Gynecology_Novak

Gynecology_Novak. 375. Vigan`o P, Somigliana E, Vercellini P. Levonorgestrel-releasing intrauterine system for the treatment of endometriosis: biological and clinical evidence. Womens Health 2007;3:207–214. 376. Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system (LNG-IUS)—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol 2006;125:9–28. 377. Vercellini P, Aimi G, Panazza S, et al. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999;72:505–508. 378. Fedele L, Bianchi S, Zanconato G, et al. Use of a levonorgestrelreleasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril 2001;75:485–488. 379.


Gynecology_Novak

Gynecology_Novak. 378. Fedele L, Bianchi S, Zanconato G, et al. Use of a levonorgestrelreleasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril 2001;75:485–488. 379. Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993–1998. 380. Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra-uterine administered progestogen (levonorgestrel): a 3-year follow-up. Hum Reprod 2005;20:789–793. 381. Murphy AA, Zhou MH, Malkapuram S, et al. RU486induced growth inhibition of human endometrial cells. Fertil Steril 2000;74:1014–1019. 382. Koide SS. Mifepristone: auxiliary therapeutic use in cancer and related disorders. J Reprod Med 1998;43:551–560. 383.


Gynecology_Novak

Gynecology_Novak. 382. Koide SS. Mifepristone: auxiliary therapeutic use in cancer and related disorders. J Reprod Med 1998;43:551–560. 383. Kettel LM, Murphy AA, Morales AJ, et al. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril 1996;65:23–28. 384. Kettel LM, Murphy AA, Morales AJ, et al. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU486). Am J Obstet Gynecol 1998;178:1151–1156. 385. Stoeckemann K, Hegele-Hartung C, Chwalisz K. Effects of the progesterone antagonists onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis in intact rats. Hum Reprod 1995;10:3264–3271. 386. Fuhrmann U, Hess Stummp H, Cleve A, et al. Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem 2000;43:5010–5016. 387. Slayden OD, Chwalisz K, Brenner RM. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques. Hum Reprod 2001;8:1562–1574.


Gynecology_Novak

Gynecology_Novak. 387. Slayden OD, Chwalisz K, Brenner RM. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques. Hum Reprod 2001;8:1562–1574. 388. Brosens IA, Verleyen A, Cornillie FJ. The morphologic effect of short-term medical therapy of endometriosis. Am J Obstet Gynecol 1987;157:1215–1221. 389. Fedele L, Bianchi S, Viezzoli T, et al. Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril 1989;51:781–785. 390. Wingfield M, Healy DL. Endometriosis: medical therapy. Baillieres Clin Obstet Gynecol 1993;7:813–838. 391. Hornstein MD, Gleason RE, Barbieri RL. A randomized double-blind prospective trial of two doses of gestrinone in the treatment of endometriosis. Fertil Steril 1990;53:237–241. 392. Gestrinone Italian Study Group. Gestrinone versus a GnRHa for the treatment of pelvic pain associated with endometriosis: a multicenter, randomized, double-blind study. Fertil Steril 1996;66:911– 919. 393.


Gynecology_Novak

Gynecology_Novak. 393. Barbieri RL, Ryan KJ. Danazol: endocrine pharmacology and therapeutic applications. Am J Obstet Gynecol 1981;141:453–463. 394. El-Roeiy A, Dmowski WP, Gleicher N, et al. Danazol but not gonadotropin-releasing hormone agonists suppresses autoantibodies in endometriosis. Fertil Steril 1988:50;864–871. 395. Ota H, Maki M, Shidara Y, et al. Effects of danazol at the immunologic level in patients with adenomyosis, with special reference to autoantibodies: a multi-center cooperative study. Am J Obstet Gynecol 1992;167:481–486. 396. Hill JA, Haimovici F, Politch JA, et al. Effects of soluble products of activated macrophages (lymphokines and monokines) on human sperm motion parameters. Fertil Steril 1987;47:460–465. 397. Mori H, Nakagawa M, Itoh N, et al. Danazol suppresses the production of interleukin-1b and tumor necrosis factor by human monocytes. Am J Reprod Immunol 1990;24:45–50. 398.


Gynecology_Novak

Gynecology_Novak. 397. Mori H, Nakagawa M, Itoh N, et al. Danazol suppresses the production of interleukin-1b and tumor necrosis factor by human monocytes. Am J Reprod Immunol 1990;24:45–50. 398. Braun DP, Gebel H, Rotman C, et al. The development of cytotoxicity in peritoneal macrophages from women with endometriosis. Fertil Steril 1992;1203:1203–1210. 399. Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol. N Engl J Med 1976;295:1444– 1448. 400. Ahn YS, Harrington WJ, Mylvaganam R, et al. Danazol therapy for autoimmune hemolytic anemia. Ann Intern Med 1985;102:298– 301. 401. Agnello V, Pariser K, Gell J, et al. Preliminary observations on danazol therapy of systemic lupus erythematosus: effect on DNA antibodies, thrombocytopenia and complement. J Rheumatol 1983;10:682–687. 402. Schreiber AD, Chien P, Tomaski A, et al. Effect of danazol in immune thrombocytopenic purpura. N Engl J Med 1987;316:503– 508. 403.


Gynecology_Novak

Gynecology_Novak. 402. Schreiber AD, Chien P, Tomaski A, et al. Effect of danazol in immune thrombocytopenic purpura. N Engl J Med 1987;316:503– 508. 403. Mylvaganam R, Ahn YS, Harrington WJ, et al. Immune modulation by danazol in autoimmune thrombocytopenia. Clin Immunol Immunopathol 1987;42:281–287. 404. Selak V, Farquhar C, Prentice A, et al. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2007;4:CD000068. 405. Igarashi M, Iizuka M, Abe Y, et al. Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Hum Reprod 1998;13:1952–1956. 406. Borroni R, Di Blasio AM, Gaffuri B, et al. Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate. Mol Cell Endocrinol 2000;159:37–43 407.


Gynecology_Novak

Gynecology_Novak. Sharpe-Timms KL, Zimmer RL, Jolliff WJ, et al. GnRHa therapy alters activity of plasminogen activators, matrix metalloproteinases, and their inhibitors in rat models for adhesion formation and endometriosis: potential GnRHa regulated mechanisms reducing adhesion formation. Fertil Steril 1998;68:916–923. 408. Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol 1992;166:740–745. 409. Riis BJ, Christiansen C, Johansen JS, et al. Is it possible to prevent bone loss in young women treated with luteinizing hormone-releasing agonists? J Clin Endocrinol Metab 1990;70:920– 924. 410. Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol 1998;91:16–24. 411. Sillem M, Parviz M, Woitge HW, et al. Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin. Exp Clin Endocrinol Diabetes 1999;107:379–385. 412.


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Gynecology_Novak. 411. Sillem M, Parviz M, Woitge HW, et al. Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin. Exp Clin Endocrinol Diabetes 1999;107:379–385. 412. Taskin O, Uryan I, Yalcinoglu I, et al. Effectiveness of tibolone on hypoestrogenic symptoms induced by goserelin treatment in patients with endometriosis. Fertil Steril 1997;67:40–45. 413. Lindsay PC, Shaw RW, Bennink HJC, et al. The effect of add-back treatment with tibolone (Livial) on patients treated with the GnRHa triptorelin (Decapeptyl). Fertil Steril 1996;65:342–348. 414. Franke HR, van de Weijere PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective randomized placebo-controlled double-blind trial. Fertil Steril 2000;74:534–539. 415.


Gynecology_Novak

Gynecology_Novak. 415. Sagsveen M, Farmer JE, Prentice A, et al. Gonadotrophinreleasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev 2003;4:CD001297. 416. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril 2000;74:964–968. 417. Tahara M, Matsuoka T, Yokoi T, et al. Treatment of endometriosis with a decreasing dosage of gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy (“draw-back” therapy). Fertil Steril 2000;73:799–804 418. Yano S, Ikegami Y, Nakao K. Studies on the effect of the new non-steroidal aromatase inhibitor fadrozole hydrochloride in an endometriosis model in rats. Arzneimittelforschung 1996;46:192– 195. 419.


Gynecology_Novak

Gynecology_Novak. 419. Kudoh M, Susaki Y, Ideyama Y, et al. Inhibitory effects of a novel aromatase inhibitor, YM511, in rats with experimental endometriosis. J Steroid Biochem Mol Biol 1997;63:1–3. 420. Takayama K, Zeitoun K, Gunby RT, et al. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril 1998;69:709–713. 421. Nawathe A, Patwardhan S, Yates D, et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG 2008;115:818–822. 422. Soysal S, Soysal M, Ozer S, et al. The effects of post-surgical administration of goserelin plus anastrazole compared to goserelin alone in patients with severe endometriosis: a prospective randomised trial. Hum Reprod 2004;19:160–167. 423. Buelke SJ, Bryant HU, Francis PC. The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing. Reprod Toxicol 1998;12:217–221. 424.


Gynecology_Novak

Gynecology_Novak. 424. Stratton P, Sinaii N, Segars J, et al. Return of chronic pelvic pain from endometriosis after raloxifene treatment: a randomized controlled trial. Obstet Gynecol 2008;111:88–96. 425. D’Antonio M, Martelli F, Peano S, et al. Ability of recombinant human TNF binding protein-1 (r-hTBP-1) to inhibit the development of experimentally induced endometriosis in rats. J Reprod Immunol 2000;48:81–98. 426. Koninckx PR, Craessaerts M, Timmerman D, et al. Anti-TNFalpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod 2008;23:2017–2023. 427. Lv D, Song H, Li Y, et al. Pentoxifylline versus medical therapies for subfertile women with endometriosis. Cochrane Database Syst Rev 2009;3:CD007677. 428. Lebovic DI, Kir M, Casey CL, et al. Peroxisome proliferatoractivated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril 2004;82:1008–1013. 429.


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Gynecology_Novak. Lebovic DI, Kir M, Casey CL, et al. Peroxisome proliferatoractivated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril 2004;82:1008–1013. 429. Moravek MB, Ward EA, Lebovic DI. Thiazolidinediones as therapy for endometriosis: a case series. Gynecol Obstet Invest 2009;68:167–170. 430. Ingelmo JM, Quereda F, Acien P. Intraperitoneal and subcutaneous treatment of experimental endometriosis with recombinant human interferon-alpha-2b in a murine model. Fertil Steril 1999;71:907– 911. 431. Keenan JA, Williams-Boyce PK, Massey PJ, et al. Regression of endometrial explants in a rat model of endometriosis treated with immune modulators loxoribine and levamisole. Fertil Steril 2000;72:135–141. 432. Kyama CM, Mihalyi A, Simsa P, et al. Non-steroidal targets in the diagnosis and treatment of endometriosis [review]. Curr Med Chem 2008;15:1006–1017. 433.


Gynecology_Novak

Gynecology_Novak. 432. Kyama CM, Mihalyi A, Simsa P, et al. Non-steroidal targets in the diagnosis and treatment of endometriosis [review]. Curr Med Chem 2008;15:1006–1017. 433. Flower A, Liu JP, Chen S, et al. Chinese herbal medicine for endometriosis. Cochrane Database Syst Rev 2009;3:CD006568. 434. Olive DL, Lee KL. Analysis of sequential treatment protocols for endometriosis-associated infertility. Am J Obstet Gynecol 1986;154:613–619. 435. Jacobson TZ, Barlow DH, Koninckx PR, et al. Laparoscopic surgery for subfertility associated with endometriosis (Cochrane Review). In: The Cochrane Library, Issue 3. Chichester, UK: Wiley, 2004. 436. Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007;3:CD000155. 437. Arumugam K, Urquhart R. Efficacy of laparoscopic electrocoagulation in infertile patients with minimal or mild endometriosis. Acta Obstet Gynecol Scand 1991;70:125–127. 438.


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Gynecology_Novak. 437. Arumugam K, Urquhart R. Efficacy of laparoscopic electrocoagulation in infertile patients with minimal or mild endometriosis. Acta Obstet Gynecol Scand 1991;70:125–127. 438. Adamson GD, Hurd SJ, Pasta DJ, et al. Laparoscopic endometriosis treatment: is it better? Fertil Steril 1993;59:35–44. 439. Guzick DS, Canis M, Silliman NP, et al. Prediction of pregnancy in infertile women based on the ASRM’s revised classification for endometriosis. Fertil Steril 1997;67:822–836. 440. Osuga Y, Koga K, Tsutsumi O, et al. Role of laparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest 2002;53(Suppl 1):33–39. 441. Canis M, Pouly JL, Wattiez A, et al. Incidence of bilateral adnexal disease in severe endometriosis (revised American Fertility Society [AFS] stage IV): should a stage V be included in the AFS classification? Fertil Steril 1992;57:691–692. 442.


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Gynecology_Novak. 442. Chapron C, Fritel X, Dubuisson JB. Fertility after laparoscopic management of deep endometriosis infiltrating the uterosacral ligaments. Hum Reprod 1999;14:329–332. 443. Pagidas K, Falcone T, Hemmings R, et al. Comparison of reoperation for moderate (stage III) and severe (stage IV) endometriosisrelated infertility. Fertil Steril 1996;65:791–795. 444. Rock JA, Guzick DS, Dengos C, et al. The conservative surgical treatment of endometriosis: evaluation of pregnancy success with respect to the extent of disease as categorized using contemporary classification systems. Fertil Steril 1981;35:131–137. 445. Somigliana E, Daguati R, Vercellini P, et al. The use and effectiveness of in vitro fertilization in women with endometriosis: the surgeon’s perspective. Fertil Steril 2009;91:1775–1779. 446. Goldstein DP, De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care 1980;1:37–41. 447.


Gynecology_Novak

Gynecology_Novak. 446. Goldstein DP, De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care 1980;1:37–41. 447. Bai SW, Cho HJ, Kim JY, et al. Endometriosis in an adolescent population: the severance hospital in Korean experience. Yonsei Med J 2002;43:48–52. 448. Ballweg ML. Big picture of endometriosis helps provide guidance on approach to teens: comparative historical data show endo starting younger, is more severe. J Pediatr Adolesc Gynecol 2003;16:S21– A26. 449. Reese KA, Reddy S, Rock JA. Endometriosis in an adolescent population: the Emory experience. J Pediatr Adolesc Gynecol 1996;9:125–128. 450. Laufer MR, Goitein L, Bush M, et al. Prevalence of endometriosis in adolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol 1997;10:199–202. 451. Vercellini P, Fedele L, Arcaini L, et al. Laparoscopy in the diagnosis of chronic pelvic pain in adolescent women. J Reprod Med 1989;34:827–830. 452.


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Gynecology_Novak. 451. Vercellini P, Fedele L, Arcaini L, et al. Laparoscopy in the diagnosis of chronic pelvic pain in adolescent women. J Reprod Med 1989;34:827–830. 452. Emmert C, Romann D, Riedel HH. Endometriosis diagnosed by laparoscopy in adolescent girls. Arch Gynecol Obstet 1998;261:89– 93. 453. Hassan E, Kontoravdis A, Hassiakos D, et al. Evaluation of combined endoscopic and pharmaceutical management of endometriosis during adolescence. Clin Exp Obstet Gynecol 1999;26:85–87. 454. Kontoravdis A, Hassan E, Hassiakos D, et al. Laparoscopic evaluation and management of chronic pelvic pain during adolescence. Clin Exp Obstet Gynecol 1999;26:76–77. 455. Shin SY, Lee YY, Yang SY, et al. Characteristics of menstruation-related problems for adolescents and premarital women in Korea. Eur J Obstet Gynecol Reprod Biol 2005;121:236–242. 456. Stavroulis AI, Saridogan E, Creighton SM, et al. Laparoscopic treatment of endometriosis in teenagers. Eur J Obstet Gynecol Reprod Biol 2006;125:248–250.


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Gynecology_Novak. 456. Stavroulis AI, Saridogan E, Creighton SM, et al. Laparoscopic treatment of endometriosis in teenagers. Eur J Obstet Gynecol Reprod Biol 2006;125:248–250. 457. Davis GD, Thillet E, Lindemann J. Clinical characteristics of adolescent endometriosis. J Adolesc Health 1993;14:362–368. 458. Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly. Fertil Steril 2005;83:758–760. 459. Evers JLH. The pregnancy rate of the no-treatment group in randomized clinical trials of endometriosis therapy. Fertil Steril 1989;52:906–909. 460. Propst AM, Laufer M. Endometriosis in adolescents: incidence, diagnosis and treatment. J Reprod Med 1999;44:751–758. 461. American College of Obstetricians and Gynecologists. ACOG Committee Opinion. No. 310. Endometriosis in adolescents. Obstet Gynecol 2005;105:921–927. 462.


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Gynecology_Novak. 461. American College of Obstetricians and Gynecologists. ACOG Committee Opinion. No. 310. Endometriosis in adolescents. Obstet Gynecol 2005;105:921–927. 462. Sanfilippo JS, Wakim NG, Schikler KN, et al. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 1986;154:39–43. 463. Ugur M, Turan C, Mungan T, et al. Endometriosis in association with mullerian anomalies. Gynecol Obstet Invest 1995;40:261–264. 464. Hur JY, Shin JH, Lee JK, et al. Septate uterus with double cervices, unilaterally obstructed vaginal septum, and ipsilateral renal agenesis: a rare combination of m¨ullerian and wolffian anomalies complicated by severe endometriosis in an adolescent. J Minim Invasive Gynecol 2007;14:128–131. 465. Al Kadri H, Hassan S, Al-Fozan HM, et al. Hormone therapy for endometriosis and surgical menopause. Cochrane Database Syst Rev 2009;1:CD005997. 466.


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Gynecology_Novak. 465. Al Kadri H, Hassan S, Al-Fozan HM, et al. Hormone therapy for endometriosis and surgical menopause. Cochrane Database Syst Rev 2009;1:CD005997. 466. Fedele L, Bianchi S, Rafaelli R, et al. Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis. Maturitas 1999;32:189–193. 467. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent of recurrent disease. Fertil Steril 1991;56:628–634. 468. Vercellini P, Barbara G, Abbiati A, et al. Repetitive surgery for recurrent symptomatic endometriosis: what to do? Eur J Obstet Gynecol Reprod Biol 2009;146:15–21. 469. Vercellini P, Fedele L, Aimi G, et al. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod 2006;21:2679–2685. 470.


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Gynecology_Novak. 470. Berlanda N, Vercellini P, Fedele L. The outcomes of repeat surgery for recurrent symptomatic endometriosis. Curr Opin Obstet Gynecol 2010;22:320–325. 471. Vercellini P, Somigliana E, Vigan`oP,etal. The effect of second-line surgery on reproductive performance of women with recurrent endometriosis: a systematic review. Acta Obstet Gynecol Scand 2009;88:1074–1082. 472. Busacca M, Marana R, Caruana P, et al. Recurrence of ovarian endometrioma after laparoscopic excision. Am J Obstet Gynecol 1999;180:519–523. 473. Schindler AE, Foertig P, Kienle E, et al. Early treatment of endometriosis with GnRH-agonists: impact on time to recurrence. Eur J Obstet Gynecol 2000;93:123–125. 474. Dmowski WP, Cohen MR. Antigonadotropin (danazol) in the treatment of endometriosis: evaluation of posttreatment fertility and three-year follow-up data. Am J Obstet Gynecol 1978;130:41–48. 475.


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Gynecology_Novak. Dmowski WP, Cohen MR. Antigonadotropin (danazol) in the treatment of endometriosis: evaluation of posttreatment fertility and three-year follow-up data. Am J Obstet Gynecol 1978;130:41–48. 475. Ghezzi F, Beretta P, Franchi M, et al. Recurrence of endometriosis and anatomical location of the primary lesion. Fertil Steril 2001;75:136–140. 476. Parker JD, Leondires M, Sinaii N, et al. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril 2006;86:711–715. 477. Vercellini P, Somigliana E, Vigan`oP,etal. Post-operative endometriosis recurrence: a plea for prevention based on pathogenetic, epidemiological and clinical evidence. Reprod Biomed Online 2010;21:259–265. 478. Razzi S, Luisi S, Ferretti C, et al. Use of a progestogen only preparation containing desogestrel in the treatment of recurrent pelvic pain after conservative surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol 2007;135:188–190. 479.


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Gynecology_Novak. 479. Vercellini P, Somigliana E, Daguati R, et al. The second time around: reproductive performance after repetitive versus primary surgery for endometriosis. Fertil Steril 2009;92:1253–1255. David E. Soper Vaginitis is diagnosed by office-based testing. More prolonged antifungal therapy is indicated for women with complicated vulvovaginal candidiasis (VVC) than for those with uncomplicated disease. Women with normal physical examination findings and no evidence of fungal infection disclosed by microscopy are unlikely to have VVC and should not be treated empirically unless results of a vaginal yeast culture are positive. Cervicitis is commonly associated with bacterial vaginosis (BV), which, if not treated concurrently, leads to significant persistence of the symptoms and signs of cervicitis. Women with mild-to-moderate pelvic inﬂammatory disease (PID) can be treated as outpatients.


Gynecology_Novak

Gynecology_Novak. Women with mild-to-moderate pelvic inﬂammatory disease (PID) can be treated as outpatients. Trocar drainage, with or without placement of a drain, is successful in as many as 90% of patients with PID complicated by tubo-ovarian abscess that fails to respond to antimicrobial therapy within 72 hours. Because false-negative results are common with herpes simplex virus (HSV) cultures, especially in patients with recurrent infections, type-specific glycoprotein G-based antibody assay tests are useful in confirming a clinical diagnosis of genital herpes. Suppressive treatment partially decreases symptomatic and asymptomatic viral shedding and the potential for transmission.


Gynecology_Novak

Gynecology_Novak. Suppressive treatment partially decreases symptomatic and asymptomatic viral shedding and the potential for transmission. Genitourinary tract infections are among the most frequent disorders for which patients seek care from gynecologists. By understanding the pathophysiology of these diseases and having an effective approach to their diagnosis, physicians can institute appropriate antimicrobial therapy to treat these conditions and reduce long-term sequelae. The Normal Vagina


Gynecology_Novak

Gynecology_Novak. The Normal Vagina Normal vaginal secretions are composed of vulvar secretions from sebaceous, sweat, Bartholin, and Skene glands; transudate from the vaginal wall; exfoliated vaginal and cervical cells; cervical mucus; endometrial and oviductal ﬂuids; and micro-organisms and their metabolic products. The type and amount of exfoliated cells, cervical mucus, and upper genital tract ﬂuids are determined by biochemical processes that are inﬂuenced by hormone levels (1). Vaginal secretions may increase in the middle of the menstrual cycle because of an increase in the amount of cervical mucus. These cyclic variations do not occur when oral contraceptives are used and ovulation does not occur.


Gynecology_Novak

Gynecology_Novak. The vaginal desquamative tissue is made up of vaginal epithelial cells that are responsive to varying amounts of estrogen and progesterone. Superficial cells, the main cell type in women of reproductive age, predominate when estrogen stimulation is present. Intermediate cells predominate during the luteal phase because of stimulation by progesterone. Parabasal cells predominate in the absence of either hormone, a condition that may be found in postmenopausal women who are not receiving hormonal therapy. The normal vaginal ﬂora is mostly aerobic, with an average of six different species of bacteria, the most common of which is hydrogen peroxide–producing lactobacilli. The microbiology of the vagina is determined by factors that affect the ability of bacteria to survive (2). These factors include vaginal pH and the availability of glucose for bacterial metabolism.


Gynecology_Novak

Gynecology_Novak. The pH level of the normal vagina is lower than 4.5, which is maintained by the production of lactic acid. Estrogen-stimulated vaginal epithelial cells are rich in glycogen. Vaginal epithelial cells break down glycogen to monosaccharides, which can be converted by the cells themselves, and lactobacilli to lactic acid.


Gynecology_Novak

Gynecology_Novak. Normal vaginal secretions are ﬂoccular in consistency, white in color, and usually located in the dependent portion of the vagina (posterior fornix). Vaginal secretions can be analyzed by a wet-mount preparation. A sample of vaginal secretions is suspended in 0.5 mL of normal saline in a tube, transferred to a slide, covered with a slip, and assessed by microscopy. Some clinicians prefer to prepare slides by suspending secretions in saline placed directly on the slide. Secretions should not be placed on the slide without saline because this method causes drying of the vaginal secretions and does not result in a well-suspended preparation. Microscopy of normal vaginal secretions reveals many superficial epithelial cells, few white blood cells (less than 1 per epithelial cell), and few, if any, clue cells. Clue cells are superficial vaginal epithelial cells with adherent bacteria, usually Gardnerella vaginalis, which obliterates the crisp cell border when visualized microscopically.


Gynecology_Novak

Gynecology_Novak. if any, clue cells. Clue cells are superficial vaginal epithelial cells with adherent bacteria, usually Gardnerella vaginalis, which obliterates the crisp cell border when visualized microscopically. Potassium hydroxide 10% (KOH) may be added to the slide, or a separate preparation can be made, to examine the secretions for evidence of fungal elements. The results are negative in women with normal vaginal microbiology. Gram stain reveals normal superficial epithelial cells and a predominance of gram-positive rods (lactobacilli).


Gynecology_Novak

Gynecology_Novak. Bacterial Vaginosis Bacterial vaginosis (BV) is an alteration of normal vaginal bacterial ﬂora that results in the loss of hydrogen peroxide–producing lactobacilli and an overgrowth of predominantly anaerobic bacteria (3,4). The most common form of vaginitis in the United States is BV (5). Anaerobic bacteria can be found in less than 1% of the ﬂora of normal women. In women with BV, however, the concentration of anaerobes, and G. vaginalis and Mycoplasma hominis, is 100 to 1,000 times higher than in normal women. Lactobacilli are usually absent. It is not known what triggers the disturbance of normal vaginal ﬂora. It is postulated that repeated alkalinization of the vagina, which occurs with frequent sexual intercourse or use of douches, plays a role. After normal hydrogen peroxide–producing lactobacilli disappear, it is difficult to reestablish normal vaginal ﬂora, and recurrence of BV is common.


Gynecology_Novak

Gynecology_Novak. Numerous studies show an association of BV with significant adverse sequelae. Women with BV are at increased risk for pelvic inﬂammatory disease (PID), postabortal PID, postoperative cuff infections after hysterectomy, and abnormal cervical cytology (6–9). Pregnant women with BV are at risk for premature rupture of the membranes, preterm labor and delivery, chorioamnionitis, and postcesarean endometritis (10,11). In women with BV who are undergoing surgical abortion or hysterectomy, perioperative treatment with metronidazole eliminates this increased risk (12,13). Diagnosis Office-based testing is required to diagnose BV. It is diagnosed on the basis of the following findings (14): 1. A fishy vaginal odor, which is particularly noticeable following coitus, and vaginal discharge are present. 2. Vaginal secretions are gray and thinly coat the vaginal walls. 3. The pH of these secretions is higher than 4.5 (usually 4.7 to 5.7). 4.


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Gynecology_Novak. 2. Vaginal secretions are gray and thinly coat the vaginal walls. 3. The pH of these secretions is higher than 4.5 (usually 4.7 to 5.7). 4. Microscopy of the vaginal secretions reveals an increased number of clue cells, and leukocytes are conspicuously absent. In advanced cases of BV, more than 20% of the epithelial cells are clue cells. 5. The addition of KOH to the vaginal secretions (the “whiff” test) releases a fishy, aminelike odor. Clinicians who are unable to perform microscopy should use alternative diagnostic tests such as a pH and amines test card, detection of G. vaginalis ribosomal RNA, or Gram stain (15). Culture of G. vaginalis is not recommended as a diagnostic tool because of its lack of specificity. Treatment Ideally, treatment of BV should inhibit anaerobes but not vaginal lactobacilli. The following treatments are effective: 1.


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Gynecology_Novak. Treatment Ideally, treatment of BV should inhibit anaerobes but not vaginal lactobacilli. The following treatments are effective: 1. Metronidazole, an antibiotic with excellent activity against anaerobes but poor activity against lactobacilli, is the drug of choice for the treatment of BV. A dose of 500 mg administered orally twice a day for 7 days should be used. Patients should be advised to avoid using alcohol during treatment with oral metronidazole and for 24 hours thereafter. 2. Metronidazole gel, 0.75%, one applicator (5 g) intravaginally once daily for 5 days, may also be prescribed. The overall cure rates range from 75% to 84% with the aforementioned regimens (16). Clindamycin in the following regimens is effective in treating BV: 1. Clindamycin ovules, 100 mg, intravaginally once at bedtime for 3 days 2. Clindamycin bioadhesive cream, 2%, 100 mg intravaginally in a single dose 3. Clindamycin cream, 2%, one applicator full (5 g) intravaginally at bedtime for 7 days 4.


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Gynecology_Novak. Clindamycin bioadhesive cream, 2%, 100 mg intravaginally in a single dose 3. Clindamycin cream, 2%, one applicator full (5 g) intravaginally at bedtime for 7 days 4. Clindamycin, 300 mg, orally twice daily for 7 days Many clinicians prefer intravaginal treatment to avoid systemic side effects such as mild to moderate gastrointestinal upset and unpleasant taste. Treatment of the male sexual partner does not improve therapeutic response and therefore is not recommended (16).


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Gynecology_Novak. Trichomonas Vaginitis Trichomonas vaginitis is caused by the sexually transmitted, ﬂagellated parasite, Trichomonas vaginalis. The transmission rate is high; 70% of men contract the disease after a single exposure to an infected woman, which suggests that the rate of male-to-female transmission is even higher. The parasite, which exists only in trophozoite form, is an anaerobe that has the ability to generate hydrogen to combine with oxygen to create an anaerobic environment. It often accompanies BV, which can be diagnosed in as many as 60% of patients with trichomonas vaginitis (17). Diagnosis Local immune factors and inoculum size inﬂuence the appearance of symptoms. Symptoms and signs may be much milder in patients with small inocula of trichomonads, and trichomonas vaginitis often is asymptomatic (17,18). 1. Trichomonas vaginitis is associated with a profuse, purulent, malodorous vaginal discharge that may be accompanied by vulvar pruritus. 2.


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Gynecology_Novak. 1. Trichomonas vaginitis is associated with a profuse, purulent, malodorous vaginal discharge that may be accompanied by vulvar pruritus. 2. A purulent vaginal discharge may exude from the vagina. 3. In patients with high concentrations of organisms, a patchy vaginal erythema and colpitis macularis (“strawberry” cervix) may be observed. 4. The pH of the vaginal secretions is usually higher than 5.0. 5. Microscopy of the secretions reveals motile trichomonads and increased numbers of leukocytes. 6. Clue cells may be present because of the common association with BV. 7. The whiff test may be positive.


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Gynecology_Novak. 6. Clue cells may be present because of the common association with BV. 7. The whiff test may be positive. Morbidity associated with trichomonal vaginitis may be related to BV. Patients with trichomonas vaginitis are at increased risk for postoperative cuff cellulitis following hysterectomy (8). Pregnant women with trichomonas vaginitis are at increased risk for premature rupture of the membranes and preterm delivery. Because of the sexually transmitted nature of trichomonas vaginitis, women with this infection should be tested for other sexually transmitted diseases (STDs), particularly Neisseria gonorrhoeae and Chlamydia trachomatis. Serologic testing for syphilis and HIV infection should be considered. Treatment The treatment of trichomonal vaginitis can be summarized as follows: 1.


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Gynecology_Novak. Treatment The treatment of trichomonal vaginitis can be summarized as follows: 1. Metronidazole is the drug of choice for treatment of vaginal trichomoniasis. Both a single-dose (2 g orally) and a multidose (500 mg twice daily for 7 days) regimen are highly effective and have cure rates of about 95%. 2. The sexual partner should be treated. 3. Metronidazole gel, although effective for the treatment of BV, should not be used for the treatment of vaginal trichomoniasis. 4. Women who do not respond to initial therapy should be treated again with metronidazole, 500 mg, twice daily for 7 days. If repeated treatment is not effective, the patient should be treated with a single 2-g dose of metronidazole once daily for 5 days or tinidazole, 2 g, in a single dose for 5 days. 5.


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Gynecology_Novak. 5. Patients who do not respond to repeated treatment with metronidazole or tinidazole and for whom the possibility of reinfection is excluded should be referred for expert consultation. In these uncommon refractory cases, an important part of management is to obtain cultures of the parasite to determine its susceptibility to metronidazole and tinidazole. An estimated 75% of women experience at least one episode of vulvovaginal candidiasis during their lifetimes (19). Nearly 45% of women will experience two or more episodes (20). Few are plagued with a chronic, recurrent infection. Candida albicans is responsible for 85% to 90% of vaginal yeast infections. Other species of Candida, such as C. glabrata and C.


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Gynecology_Novak. C. tropicalis, can cause vulvovaginal symptoms and tend to be resistant to therapy. Candida are dimorphic fungi existing as blastospores, which are responsible for transmission and asymptomatic colonization, and as mycelia, which result from blastospore germination and enhance colonization and facilitate tissue invasion. The extensive areas of pruritus and inﬂammation often associated with minimal invasion of the lower genital tract epithelial cells suggest that an extracellular toxin or enzyme may play a role in the pathogenesis of this disease. A hypersensitivity phenomenon may be responsible for the irritative symptoms associated with VVC, especially for patients with chronic, recurrent disease. Patients with symptomatic disease usually have an increased concentration of these micro-organisms (>104 per mL) compared with asymptomatic patients (<103 per mL) (21).


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Gynecology_Novak. Factors that predispose women to the development of symptomatic VVC include antibiotic use, pregnancy, and diabetes (22–25). Pregnancy and diabetes are associated with a qualitative decrease in cell-mediated immunity, leading to a higher incidence of candidiasis. Table 18.1 Classification of Vulvovaginal Candidiasis From Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178:203–211. It is helpful to categorize women with VVC as having either uncomplicated or complicated disease (Table 18.1) Diagnosis The symptoms of VVC consist of vulvar pruritus associated with a vaginal discharge that typically resembles cottage cheese. 1.


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Gynecology_Novak. Diagnosis The symptoms of VVC consist of vulvar pruritus associated with a vaginal discharge that typically resembles cottage cheese. 1. The discharge can vary from watery to homogeneously thick. Vaginal soreness, dyspareunia, vulvar burning, and irritation may be present. External dysuria (“splash” dysuria) may occur when micturition leads to exposure of the inﬂamed vulvar and vestibular epithelium to urine. Examination reveals erythema and edema of the labia and vulvar skin. Discrete pustulopapular peripheral lesions may be present. The vagina may be erythematous with an adherent, whitish discharge. The cervix appears normal. 2. The pH of the vagina in patients with VVC is usually normal (<4.5). 3. Fungal elements, either budding yeast forms or mycelia, appear in as many as 80% of cases. The results of saline preparation of the vaginal secretions usually are normal, although there may be a slight increase in the number of inﬂammatory cells in severe cases. 4.


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Gynecology_Novak. 4. The whiff test is negative. 5. A presumptive diagnosis can be made in the absence of fungal elements confirmed by microscopy if the pH and the results of the saline preparation evaluations are normal and the patient has increased erythema based on examination of the vagina or vulva. A fungal culture is recommended to confirm the diagnosis. Conversely, women with a normal physical examination findings and no evidence of fungal elements disclosed by microscopy are unlikely to have VVC and should not be empirically treated unless a vaginal yeast culture is positive. Treatment The treatment of VVC is summarized as follows: 1.


Gynecology_Novak

Gynecology_Novak. Treatment The treatment of VVC is summarized as follows: 1. Topically applied azole drugs are the most commonly available treatment for VVC and are more effective than nystatin (16) (Table 18.2). Treatment with azoles results in relief of symptoms and negative cultures in 80% to 90% of patients who have completed therapy. Symptoms usually resolve in 2 to 3 days. Short-course regimens up to 3 days are recommended. Although the shorter period of therapy implies a shortened duration of treatment, the short-course formulations have higher concentrations of the antifungal agent, causing an inhibitory concentration in the vagina that persists for several days. 2.


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Gynecology_Novak. 2. The oral antifungal agent, ﬂuconazole, used in a single 150-mg dose, is recommended for the treatment of VVC. It appears to have equal efficacy when compared with topical azoles in the treatment of mild to moderate VVC (26). Patients should be advised that their symptoms will persist for 2 to 3 days so they will not expect additional treatment. 3. Women with complicated VVC (Table 18.1) benefit from an additional 150-mg dose of ﬂuconazole given 72 hours after the first dose. Patients with complications can be treated with a more prolonged topical regimen lasting 10 to 14 days. Adjunctive


Gynecology_Novak

Gynecology_Novak. Table 18.2 Vulvovaginal Candidiasis—Topical Treatment Regimens 2% cream, 5 g intravaginally for 3 daysa,b 1% cream, 5 g intravaginally for 7–14 daysa,b 2% cream 5 g intravaginally for 3 days 2% cream, 5 g intravaginally for 7 daysa,b 200-mg vaginal suppository for 3 daysa 100-mg vaginal suppository for 7 daysa,b 4% cream 5 g intravaginally for 3 days 1,200 mg vaginal suppository, one suppository for one day 100,000-U vaginal tablet, one tablet for 14 days 6.5% ointment, 5 g intravaginally, single dosea 0.4% cream, 5 g intravaginally for 7 daysa 0.8% cream, 5 g intravaginally for 3 daysa 80-mg suppository for 3 daysa aOil-based, may weaken latex condoms. bAvailable as over-the-counter preparation. Adapted from Centers for Disease Control and Prevention. The sexually transmitted diseases treatment guidelines. MMWR 2006;55:[RR-11]:1–94. treatment with a weak topical steroid, such as 1% hydrocortisone cream, may be helpful in relieving some of the external irritative symptoms.


Gynecology_Novak

Gynecology_Novak. treatment with a weak topical steroid, such as 1% hydrocortisone cream, may be helpful in relieving some of the external irritative symptoms. A small number of women develop recurrent VVC (RVVC), defined as four or more episodes in a year. These women experience persistent irritative symptoms of the vestibule and vulva. Burning replaces itching as the prominent symptom in patients with RVVC. The diagnosis should be confirmed by direct microscopy of the vaginal secretions and by fungal culture. Many women with RVVC presume incorrectly they have a chronic yeast infection. Many of these patients have chronic atopic dermatitis or atrophic vulvovaginitis.


Gynecology_Novak

Gynecology_Novak. The treatment of patients with RVVC consists of inducing a remission of chronic symptoms with ﬂuconazole (150 mg every 3 days for three doses). Patients should be maintained on a suppressive dose of this agent (ﬂuconazole, 150 mg weekly) for 6 months. On this regimen, 90% of women with RVVC will remain in remission. After suppressive therapy, approximately half will remain asymptomatic. Recurrence will occur in the other half and should prompt reinstitution of suppressive therapy (27).


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Gynecology_Novak. Inﬂammatory Vaginitis Desquamative inﬂammatory vaginitis is a clinical syndrome characterized by diffuse exudative vaginitis, epithelial cell exfoliation, and a profuse purulent vaginal discharge (28). The cause of inﬂammatory vaginitis is unknown, but Gram stain findings reveal a relative absence of normal long gram-positive bacilli (lactobacilli) and their replacement with gram-positive cocci, usually streptococci. Women with this disorder have a purulent vaginal discharge, vulvovaginal burning or irritation, and dyspareunia. A less frequent symptom is vulvar pruritus. Vaginal erythema is present, and there may be an associated vulvar erythema, vulvovaginal ecchymotic spots, and colpitis macularis. The pH of the vaginal secretions is uniformly higher than 4.5 in these patients.


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Gynecology_Novak. Initial therapy is the use of 2% clindamycin cream, one applicator full (5 g) intravaginally once daily for 7 days. Relapse occurs in about 30% of patients, who should be retreated with intravaginal 2% clindamycin cream for 2 weeks. When relapse occurs in postmenopausal patients, supplementary hormonal therapy should be considered (28).


Gynecology_Novak

Gynecology_Novak. Atrophic Vaginitis Estrogen plays an important role in the maintenance of normal vaginal ecology. Women undergoing menopause, either naturally or secondary to surgical removal of the ovaries, may develop inﬂammatory vaginitis, which may be accompanied by an increased, purulent vaginal discharge. In addition, they may have dyspareunia and postcoital bleeding resulting from atrophy of the vaginal and vulvar epithelium. Examination reveals atrophy of the external genitalia, along with a loss of the vaginal rugae. The vaginal mucosa may be somewhat friable in areas. Microscopy of the vaginal secretions shows a predominance of parabasal epithelial cells and an increased number of leukocytes. Atrophic vaginitis is treated with topical estrogen vaginal cream. Use of 1 g of conjugated estrogen cream intravaginally each day for 1 to 2 weeks generally provides relief. Maintenance estrogen therapy, either topical or systemic, should be considered to prevent recurrence of this disorder.


Gynecology_Novak

Gynecology_Novak. Cervicitis The cervix is made up of two different types of epithelial cells: squamous epithelium and glandular epithelium. The cause of cervical inﬂammation depends on the epithelium affected. The ectocervical epithelium can become inﬂamed by the same micro-organisms that are responsible for vaginitis. In fact, the ectocervical squamous epithelium is an extension of and is continuous with the vaginal epithelium. Trichomonas, candida, and herpes simplex virus (HSV) can cause inﬂammation of the ectocervix. Conversely, N. gonorrhoeae and C. trachomatis infect only the glandular epithelium (29). Diagnosis The diagnosis of cervicitis is based on the finding of a purulent endocervical discharge, generally yellow or green in color and referred to as “mucopus” (30). 1.


Gynecology_Novak

Gynecology_Novak. Diagnosis The diagnosis of cervicitis is based on the finding of a purulent endocervical discharge, generally yellow or green in color and referred to as “mucopus” (30). 1. After removal of ectocervical secretions with a large swab, a small cotton swab is placed into the endocervical canal and the cervical mucus is extracted. The cotton swab is inspected against a white or black background to detect the green or yellow color of the mucopus. In addition, the zone of ectopy (glandular epithelium) is friable or easily induced to bleed. This characteristic can be assessed by touching the ectropion with a cotton swab or spatula. 2.


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Gynecology_Novak. 2. Placement of the mucopus on a slide that can be Gram stained will reveal the presence of an increased number of neutrophils (>30 per high-power field). The presence of intracellular gram-negative diplococci, leading to the presumptive diagnosis of gonococcal endocervicitis, may be detected. If the Gram stain results are negative for gonococci, the presumptive diagnosis is chlamydial cervicitis. 3. Tests for gonorrhea and chlamydia, preferably using nucleic acid amplification tests, should be performed. The microbial etiology of endocervicitis is unknown in about 50% of cases in which neither gonococci nor chlamydia is detected.


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Gynecology_Novak. Treatment Treatment of cervicitis consists of an antibiotic regimen recommended for the treatment of uncomplicated lower genital tract infection with both chlamydia and gonorrhea (16) (Table 18.3). Fluoroquinolone resistance is common in Neisseria gonorrhoeae isolates, and, therefore, these agents are no longer recommended for the treatment of women with gonococcal cervicitis. It is imperative that all sexual partners be treated with a similar antibiotic regimen. Cervicitis is commonly associated with BV, which, if not treated concurrently, leads to significant persistence of the symptoms and signs of cervicitis. Table 18.3 Treatment Regimens for Gonococcal and Chlamydial Infections Ceftriaxone, 250 mg IM in a single dose, or, if not an option Cefexime, 400 mg in a single dose Azithromycin, 1 g orally (single dose), or Doxycycline, 100 mg orally twice daily for 7 days


Gynecology_Novak

Gynecology_Novak. Ceftriaxone, 250 mg IM in a single dose, or, if not an option Cefexime, 400 mg in a single dose Azithromycin, 1 g orally (single dose), or Doxycycline, 100 mg orally twice daily for 7 days Adapted from Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1–110. Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18. Dosage error in article text. PID is caused by micro-organisms colonizing the endocervix and ascending to the endometrium and fallopian tubes. It is a clinical diagnosis implying that the patient has upper genital tract infection and inﬂammation. The inﬂammation may be present at any point along a continuum that includes endometritis, salpingitis, and peritonitis (Fig. 18.1). PID is commonly caused by the sexually transmitted micro-organisms N. gonorrhoeae and


Gynecology_Novak

Gynecology_Novak. PID is commonly caused by the sexually transmitted micro-organisms N. gonorrhoeae and C. trachomatis (31–33). Recent evidence suggests that Mycoplasma genitalium can cause PID and presents with mild clinical symptoms similar to chlamydial PID (34). Endogenous microorganisms found in the vagina, particularly the BV micro-organisms, are often isolated from the upper genital tract of women with PID. The BV micro-organisms include anaerobic bacteria such as Prevotella and peptostreptococci as well as G. vaginalis. BV often occurs in women with PID, and the resultant complex alteration of vaginal ﬂora may facilitate the ascending spread of pathogenic bacteria by enzymatically altering the cervical mucus barrier (35). Less frequently, respiratory pathogens such as Haemophilus inﬂuenzae, group A streptococci, and pneumococci can colonize the lower genital tract and cause PID.


Gynecology_Novak

Gynecology_Novak. Figure 18.1 Micro-organisms originating in the endocervix ascend into the endometrium, fallopian tubes, and peritoneum, causing pelvic inﬂammatory disease (endometritis, salpingitis, peritonitis). (From Soper DE. Upper genital tract infections. In: Copeland LJ, ed. Textbook of gynecology. Philadelphia, PA: Saunders, 1993:521, with permission.) Diagnosis Traditionally, the diagnosis of PID is based on a triad of symptoms and signs, including pelvic pain, cervical motion and adnexal tenderness, and the presence of fever. It is recognized that there is wide variation in many symptoms and signs among women with this condition, which makes the diagnosis of acute PID difficult. Many women with PID exhibit subtle or mild symptoms that are not readily recognized as PID. Consequently, delay in diagnosis and therapy probably contributes to the inﬂammatory sequelae in the upper reproductive tract (36).


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Gynecology_Novak. In the diagnosis of PID, the goal is to establish guidelines that are sufficiently sensitive to avoid missing mild cases but sufficiently specific to avoid giving antibiotic therapy to women who are not infected. Genitourinary tract symptoms may indicate PID; therefore, the diagnosis of PID should be considered in women with any genitourinary symptoms, including, but not limited to, lower abdominal pain, excessive vaginal discharge, menorrhagia, metrorrhagia, fever, chills, and urinary symptoms (37). Some women may develop PID without having any symptoms. Pelvic organ tenderness, either uterine tenderness alone or uterine tenderness with adnexal tenderness, is present in patients with PID. Cervical motion tenderness suggests the presence of peritoneal inﬂammation, which causes pain when the peritoneum is stretched by moving the cervix and causing traction of the adnexa on the pelvic peritoneum. Direct or rebound abdominal tenderness may be present.


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Gynecology_Novak. Evaluation of both vaginal and endocervical secretions is a crucial part of the workup of a patient with PID (38). In women with PID, an increased number of polymorphonuclear leukocytes may be detected in a wet mount of the vaginal secretions or in the mucopurulent discharge. More elaborate tests may be used in women with severe symptoms because an incorrect diagnosis may cause unnecessary morbidity (39) (Table 18.4). These tests include endometrial biopsy to confirm the presence of endometritis, ultrasound or radiologic tests to characterize a tubo-ovarian abscess, and laparoscopy to confirm salpingitis visually. Treatment Therapy regimens for PID must provide empirical, broad-spectrum coverage of likely pathogens, including N. gonorrhoeae, C. trachomatis, M. genitalium, gram-negative Table 18.4 Clinical Criteria for the Diagnosis of Pelvic Inﬂammatory Disease Additional criteria to increase the specificity of the diagnosis


Gynecology_Novak

Gynecology_Novak. Table 18.4 Clinical Criteria for the Diagnosis of Pelvic Inﬂammatory Disease Additional criteria to increase the specificity of the diagnosis Endometrial biopsy showing endometritis Elevated C-reactive protein or erythrocyte sedimentation rate Temperature higher than 38◦C (100.4◦F) Leukocytosis Positive test for gonorrhea or chlamydia Table 18.5 Guidelines for Treatment of Pelvic Inﬂammatory Disease Cefoxitin, 2 g intramuscularly, plus probenecid, 1 g orally concurrently, or Ceftriaxone, 250 mg intramuscularly, or Plus: Doxycycline, 100 mg orally 2 times daily for 14 days, or Azithromycin, 500 mg initially and then 250 mg daily for a total of 7 days Cefoxitin, 2 g intravenously every 6 hours, or Cefotetan, 2 g intravenously every 12 hours Plus: Doxycycline, 100 mg orally or intravenously every 12 hours Clindamycin, 900 mg intravenously every 8 hours Plus:


Gynecology_Novak

Gynecology_Novak. Cefotetan, 2 g intravenously every 12 hours Plus: Doxycycline, 100 mg orally or intravenously every 12 hours Clindamycin, 900 mg intravenously every 8 hours Plus: Ceftriaxone, 1–2 g intravenously every 12 hours, or Gentamicin, loading dose intravenously or intramuscularly (2 mg/kg of body weight) followed by a maintenance dose (1.5 mg/kg) every 8 hours aOutpatient treatment only, i.e., women treated for PID as an outpatient should also receive metronidazole gel for BV if they have BV. Adapted from Soper DE. Pelvic inﬂammatory disease. Obstet Gynecol 2010;116:419–428.


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Gynecology_Novak. facultative bacteria, anaerobes, and streptococci (16,40). Recommended regimens for the treatment of PID are listed in Table 18.5. An outpatient regimen of cefoxitin and doxycycline is as effective as an inpatient parenteral regimen of the same antimicrobials (41). Therefore, hospitalization is recommended only when the diagnosis is uncertain, pelvic abscess is suspected, clinical disease is severe, or compliance with an outpatient regimen is in question. Hospitalized patients can be considered for discharge when their fever has lysed (<99.5◦F for more than 24 hours), the white blood cell count has become normal, rebound tenderness is absent, and repeat examination shows marked amelioration of pelvic organ tenderness (42). Sexual partners of women with PID should be evaluated and treated for urethral infection with chlamydia or gonorrhea (Table 18.3). One of these STDs usually is found in the male sexual partners of women with PID not associated with chlamydia or gonorrhea (43,44).


Gynecology_Novak

Gynecology_Novak. Tubo-ovarian Abscess An end-stage process of acute PID, tubo-ovarian abscess is diagnosed when a patient with PID has a pelvic mass that is palpable during bimanual examination. The condition usually reﬂects an agglutination of pelvic organs (tube, ovary, bowel) forming a palpable complex. Occasionally, an ovarian abscess can result from the entrance of micro-organisms through an ovulatory site. Tuboovarian abscess is treated with an antibiotic regimen administered in a hospital (Table 18.5). About 75% of women with tubo-ovarian abscess respond to antimicrobial therapy alone. Failure of medical therapy suggests the need for drainage of the abscess (45). Although drainage may require surgical exploration, percutaneous drainage guided by imaging studies (ultrasound or computed tomography) should be used as an initial option if possible. Trocar drainage, with or without placement of a drain, is successful in up to 90% of cases in which the patient failed to respond to antimicrobial


Gynecology_Novak

Gynecology_Novak. should be used as an initial option if possible. Trocar drainage, with or without placement of a drain, is successful in up to 90% of cases in which the patient failed to respond to antimicrobial therapy after 72 hours (46).


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Gynecology_Novak. Figure 18.2 Showing the appearance of the ulcers of chancroid (A), herpes (B), and syphilis (C). The ulcer of chancroid has irregular margins and is deep with undermined edges. The syphilis ulcer has a smooth, indurated border and a smooth base. The genital herpes ulcer is superficial and inﬂamed. (Modified from Schmid GP, Shcalla WO, DeWitt WE. Chancroid. In: Morse SA, Moreland AA, Thompson SE, eds. Atlas of sexually transmitted diseases. Philadelphia, PA: Lippincott, 1990.) Genital Ulcer Disease In the United States, most patients with genital ulcers have genital HSV or syphilis (47–50). Chancroid is the next most common cause of sexually transmitted genital ulcers, followed by the rare occurrence of lymphogranuloma venereum (LGV) and granuloma inguinale (donovanosis). These diseases are associated with an increased risk for HIV infection. Other infrequent and noninfectious causes of genital ulcers include abrasions, fixed drug eruptions, carcinoma, and Behcet’s disease.


Gynecology_Novak

Gynecology_Novak. Diagnosis A diagnosis based on history and physical examination alone is often inaccurate. Therefore, all women with genital ulcers should undergo a serologic test for syphilis (50). Because of the consequences of inappropriate therapy, such as tertiary disease and congenital syphilis in pregnant women, diagnostic efforts are directed at excluding syphilis. Optimally, the evaluation of a patient with a genital ulcer should include dark-field examination or direct immunoﬂuorescence testing for Treponema pallidum, culture or antigen testing for HSV, and culture for Haemophilus ducreyi. Dark-field or ﬂuorescent microscopes and selective media to culture for H. ducreyi often are not available in most offices and clinics. Even after complete testing, the diagnosis remains unconfirmed in one-fourth of patients with genital ulcers. For this reason, most clinicians base their initial diagnosis and treatment recommendations on their clinical impression of the appearance of the genital ulcer


Gynecology_Novak

Gynecology_Novak. of patients with genital ulcers. For this reason, most clinicians base their initial diagnosis and treatment recommendations on their clinical impression of the appearance of the genital ulcer (Fig. 18.2) and knowledge of the most likely cause in their patient population (48).


Gynecology_Novak

Gynecology_Novak. Several clinical presentations are highly suggestive of specific diagnoses: 1. A painless and minimally tender ulcer, not accompanied by inguinal lymphadenopathy, is likely to be syphilis, especially if the ulcer is indurated. A nontreponemal rapid plasma reagin (RPR) test, or venereal disease research laboratory (VDRL) test, and a confirmatory treponemal test—ﬂuorescent treponemal antibody absorption (FTA ABS) or microhemagglutinin–T. pallidum (MHA TP)—should be used to diagnose syphilis presumptively. Some laboratories screen samples with treponemal enzyme immunoassay (EIA) tests, the results of which should be confirmed with nontreponemal tests. The results of nontreponemal tests usually correlate with disease activity and should be reported quantitatively. 2.


Gynecology_Novak

Gynecology_Novak. 2. Grouped vesicles mixed with small ulcers, particularly with a history of such lesions, are almost always pathognomonic of genital herpes. Nevertheless, laboratory confirmation of the findings is recommended because the diagnosis of genital herpes is traumatic for many women, alters their self-image, and affects their perceived ability to enter new sexual relationships and bear children. A culture test is the most sensitive and specific test; sensitivity approaches 100% in the vesicle stage and 89% in the pustular stage and drops to as low as 33% in patients with ulcers. Nonculture tests are about 80% as sensitive as culture tests. Because false-negative results are common with HSV cultures, especially in patients with recurrent infections, type-specific glycoprotein G-based antibody assays are useful in confirming a clinical diagnosis of genital herpes. 3.


Gynecology_Novak

Gynecology_Novak. 3. One to three extremely painful ulcers, accompanied by tender inguinal lymphadenopathy, are unlikely to be anything except chancroid. This is especially true if the adenopathy is ﬂuctuant. 4. An inguinal bubo accompanied by one or several ulcers is most likely chancroid. If no ulcer is present, the most likely diagnosis is LGV. Recommended regimens for the treatment of chancroid include azithromycin, 1 g orally in a single dose; ceftriaxone, 250 mg intramuscularly in a single dose; ciproﬂoxacin, 500 mg orally twice a day for 3 days; or erythromycin base, 500 mg orally four times daily for 7 days. Patients should be reexamined 3 to 7 days after initiation of therapy to ensure the gradual resolution of the genital ulcer, which can be expected to heal within 2 weeks unless it is unusually large.


Gynecology_Novak

Gynecology_Novak. A first episode of genital herpes should be treated with acyclovir, 400 mg orally three times a day; or famciclovir, 250 mg orally three times a day; or valacyclovir, 1.0 orally twice a day for 7 to 10 days or until clinical resolution is attained. Although these agents provide partial control of the symptoms and signs of clinical herpes, it neither eradicates latent virus nor affects subsequent risk, frequency, or severity of recurrences after the drug is discontinued. Daily suppressive therapy (acyclovir, 400 mg orally twice daily; or famciclovir, 250 mg twice daily; or valacyclovir, 1.0 g orally once a day) reduces the frequency of HSV recurrences by at least 75% among patients with six or more recurrences of HSV per year. Suppressive treatment partially, but not totally, decreases symptomatic and asymptomatic viral shedding and the potential for transmission (49). Parenteral administration of penicillin G is the preferred treatment of all stages of syphilis.


Gynecology_Novak

Gynecology_Novak. Parenteral administration of penicillin G is the preferred treatment of all stages of syphilis. Benzathine penicillin G, 2.4 million units intramuscularly in a single dose, is the recommended treatment for adults with primary, secondary, or early latent syphilis. The Jarisch-Herxheimer reaction—an acute febrile response accompanied by headache, myalgia, and other symptoms— may occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction. Table 18.6 Treatment Options for External Genital and Perianal Warts ND, no data. a May be self-applied by patients at home. bExpensive; reserve for patients who have not responded to other regimens.


Gynecology_Novak

Gynecology_Novak. ND, no data. a May be self-applied by patients at home. bExpensive; reserve for patients who have not responded to other regimens. Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive but show no other evidence of disease. Patients with latent syphilis of longer than 1 year’s duration or of unknown duration should be treated with benzathine penicillin G, 7.2 million units total, administered as three doses of 2.4 million units intramuscularly each, at 1-week intervals. All patients with latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, neurosyphilis, gumma, and iritis). Quantitative nontreponemal serologic tests should be repeated at 6 months and again at 12 months. An initially high titer (1:32) should decline at least fourfold (two dilutions) within 12 to 24 months.


Gynecology_Novak

Gynecology_Novak. Genital Warts External genital warts are a manifestation of human papillomavirus (HPV) infection (51). The nononcogenic HPV types 6 and 11 are usually responsible for external genital warts. The warts tend to occur in areas most directly affected by coitus, namely the posterior fourchette and lateral areas on the vulva. Less frequently, warts can be found throughout the vulva, in the vagina, and on the cervix. Minor trauma associated with coitus can cause breaks in the vulvar skin, allowing direct contact between the viral particles from an infected man and the basal layer of the epidermis of his susceptible sexual partner. Infection may be latent or may cause viral particles to replicate and produce a wart. External genital warts are highly contagious; more than 75% of sexual partners develop this manifestation of HPV infection when exposed.


Gynecology_Novak

Gynecology_Novak. The goal of treatment is removal of the warts; it is not possible to eradicate the viral infection. Treatment is most successful in patients with small warts that were present for less than 1 year. It is not determined whether treatment of genital warts reduces transmission of HPV. Selection of a specific treatment regimen depends on the anatomic site, size, and number of warts, and expense, efficacy, convenience, and potential adverse effects (Table 18.6). Recurrences more often result from reactivation of subclinical infection than reinfection by a sex partner; therefore, examination of sex partners is not absolutely necessary. However, many of these sex partners may have external genital warts and may benefit from therapy and counseling concerning transmission of warts. HPV infection with types 6,11, 16, and 18 can be prevented by vaccination.


Gynecology_Novak

Gynecology_Novak. It is estimated that almost 40% to 50% of individuals with HIV are women. Intravenous drug use and heterosexual transmission are responsible for most of the cases of AIDS in women in the United States (52). Infection with HIV produces a spectrum of disease that progresses from an asymptomatic state to full-blown AIDS. The pace of disease progression in untreated adults is variable. The median time between infection with HIV and the development of AIDS is 10 years, with a range from a few months to more than 12 years. In a study of adults infected with HIV, symptoms developed in 70% to 85% of infected adults, and AIDS developed in 55% to 60% within 12 years after infection. The natural history of the disease can be significantly altered by antiretroviral therapy. Women with HIV-induced altered immune function are at increased risk for infections such as tuberculosis (TB), bacterial pneumonia, and Pneumocystis jiroveci pneumonia (PCP). Because of its impact on the immune system, HIV


Gynecology_Novak

Gynecology_Novak. altered immune function are at increased risk for infections such as tuberculosis (TB), bacterial pneumonia, and Pneumocystis jiroveci pneumonia (PCP). Because of its impact on the immune system, HIV affects the diagnosis, evaluation, treatment, and follow-up of many other diseases and may decrease the efficacy of antimicrobial therapy for some STDs.


Gynecology_Novak

Gynecology_Novak. Diagnosis Infection is most often diagnosed by HIV antibody tests. Antibody testing begins with a sensitive screening test such as enzyme-linked immunosorbent assay (ELISA) or a rapid assay. If confirmed by Western blot, a positive antibody test result confirms that a person is infected with HIV and is capable of transmitting the virus to others. HIV antibody is detectable in more than 95% of patients within 6 months of infection. Women diagnosed with any STI, particularly genital ulcer disease, should be offered HIV testing (48). Routine HIV screening is recommended for women aged 19 to 64 years and targeted screening for women with risk factors outside of that age range, for example, sexually active adolescents (53).


Gynecology_Novak

Gynecology_Novak. The initial evaluation of an HIV-positive woman includes screening for diseases associated with HIV such as TB and STIs, administration of recommended vaccinations (hepatitis B, pneumococcal, meningococcal and inﬂuenza), and behavioral and psychosocial counseling. Intraepithelial neoplasia is strongly associated with HPV infection and occurs in high frequency in women with both HPV and HIV.


Gynecology_Novak

Gynecology_Novak. Treatment Decisions regarding the initiation of antiretroviral therapy should be guided by monitoring the laboratory parameters of HIV RNA (viral load) and CD4+ T-cell count, and the clinical condition of the patient. The primary goals of antiretroviral therapy are maximal and durable suppression of viral load, restoration or preservation of immunologic function, improvement of quality of life, reduction of HIV-related morbidity and mortality, and prevention of HIV transmission. Antiretroviral therapy should be initiated in all women with a history of an AIDS-defining illness or with a CD4 count less than 350 cells per mm3 . Antiretroviral treatment should be started regardless of CD4 count in women with the following conditions: pregnancy, HIV-associated nephropathy, and hepatitis B coinfection when treatment of hepatitis B is indicated. Patients must be willing to accept therapy to avoid the emergence of resistance caused by poor compliance. Dual nucleoside regimens used in addition


Gynecology_Novak

Gynecology_Novak. when treatment of hepatitis B is indicated. Patients must be willing to accept therapy to avoid the emergence of resistance caused by poor compliance. Dual nucleoside regimens used in addition to a protease inhibitor or nonnucleoside reverse transcriptase inhibitor provide a better durable clinical benefit than monotherapy.


Gynecology_Novak

Gynecology_Novak. Patients with less than 200 CD4+ T cells per μL should receive prophylaxis against opportunistic infections, such as trimethoprim/sulfamethoxazole or aerosol pentamidine for the prevention of PCP pneumonia. Those with less than 50 CD4+ T cells per uL should receive azithromycin prophylaxis for mycobacterial infections (54). Acute Cystitis Women with acute cystitis generally have an abrupt onset of multiple, severe urinary tract symptoms including dysuria, frequency, and urgency associated with suprapubic or low-back pain. Suprapubic tenderness may be noted on physical examination. Urinalysis reveals pyuria and sometimes hematuria. Several factors increase the risk for cystitis, including sexual intercourse, the use of a diaphragm and a spermicide, delayed postcoital micturition, and a history of a recent urinary tract infection (55–57).


Gynecology_Novak

Gynecology_Novak. Diagnosis Escherichia coli is the most common pathogen isolated from the urine of young women with acute cystitis, and it is present in 80% of cases (58). Staphylococcus saprophyticus is present in an additional 5% to 15% of patients with cystitis. The pathophysiology of cystitis in women involves the colonization of the vagina and urethra with coliform bacteria from the rectum. For this reason, the effects of an antimicrobial agent on the vaginal ﬂora play a role in the eradication of bacteriuria.


Gynecology_Novak

Gynecology_Novak. Treatment High concentrations of trimethoprim and ﬂuoroquinolone in vaginal secretions can eradicate E. coli while minimally altering normal anaerobic and microaerophilic vaginal ﬂora. An increasing linear trend in the prevalence of resistance of E. coli (>10%) to the ﬂuoroquinolones (e.g., ciproﬂoxacin) was noted. Despite a similar increase in E. coli resistance (9%–18%) to trimethoprim/sulfamethoxazole, therapeutic efficacy remains stable. In contrast, no such increase in resistance was noted with nitrofurantoin. Nitrofurantoin (macrocrystals, 100 mg orally twice daily for 5 days) or trimethoprim/sulfamethoxazole 160/800 mg orally twice daily for 3 days) are the optimal choices for empirical therapy for uncomplicated cystitis (59).


Gynecology_Novak

Gynecology_Novak. In patients with typical symptoms, an abbreviated laboratory workup followed by empirical therapy is suggested. The diagnosis can be presumed if pyuria is detected by microscopy or leukocyte esterase testing. Urine culture is not necessary, and a short course of antimicrobial therapy should be given. No follow-up visit or culture is necessary unless symptoms persist or recur. Recurrent Cystitis About 20% of premenopausal women with an initial episode of cystitis have recurrent infections. More than 90% of these recurrences are caused by exogenous reinfection. Recurrent cystitis should be documented by culture to rule out resistant micro-organisms. Patients may be treated by one of three strategies: (i) continuous prophylaxis, (ii) postcoital prophylaxis, or (iii) therapy initiated by the patient when symptoms are first noted.


Gynecology_Novak

Gynecology_Novak. Postmenopausal women may have frequent reinfections. Hormonal therapy or topically applied estrogen cream, along with antimicrobial prophylaxis, is helpful in treating these patients. Urethritis Women with dysuria caused by urethritis have a more gradual onset of mild symptoms, which may be associated with abnormal vaginal discharge or bleeding related to concurrent cervicitis. Patients may have a new sex partner or experience lower abdominal pain. Physical examination may reveal the presence of mucopurulent cervicitis or vulvovaginal herpetic lesions. C. trachomatis, N. gonorrhoeae, or genital herpes may cause acute urethritis. Pyuria is present on urinalysis, but hematuria is rarely seen. Treatment regimens for chlamydia and gonococcal infections are presented in Table 18.3.


Gynecology_Novak

Gynecology_Novak. Occasionally, vaginitis caused by C. albicans or trichomonas is associated with dysuria. On careful questioning, patients generally describe external dysuria, sometimes associated with vaginal discharge, and pruritus and dyspareunia. They usually do not experience urgency or frequency. Pyuria and hematuria are absent.


Gynecology_Novak

Gynecology_Novak. Acute Pyelonephritis The clinical spectrum of acute, uncomplicated pyelonephritis in young women ranges from gram-negative septicemia to a cystitislike illness with mild ﬂank pain. E. coli accounts for more than 80% of these cases (58). Microscopy of unspun urine reveals pyuria and gram-negative bacteria. A urine culture should be obtained in all women with suspected pyelonephritis; blood cultures should be performed in those who are hospitalized because results are positive in 15% to 20% of cases. In the absence of nausea and vomiting and severe illness, outpatient oral therapy can be given safely. Patients who have nausea and vomiting, are moderately to severely ill, or are pregnant should be hospitalized. Outpatient treatment regimens include trimethoprim/ sulfamethoxazole (160/800 mg every 12 hours for 14 days) or a quinolone (e.g., levoﬂoxacin, 750 mg daily for 7 days). Inpatient treatment regimens include the use of parenteral levoﬂoxacin (750 mg daily), ceftriaxone (1–2 g


Gynecology_Novak

Gynecology_Novak. mg every 12 hours for 14 days) or a quinolone (e.g., levoﬂoxacin, 750 mg daily for 7 days). Inpatient treatment regimens include the use of parenteral levoﬂoxacin (750 mg daily), ceftriaxone (1–2 g daily), ampicillin (1 g every 6 hours), and gentamicin (especially if Enterococcus species are suspected) or aztreonam (1 g every 8–12 hours). Symptoms should resolve after 48 to 72 hours. If fever and ﬂank pain persist after 72 hours of therapy, ultrasound or computed tomography should be considered to rule out a perinephric or intrarenal abscess or ureteral obstruction. A follow-up culture should be obtained 2 weeks after the completion of therapy (60).


Gynecology_Novak

Gynecology_Novak. 1. Huggins GR, Preti G. Vaginal odors and secretions. Clin Obstet Gynecol 1981;24:355–377. 2. Larsen B. Microbiology of the female genital tract. In: Pastorek J, ed. Obstetric and gynecologic infectious disease. New York: Raven Press, 1994:11–26. 3. Eschenbach DA, Davick PR, Williams BL, et al. Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with vaginal vaginosis. J Clin Microbiol 1989;27:251– 256. 4. Spiegel CA, Amsel R, Eschenbach DA, et al. Anaerobic bacteria in nonspecific vaginitis. N Engl J Med 1980;303:601–607. 5. Kent HL. Epidemiology of vaginitis. Am J Obstet Gynecol 1991;165: 1168–1176. 6. Eschenbach DA, Hillier S, Critchlow C, et al. Diagnosis and clinical manifestations of bacterial vaginosis. Am J Obstet Gynecol 1988;158:819–828. 7.


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Gynecology_Novak. 6. Eschenbach DA, Hillier S, Critchlow C, et al. Diagnosis and clinical manifestations of bacterial vaginosis. Am J Obstet Gynecol 1988;158:819–828. 7. Larsson P, Platz-Christensen JJ, Thejls H, et al. Incidence of pelvic inﬂammatory disease after first trimester legal abortion in women with bacterial vaginosis after treatment with metronidazole: a double-blind randomized study. Am J Obstet Gynecol 1992;166:100–103. 8. Soper DE, Bump RC, Hurt WG. Bacterial vaginosis and trichomoniasis vaginitis are risk factors for cuff cellulitis after abdominal hysterectomy. Am J Obstet Gynecol 1990;163:1016–1023. 9. Platz-Christensen JJ, Sundstrom E, Larsson PG. Bacterial vaginosis and cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand 1994;73:586–588. 10. Martius J, Eschenbach DA. The role of bacterial vaginosis as a cause of amniotic ﬂuid infection, chorioamnionitis and prematurity: a review. Arch Gynecol Obstet 1900;247:1–13. 11.


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Gynecology_Novak. 10. Martius J, Eschenbach DA. The role of bacterial vaginosis as a cause of amniotic ﬂuid infection, chorioamnionitis and prematurity: a review. Arch Gynecol Obstet 1900;247:1–13. 11. Watts DH, Krohn MA, Hillier SL, et al. Bacterial vaginosis as a risk factor for postcesarean endometritis. Obstet Gynecol 1990;75:52–58. 12. Larsson PG, Carlsson B. Does pre-and postoperative metronidazole treatment lower vaginal cuff infection rate after abdominal hysterectomy among women with bacterial vaginosis? Infect Dis Obstet Gynecol 2002;10:133–140. 13. Larsson PG, Platz-Christensen JJ, Thejls H, et al. Incidence of pelvic inﬂammatory disease after first-trimester legal abortion in women with bacterial vaginosis after treatment with metronidazole: a double-blind, randomized study. Am J Obstet Gynecol 1992;166:100– 103. 14. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983;74:14–22. 15.


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Gynecology_Novak. 14. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983;74:14–22. 15. Soper DE. Taking the guesswork out of vaginitis. Contemp Obstet Gynecol 2005;50:32–39. 16. Centers for Disease Control and Prevention. The sexually transmitted diseases treatment guidelines. MMWR 2006;55:[RR-11]:1–94. 17. Wolner-Hanssen P, Krieger JN, Stevens CE, et al. Clinical manifestations of vaginal trichomoniasis. JAMA 1989;261:571–576. 18. Krieger JN, Tam MR, Stevens CE, et al. Diagnosis of trichomoniasis: comparison of conventional wet-mount examination with cytologic studies, cultures, and monoclonal antibody staining of direct specimens. JAMA 1988;259:1223–1227. 19. Hurley R, De Louvois J. Candida vaginitis. Postgrad Med J 1979; 55:645–647. 20. Hurley R. Recurrent Candida infection. Clin Obstet Gynecol 1981;8: 208–213. 21.


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Gynecology_Novak. 19. Hurley R, De Louvois J. Candida vaginitis. Postgrad Med J 1979; 55:645–647. 20. Hurley R. Recurrent Candida infection. Clin Obstet Gynecol 1981;8: 208–213. 21. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178:203–211. 22. Caruso LJ. Vaginal moniliasis after tetracycline therapy. Am J Obstet Gynecol 1964;90:374. 23. Oriel JD, Waterworth PM. Effect of minocycline and tetracycline on the vaginal yeast ﬂora. J Clin Pathol 1975;28:403. 24. Morton RS, Rashid S. Candidal vaginitis: natural history, predisposing factors and prevention. Proc R Soc Med 1977;70[Suppl 4]:3–12. 25. McClelland RS, Richardson BA, Hassan WM, et al. Prospective study of vaginal bacterial ﬂora and other risk factors for vulvovaginal candidiasis. J Infect Dis 2009;199:1883–1890. 26.


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Gynecology_Novak. 25. McClelland RS, Richardson BA, Hassan WM, et al. Prospective study of vaginal bacterial ﬂora and other risk factors for vulvovaginal candidiasis. J Infect Dis 2009;199:1883–1890. 26. Brammer KW. Treatment of vaginal candidiasis with a single oral dose of ﬂuconazole. Eur J Clin Microbiol Infect Dis 1988;7:364–367. 27. Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance ﬂuconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004;351:876–883. 28. Sobel JD. Desquamative inﬂammatory vaginitis: a new subgroup of purulent vaginitis responsive to topical 2% clindamycin therapy. Am J Obstet Gynecol 1994;171:1215–1220. 29. Kiviat NB, Paavonen JA, Wolner-Hanssen P, et al. Histopathology of endocervical infection caused by Chlamydia trachomatis, herpes simplex virus, Trichomonas vaginalis, and Neisseria gonorrhoeae. Hum Pathol 1990;21:831–837. 30.


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Gynecology_Novak. 30. Brunham RC, Paavonen J, Stevens CE, et al. Mucopurulent cervicitis: the ignored counterpart in women of urethritis in men. N Engl J Med 1984;311:1–6. 31. Soper DE, Brockwell NJ, Dalton HP. Microbial etiology of urban emergency department acute salpingitis: treatment with oﬂoxacin. Am J Obstet Gynecol 1992;167:653–660. 32. Sweet RL, Draper DL, Schachter J, et al. Microbiology and pathogenesis of acute salpingitis as determined by laparoscopy: what is the appropriate site to sample? Am J Obstet Gynecol 1980;138:985–989. 33. Wasserheit JN, Bell TA, Kiviat NB, et al. Microbial causes of proven pelvic inﬂammatory disease and efficacy of clindamycin and tobramycin. Ann Intern Med 1986;104:187–193. 34. Short VL, Totten PA, Ness RB, et al. Clinical presentation of Mycoplasma genitalium infection versus Neisseria gonorrhoeae infection amoung women with pelvic inﬂammatory disease. Clin Infect Dis 2009;48:41–47. 35.


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Gynecology_Novak. 35. Soper DE, Brockwell NJ, Dalton HP, et al. Observations concerning the microbial etiology of acute salpingitis. Am J Obstet Gynecol 1994;170:1008–1017. 36. Hillis SD, Joesoef R, Marchbanks PA, et al. Delayed care of pelvic inﬂammatory disease as a risk factor for impaired fertility. Am J Obstet Gynecol 1993;168:1503–1509. 37. Wolner-Hanssen P, Kiviat NB, Holmes KK. Atypical pelvic inﬂammatory disease: subacute, chronic, or subclinical upper genital tract infection in women. In: Holmes KK, March P-A, Sparking PF, eds. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill, 1990:614–620. 38. Westrom L. Diagnosis and treatment of salpingitis. J Reprod Med 1983;28:703–708. 39. Soper DE. Diagnosis and laparoscopic grading of acute salpingitis. Am J Obstet Gynecol 1991;164:1370–1376. 40. Peterson HB, Walker CK, Kahn JG, et al. Pelvic inﬂammatory disease: key treatment issues and options. JAMA 1991;266:2605–2611. 41.


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Gynecology_Novak. 40. Peterson HB, Walker CK, Kahn JG, et al. Pelvic inﬂammatory disease: key treatment issues and options. JAMA 1991;266:2605–2611. 41. Ness RB, Soper DE, Holley RL, et al. Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inﬂammatory disease: results from the Pelvic Inﬂammatory Disease Evaluation and Clinical Health (PEACH) randomized trial. Am J Obstet Gynecol 2002;186:929–937. 42. Soper DE. Pelvic inﬂammatory disease. Obstet Gynecol 2010;116: 419–428. 43. Gilstrap LC 3rd, Herbert WN, Cunningham FG, et al. Gonorrhea screening in the male consorts of women with pelvic infection. JAMA 1977;238:965–966. 44. Potterat JJ, Phillips L, Rothenberg RB, et al. Gonococcal pelvic inﬂammatory disease: case-finding observations. Am J Obstet Gynecol 1980;138:1101–1104. 45.


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Gynecology_Novak. 44. Potterat JJ, Phillips L, Rothenberg RB, et al. Gonococcal pelvic inﬂammatory disease: case-finding observations. Am J Obstet Gynecol 1980;138:1101–1104. 45. Reed SD, Landers DV, Sweet RL. Antibiotic treatment of tuboovarian abscesses: comparison of broad-spectrum B-lactam agents versus clindamycin-containing regimens. Am J Obstet Gynecol 1991;164: 1556–1562. 46. Varghese JC, O’Neill MJ, Gervais DA, et al. Transvaginal catheter drainage of tuboovarian abscess using the trocar method: technique and literature review. AJR Am J Roentgenol 2001;177:139–144. 47. Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex virus infection: clinical manifestations, course, and complications. Ann Intern Med 1983;98:958–972. 48. Schmid GP. Approach to the patient with genital ulcer disease. Med Clin North Am 1990;74:1559–1572.


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Gynecology_Novak. 48. Schmid GP. Approach to the patient with genital ulcer disease. Med Clin North Am 1990;74:1559–1572. 49. Corey L, Wald A, Patel R, et al. HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11–20. 50. Hutchinson CM, Hook EW. Syphilis in adults. Med Clin North Am 1990;74:1389–1416. 51. Beutner KR, Richwald GA, Wiley DJ, et al. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis 1998;27:796–806. 52. Anderson JR, ed. A guide to the clinical care with women with HIV/AIDS. Washington, DC: DHHS, HRSA, HAB. 53. American College of Obstetrics and Gynecology. Routine human immunodeficiency virus screening (Committee Opinion). No. 411. August 2008. http://www.acog.org/publications/committee opinions/co411.cfm. 54.


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Gynecology_Novak. No. 411. August 2008. http://www.acog.org/publications/committee opinions/co411.cfm. 54. Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents.. December 1, 2009. Available online at: http://www.aidsinfo.nih.gov/ ContentFiles/AdultandAdolescentGL.pdf 55. Remis RS, Gurwith MJ, Gurwith D, et al. Risk factors for urinary tract infection. Am J Epidemiol 1987;126:685–694. 56. Fihn SD, Latham RH, Roberts P, et al. Association between diaphragm use and urinary tract infection. JAMA 1985;254:240– 245. 57. Strom BL, Collins M, West SL, et al. Sexual activity, contraceptive use, and other risk factors for symptomatic and asymptomatic bacteriuria: a case-control study. Ann Intern Med 1987;107:816– 823. 58. Stamm WE, Counts GW, Running KR, et al. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med 1982;307:463– 468. 59.


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Gynecology_Novak. 58. Stamm WE, Counts GW, Running KR, et al. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med 1982;307:463– 468. 59. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 1999;281:736–738. 60. Gupta K, Hooten TM, Naber KG,et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Disease Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103– e120. Intraepithelial Disease of the 19 Cervix, Vagina, and Vulva Francisco Garcia Kenneth D. Hatch Jonathan S. Berek


Gynecology_Novak

Gynecology_Novak. Intraepithelial Disease of the 19 Cervix, Vagina, and Vulva Francisco Garcia Kenneth D. Hatch Jonathan S. Berek Cervical intraepithelial neoplasia (CIN) most often arises in an area of metaplasia in the transformation zone at the advancing squamocolumnar junction (SCJ). Metaplasia advances from the original SCJ inward, toward the external os and over the columnar villi, to establish the transformation zone. CIN is most likely to begin either during menarche or after pregnancy, when metaplasia is most active; after menopause, metaplasia is less active and a woman has a lower risk of developing CIN.


Gynecology_Novak

Gynecology_Novak. Untreated, most CIN 1 and some CIN 2 lesions spontaneously regress; nevertheless, CIN refers to a lesion that may progress to invasive carcinoma. This term is equivalent to the term dysplasia, which means abnormal maturation; consequently, proliferating metaplasia without atypical mitotic activity should not be called dysplasia. Squamous metaplasia should not be diagnosed as dysplasia (or CIN) because it does not progress to invasive cancer. More than 90% of CIN is attributed to human papillomavirus (HPV) infection. Only certain types of HPV cause high-grade intraepithelial lesions and cancer (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -68). Type 16 is the most common form of HPV found in invasive cancer and in CIN 2 and CIN 3; it is found in 47% of women with cancer.


Gynecology_Novak

Gynecology_Novak. Potentially premalignant squamous lesions fall into three categories: (i) atypical squamous cells (ASC), (ii) low-grade squamous intraepithelial lesions (LSIL), and (iii) high-grade squamous intraepithelial lesions (HSIL). The ASC category is subdivided into two categories: those of unknown significance (ASC-US) and those in which high-grade lesions must be excluded (ASC-H). The LSIL category includes CIN 1 (mild dysplasia) and the changes of HPV, termed koilocytotic atypia. The HSIL category includes CIN 2 and CIN 3 (moderate dysplasia, severe dysplasia, and carcinoma in situ).


Gynecology_Novak

Gynecology_Novak. The spontaneous regression rate of biopsy-proven CIN 1 is 60% to 85% in prospective studies. The regressions typically occur within a 2-year follow-up with cytology and colposcopy. For LSIL that persists longer than 2 years, the choice of treatment is optional. Expectant management is still appropriate in some patients, and ablative therapies, including cryotherapy and laser ablation, are acceptable treatment modalities. When a cytologic specimen suggests the presence of HSIL, colposcopy and directed biopsy should be performed. Although high-grade CIN can be treated with a variety of techniques, the preferred treatment for CIN 2 or 3 in nonadolescent patients is loop electrosurgical excision procedure (LEEP). Atypical endocervical cells pose a risk for adenocarcinoma in situ (AIS), which must be considered a precursor of adenocarcinoma.


Gynecology_Novak

Gynecology_Novak. Atypical endocervical cells pose a risk for adenocarcinoma in situ (AIS), which must be considered a precursor of adenocarcinoma. After sampling to rule out invasive disease, vaginal intraepithelial neoplasia (VAIN 3 lesions can be treated with laser or outpatient excisional therapy. Patients with vaginal intraepithelial neoplasia (VAIN 1 and most VAIN 2 and HPV infection do not require treatment. These lesions are multifocal and often regress, but may recur after ablative therapy. Vulvar intraepithelial neoplasia, grade 3 (VIN 3), is treated by simple excision, laser ablation, or superficial (partial) vulvectomy, with or without split-thickness skin grafting. Excision of small foci of disease produces excellent results, and although multifocal or extensive lesions may be difficult to treat by this approach, it offers the most cosmetic result. VIN 1 or 2 is generally associated with dystrophic changes or HPV and can be managed expectantly.


Gynecology_Novak

Gynecology_Novak. Intraepithelial disease frequently occurs in the cervix, vagina, and vulva, and it may coexist in these areas. The cause and epidemiologic basis are common to all three locations, and treatment typically is ablative, excisional, and conservative. Early diagnosis and management are essential to prevent disease from progressing to invasive cancer.


Gynecology_Novak

Gynecology_Novak. The concept of preinvasive disease of the cervix was introduced in 1947, when it was recognized that epithelial changes could be identified that had the appearance of invasive cancer but were confined to the epithelium (1). Subsequent studies showed that these lesions, if left untreated, could progress to cervical cancer (2). Improvements in cytologic assessment led to the identification of early precursor lesions called dysplasia, a name that acknowledges the malignant potential of these lesions. Historically carcinoma in situ (CIS) was treated very aggressively (most often with hysterectomy), whereas dysplasias were believed to be less significant and were not treated or were treated by colposcopic biopsy and cryosurgery. The concept of cervical intraepithelial neoplasia (CIN) was introduced in 1968, when Richart suggested that dysplasias have the potential for progression (3). Most untreated CIN 1 and some CIN 2 lesions regress spontaneously; nevertheless, high-grade CIN refers to


Gynecology_Novak

Gynecology_Novak. in 1968, when Richart suggested that dysplasias have the potential for progression (3). Most untreated CIN 1 and some CIN 2 lesions regress spontaneously; nevertheless, high-grade CIN refers to a lesion that may progress to invasive carcinoma when left untreated (4). Proliferating metaplasia without mitotic activity should not be called dysplasia or CIN because it does not progress to invasive cancer.


Gynecology_Novak

Gynecology_Novak. The criteria for the diagnosis of intraepithelial neoplasia may vary according to the pathologist, but the significant features are cellular immaturity, cellular disorganization, nuclear abnormality, and increased mitotic activity. The extent of the mitotic activity, immature cellular proliferation, and nuclear atypia identifies the degree of neoplasia. If the presence of mitoses and immature cells is limited to the lower third of the epithelium, the lesion usually is designated as CIN 1. Involvement of the middle and upper thirds is diagnosed as CIN 2 and CIN 3, respectively (Fig. 19.1). Cervical Anatomy The cervix is composed of columnar epithelium, which lines the endocervical canal, and squamous epithelium, which covers the exocervix (5). The point at which they meet is called the squamocolumnar junction (SCJ) (Figs. 19.2 and 19.3). Figure 19.1 Diagram of cervical intraepithelial neoplasia compared with normal epithelium. The Squamocolumnar Junction


Gynecology_Novak

Gynecology_Novak. Figure 19.1 Diagram of cervical intraepithelial neoplasia compared with normal epithelium. The Squamocolumnar Junction The SCJ rarely remains restricted to the external os. Instead, it is a dynamic point that changes in response to puberty, pregnancy, menopause, and hormonal stimulation (Fig. 19.4). In neonates, the SCJ is located on the exocervix. At menarche, the production of estrogen causes the vaginal epithelium to fill with glycogen. Lactobacilli act on the glycogen to lower the pH, stimulating the subcolumnar reserve cells to undergo metaplasia (5). Metaplasia advances from the original SCJ inward, toward the external os and over the columnar villi. This process establishes an area called the transformation zone. The transformation zone extends from the original SCJ to the physiologically active SCJ, as Figure 19.2 The cervix and the transformation zone. CHAPTER 19 Intraepithelial Disease of the Cervix, Vagina, and Vulva


Gynecology_Novak

Gynecology_Novak. Figure 19.2 The cervix and the transformation zone. CHAPTER 19 Intraepithelial Disease of the Cervix, Vagina, and Vulva Figure 19.3 Diagram of the cervix and the endocervix. demarcated by the squamocolumnar junction. As the metaplastic epithelium in the transformation zone matures, it begins to produce glycogen and eventually resembles the original squamous epithelium, both colposcopically and histologically (Fig. 19.5A and B).


Gynecology_Novak

Gynecology_Novak. In most cases, CIN is believed to originate as a single focus in the transformation zone at the advancing SCJ. The anterior lip of the cervix is twice as likely to develop CIN as the posterior lip, and CIN rarely originates in the lateral angles. Once CIN occurs, it can progress horizontally to involve the entire transformation zone, but it usually does not replace the original squamous epithelium. This progression usually results in CIN with a sharp external border. Proximally, CIN involves the cervical clefts, and this area tends to have the most severe CIN lesions. The extent of involvement of these cervical glands has significant therapeutic implications because the entire gland must be destroyed to ensure elimination of the CIN (5). The only way to determine where the original SCJ was located is to look for nabothian cysts or cervical cleft openings, which indicate the presence of columnar epithelium. After the metaplastic epithelium matures and forms glycogen, it is called the


Gynecology_Novak

Gynecology_Novak. located is to look for nabothian cysts or cervical cleft openings, which indicate the presence of columnar epithelium. After the metaplastic epithelium matures and forms glycogen, it is called the healed transformation zone and is relatively resistant to oncogenic stimuli. The entire SCJ with early metaplastic cells is susceptible to oncogenic factors, which may cause these cells to transform into CIN. Therefore, CIN is most likely to begin either during menarche or after pregnancy, when metaplasia is most active. Conversely, after menopause a woman undergoes little metaplasia and is at a lower risk of developing CIN from de novo human papillomavirus (HPV) infection. Oncogenic factors are introduced through sexual contact in general and intercourse in particular. Although several agents, including sperm, seminal ﬂuid histones, trichomonas, chlamydia, and herpes simplex virus, were studied, it is established that persistent high-risk oncogenic HPV infection is the overwhelming risk


Gynecology_Novak

Gynecology_Novak. including sperm, seminal ﬂuid histones, trichomonas, chlamydia, and herpes simplex virus, were studied, it is established that persistent high-risk oncogenic HPV infection is the overwhelming risk factor for the development of CIN.