commonly used. The term Müllerian agenesis has replaced the term MRKH syndrome throughout the manuscript. Comment 13: Under background, first sentence: consider citing reference 1 (even though cited after the following sentence), since this definition varies among experts and references. Reference 1 has been cited accordingly. Comment 14: Under case presentation, case 2: please clarify attempted sexual intercourse -did she report penetration? Also, specify that this finding, in addition to the dilated urethra, helped to confirm urethral coitus. The following have been added under Case 2 presentation: A detailed history revealed that dysuria had followed attempted sexual intercourse with penetration; the additional finding of a dilated urethra, helped to confirm urethral coitus. Comment 15: If the length of the manuscript allows, please specify the lab results (hormone panels) for case 2, even if normal. Hormonal profile lab results for both cases have been added in Table 1 of the revised manuscript. Reviewer: Karine Morcel Major Compulsory revisions: Comment 16: Many similar cases have already been reported in the literature. Recently, two similar cases associated with an interesting review of the literature were published by Rickman J et al. in J Pediatr Adolesc Gynecol. This paper is not referred by the authors. Urethral coitus, is a very rare sexual phenomenon; to the best of our knowledge
31 cases in the literature have been described, in women with Müllerian agenesis, as well as with other vaginal abnormalities (Sakinci M, Kokcu A, Malatyalioglu E. Satisfactory urethral coitus in a patient with vaginal stenosis: case report. Int Urogynecol J 2012;23:237-9), hymenal variations (Di Donato V, Manci N, Palaia I, Bellati F, Perniola G, Panici PB: Urethral coitus in a patient with a microperforate hymen. J Minim Invasive Gynecol 2008, 15:642-643), paraplegia, or even with an intact vagina (Ayan S, Gökçe G, Kiliçarslan H, Kaya K, Gültekin EY: An unusual cause of incontinence: urethral coitus. Scand J Urol Nephrol 2001, 35:254). The recently published paper of two similar cases (Ryckman J, Black A, Fleming N. Adolescent urethral coitus: 2 cases and review of the literature. J Pediatr Adolesc Gynecol 2013) has been referred in the revised manuscript (Reference no 11). We have also included the latest relevant paper of Rouzi AA: Urethral sex in a woman with previously undiagnosed Mayer-Rokitansky-Küster-Hauser syndrome. Clin Exp Obstet Gynecol 2013, 40:452-453 (Reference no 7). We have modified the first paragraph of the Conclusion section of the manuscript as following: Urethral coitus, is a very rare sexual phenomenon; 31 cases in the literature have been described, most commonly in women with vaginal abnormalities and only in four adolescents. Comment 17: The only interest of this manuscript would be to highlight that a gynaecologic exam must always be performed in case of primary amenorrhea despite a normal sexual activity, prior to dismiss an anatomic aetiology. In this case, the discussion should be rewritten to emphasize this point. The Conclusion section has been rewritten in order to emphasize this point as following: Our cases highlight the need for careful assessment of the external genitalia and vagina patency in all girls with amenorrhea, even if they report normal vaginal sexual activity. The American Academy of Pediatrics promotes the inclusion of the external gynecologic examination in the primary care setting as part of the annual comprehensive physical examination of children and adolescents of all ages and a complete pelvic examination for adolescents with amenorrhea. However, many pediatricians do not have the skills and equipment in their current practice setting to perform a pelvic examination and the adolescent may be fearful, anxious, may experience pain or discomfort with a bimanual or speculum exam. Therefore, we recommend that in adolescents with primary amenorrhea, at a minimum, during assessment of external genitalia, the patency of the vagina should also be checked with gentle insertion of a saline-soaked cotton swab. Despite potential negative implications (loss of patient rapport, practical barriers i.e. need for chaperone) the primary care office of the clinician who has established trust and a comfort level with the patient and often is the first to address her gynecologic issues, is the best setting to perform a
gynecologic examination. Comment 18: In last, the association between MRKH syndrome and pituitary micorprolactinemia may be random. The authors don't take into account the relative frequency of both diseases and don't discuss the possibility of a coincidental association. Prolactinomas have an estimated prevalence of 1 per 10,000 population (Colao A, Lombardi G: Growth hormone and prolactin excess. Lancet 1998; 352: 1455-1461) whereas Müllerian agenesis occurs in 1 of every 4,000-10,000 females (Müllerian agenesis: diagnosis, management, and treatment. Committee Opinion No. 562. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:1134-7). The following has been included in the revised manuscript under the Conclusion section: Although both conditions are rare, most likely the concurrence is coincidental. When the defective genes for Müllerian agenesis are known, a possible conjecture may be then formulated.