Endometriosis merupakan jaringan endometrium yang terdapat di luar kavum uteri.  Lesi-lesi endometriosis tetap dipengaruhi oleh hormon estrogen dan progesteron, dan mengalami perubahan siklik seperti endometrium. Paling sering terjadi pada usia reproduksi.

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Endometriosis merupakan kelainan ginekologi yang kompleks, kronik dan mempengaruhi fertilitas wanita. Pertama kali diperkenalkan tahun 1800-an. Dan mulai menarik perhatian pada permulaan abad ke-20

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]]> http://eddyhartono.wordpress.com/2008/09/20/endometriosis-i-presentasi/feed/ 0 eddyhartono Endometriosis PPT endometriosis_ppt endo_ppt_2 endo_ppt_3 kista_endometriosis http://eddyhartono.wordpress.com/2008/09/20/the-use-of-5-dextrose-as-a-distending-media-in-endometrial-ablation/ http://eddyhartono.wordpress.com/2008/09/20/the-use-of-5-dextrose-as-a-distending-media-in-endometrial-ablation/#comments Sat, 20 Sep 2008 01:24:55 +0000 eddyhartono http://eddyhartono.wordpress.com/?p=32 ]]>

(CASE REPORT)

Wi Liong, Eddy Hartono

Department of Obstetrics and Gynecology

Faculty of Medicine Hasanuddin University

Wahidin Sudirohusodo General Hospital

Makassar

INTRODUCTION

Menorrhagia is a common clinical problem and makes a large contribution to the workload of gynecologists. Dysfunctional uterine bleeding (DUB) affects 20-30% of women and accounts for 12% of gynecological referrals. Sixty percent of these women will have undergone hysterectomy within 5 years of referral, making it the commonest major gynecological operation. The recent VALUE Survey of over 36,000 hysterectomies reported a mortality rate of 0.38 per 1000 operations and serious morbidity rate of 3% (bleeding, visceral injury and other complications).

Endometrial ablation is a procedure that aims to destroy the endometrial lining of the uterus, causing a reduction or elimination of menstrual bleeding. To suppress menstrual bleeding effectively, it is necessary to remove the full thickness of the endometrial lining as well as the superficial myometrium. The endometrial tissue may be destroyed either by excision with an electrosurgical loop, or by ablation using an energy source which has sufficient power to produce necrosis of the entire thickness of the endometrium as well as the superficial myometrium.

Recently, several ablative techniques have been described to treat menorrhagia in order to reduce hysterectomy rates. Because the majority of women with menorrhagia have a normal sized uterus with no obvious pathology, endometrial ablation are increasingly performed. With the development of minimal access techniques, it has become possibly to destroy the endometrium in situ, in a short, day-care operation. These techniques include endometrium ablation with a Nd:YAG laser and resection of the endometrium with the operative hysteroscopy. Unfortunately, these techniques require considerable surgical skill and a long learning curve. It has been suggested that a surgeon learning the technique of resection, should treat 200 cases. Although resection is considered to be safe, it is still associated with a mortality of 2 per 10,000 and a serious complication rate of 2.1-6.4%.

Figure 1. Operative hysteroscopy with wire loop electrode and rollerball.

Common complications of endometrial ablation are mechanical complications (cervical laceration and uterine perforation), distending-media-related complications (embolism, fluid overload, hyponatremia, pulmonary edema, intravascular coagulation), bleeding and infection.

Endometrial ablation techniques are termed first-generation or second-generation. First-generation techniques [which include transcervical resection of the endometrium (TCRE), rollerball endometrial ablation (RB), TCRE/RB and Nd:YAG laser endometrial ablation] use a hysteroscope and fluid medium, and require a high level of technical skill. Second-generation endometrial ablation techniques are newer techniques which are usually nonhysteroscopic, do not require a fluid medium, and require less training to perform.

Second-generation endometrial ablation techniques are microwave endometrial ablation (MEA), thermal balloon endometrial ablation (TBEA), hydrothermal ablation, radiofrequency electrosurgery, cryoablation, endometrial laser intrauterine thermal therapy (ELITT).

Figure 2. Thermal Balloon Endometrial Ablation

Figure 3. Hydrothermal Endometrial Ablation

The use of media to distend uterus cavity is critical for panoramic inspection of uterine cavity in the first-generation techniques. Without media, the uterus is a narrow slit. Uterine distention during hysteroscopy improves visualization by separating the surfaces of the uterine cavity and creating sufficient pressure to inhibit intracavitary bleeding; however, the most serious hysteroscopic complications are related to excessive absorption of distending media. Intrauterine pressures needed to adequately view the endometrium are proportional to the muscle tone and thickness of the uterus. A pressure of 75 mmHg is adequate for uterine distention. Rarely is more than 100mmHg required, and higher pressure can result in increased risk of intravasation media. The refractive index of each medium option affects magnification and visualization of the endometrium.

Excessive fluid absorption or idiosyncratic reactions to distending media can occur during either diagnostic or operative hysteroscopy. The ideal distending media is isotonic, nonhemolytic, nonconductive, nontoxic, rapidly cleared from the body, and provides ample visualization. In fact, the ideal distending media does not exist; therefore, the hysteroscopist is left with several choices of media, each with certain advantages and disadvantages.

The operating time is important because more fluid absorption occurs during lengthier cases. The surgeon must operate quickly, as well as safely, and be willing to stop a procedure when fluid management becomes problematic. Excess fluid absorption can occur even when pressures are well controlled and surgery progresses appropriately. This means the most important factor in preventing fluid overload is the accurate monitoring of inflow and outflow, keeping track of the difference between them, known as the fluid deficit.

The most commonly used media are gases, low viscosity fluid and high viscosity fluids.

CASE REPORT

1. A 46-year-old female, PIII A0 who complained of bleeding for the last ten months. She has been treated with hormonal therapy, and dilatation and curettage (D&C), hystopathological examination revealed simple endometrial hyperplasia. USG showed normal sized uterus, irregular and thick endometrium, and normal adnexa. Then, she underwent monopolar TCRE/RB endometrial ablation.
2. A 43-year-old female, PII AI, who complained of prolonged periods (more than two months). She responded poorly to hormonal therapy. Afterwards, she underwent monopolar TCRE/RB endometrial ablation. During diagnostic laparoscopy, subserous leiomyoma is found, therefore laparoscopic leiomyoma enucleation was also done.
3. A 46-year-old female, PVII A0, who complained of irregular menstrual bleeding for the last two years. She has been treated with hormonal therapy and D&C, hystopathological examination revealed simple endometrial hyperplasia. Thus, she underwent monopolar TCRE/RB endometrial ablation and laparoscopic bilateral tubectomy as she requested.

All three patients above underwent endometrial ablation, using 5% Dextrose as a distending media. Until now, they all have been being amenorrhea for more than a year.

DISCUSSION

Endometrial ablation techniques, which had been done to the three patients, is TCRE/RB. TCRE/RB is a combination of two procedures (TCRE and RB). This technique is considered the gold standard for endometrial ablation by most experts in the fields.

The procedure involves using the rollerball at the cornual region and the isthmus where the myometrium is thinnest, and the loop electrode (TCRE) to excise the remainder of the endometrium.

The advantages of TCRE are that enables histological assessment of excised endometrium and also enables submucous fibroids and polyps to be excised if present. The uterine distention media used during TCRE must be electrolyte-free, and this increases the risk of hyponatraemia if excess fluid is absorbed during the procedure.

A further disadvantage of TCRE is that it is associated with a higher risk of uterine perforation than other endometrial ablation techniques, but the risk is lower when TCRE is combined with RB.

RB is similar to TCRE; however, instead of a loop electrode excising the endometrium, a rollerball electrode is used to systematically coagulate the endometrium. As with TCRE, the fluid media used must be electrolyte-free, increasing the risk of hyponatraemia if excess fluids is absorbed.

The advantage of fluid over gas is the symmetric distention of the uterus with fluid, as well as its capacity to flush blood, mucus, bubbles, and small tissue fragments more effectively out of the visual field. Both low-viscosity and high-viscosity fluid media can be used for distention.

1. High-viscosity Fluid:

The only high-viscosity medium available is dextran 70 or Hyskon, which is 32% dextran 70 in 10% dextrose in water. Dextran is a high-molecular weight substance of 70,000 d. It is a nonelectrolytic, nonconductive fluid that can be applied in operative and diagnostic procedures. Because of its high viscosity, dextran 70 is immiscible with blood and has minimal leakage through the cervix and tubes, allowing for excellent visibility during surgical procedures.

However, avoid more than 500 mL of absorption to prevent fluid overload because it is a volume expander with a high risk of pulmonary edema. With each 100 mL of dextran 70 is absorbed, the intravascular volume is increased by 800 mL. This medium has a large adverse effect profile, including allergic reactions and anaphylaxis, adult onset respiratory distress syndrome (ARDS), fluid overload, pulmonary edema, disseminated intravascular coagulopathy, and destruction of instruments (which must be cleaned shortly after use because the solution can stick to the equipment).

2. Low-viscosity Fluid:

There are two types of low-viscosity distending media: those that contain electrolytes and those that do not. Two types of electrolyte-containing fluids exist, sodium chloride (0.9% sodium chloride, which is 154 mEq/L sodium and chloride) and acetated Ringer solution. These solutions can be used for diagnostic hysteroscopy as well as for limited operative procedures.

Operative procedures using mechanical, laser, or bipolar energy are safe. Both options are readily available, and complex equipment is not needed.

Two major disadvantages are associated with these solutions. They are miscible with blood, obscuring visibility with bleeding and thus requiring larger volumes to clear the operative field, and they are excellent conductors, which precludes procedures that use monopolar.

The nonelectrolyte fluids consist of 5% mannitol, 3% sorbitol, 1.5% glycine, and 5% dextrose. These fluids do not conduct electrical current and allow for better visualization when bleeding occurs. The common disadvantage of all the nonelectrolyte media is their risk of overload from intravascular absorption (particularly >2 L), which requires fluid monitoring during use.

However, 5% mannitol can be used only with monopolar operative procedures. It is broken down by the liver to glycogen and excreted through the kidney, with a half-life of 100 minutes. If 5% mannitol is administered intravenously, it remains in the extracellular compartment when intravasation occurs with this media, fluid and electrolyte imbalances can result in pulmonary edema, which can be treated with a diuretic.

The 3% sorbitol is broken down by the liver to fructose and glucose, which increases postoperative risks of hyponatraemia and hyperglycemia, hemolytic or signs of hypervolemia.

Use caution when 1.5% glycine is used in a patient with impaired hepatic function because glycine is metabolized to ammonia and serine.

Overload with glycine may produce:

a. Nausea and vertigo

b. Hyponatraemia

c. Transient hypertension followed by hypotension associated with confusion and disorientation

d. Excess overload may produce elevated blood ammonia levels leading to encephalopathy and rarely, death.

Karci and Erkin report the case of a woman who developed transient blindness following hysteroscopic myomectomy in which a total of 800 mL of 1.5% glycine was used as the irrigation solution.

Complications with the use of 5% dextrose are very rare. In fact, there are no reports in the world literature of major morbidity or mortality with the use of 5% dextrose at hysteroscopy.

Possible complications include:

• Water intoxication (a reduction in serum osmolality) with a dilutional reduction in sodium concentration,
• Volume overload (when the circulating volume in the vascular system exceeds the ability of the heart to adequately pump this volume and the excess fluid typically begins to collect in the tissue of the lungs),
• Hypothermia (significant excess in circulating glucose concentration that may not be rapidly metabolized if the patient has insulin resistance or diabetes mellitus).

The major complication that most hysteroscopic surgeon’s focus on avoiding is water intoxication. The risk of water intoxication from 5% dextrose in a healthy woman with normal renal function is very low, since the kidneys can typically produce in excess of 1000 cc of dilute urine in response to a decrease in serum osmolality.

Besides the advantages quoted above, 5% dextrose is easier to get and cheaper than other fluid distending media.

All three cases reported are treated by endometrial ablation using 5% dextrose as a distending media and the results are satisfying.

Visualization from using 5% dextrose is adequate, therefore ablation procedure could be done with minimum difficulties. This procedure is considered success because the three patients have been being amenorrhea for more than a year.

Prevention of fluid overload (media-related complication) may be accomplished by:

1. Using appropriate distending media and delivery system

2. Keeping operating time to a minimum

3. Avoiding entering the vascular channels

4. Keeping fluid pressures below 80 mmHg and gas pressures below 100 mmHg

5. Meticulous accountancy of fluid balance

6. The procedure must be abandoned if the deficit rises to 2 litres or there is evidence of venous congestion

Besides, distending media absorption can be decreased by using GNRH analog or intracervical diluted vasopressin preoperatively.

Second-generation endometrial ablation techniques do not use a hysteroscope, therefore complications related to distending media can be avoided. But these techniques involve relatively high equipment purchase and utilization costs.

Further researches about safety and effectivity of endometrial ablation, especially related to distending media are highly needed.

CONCLUSION

TCRE/RB endometrial ablation using 5% dextrose as distending media has been done to three endometrial hyperplasia cases, and the results are satisfying.

REFERENCES

<!–[if supportFields]> ADDIN EN.REFLIST <![endif]–>1. Munro MG. Dysfunctional uterine bleeding: advances in diagnosis and treatment. Curr Opin Obstet Gynecol. 2001;13:475-89.

2. Fernandez H, Kobelt G, Gervaise A. Economic evaluation of three surgical interventions for menorrhagia. Human reproduction. 2003;18(3):583-7.

3. Endometrial ablation techniques for chronic refractory menorrhagia. Canberra: The Medical Services Advisory Committee (MSAC); 2005.

4. Lessard C, Framarin A. Endometrial ablation techniques in the treatment of dysfunctional uterine bleeding. Montreal: Agence d’Evaluation des Technologies et des Modes d’Intervention en Sante (AETMIS); 2002.

5. Shaw JA, Shaw HA. Menorrhagia. 2005 [cited 2006 06/04]; Available from: http://www.emedicine.com

6. Gervaise A, Fernandez H, Capella-Allouc S, Taylor S, La Vieille S, Hamou J, et al. Thermal balloon ablation versus endometrial resection for the treatment of abnormal uterine bleeding. Human reproduction. 1999;14(11):2743-47.

7. Munro MG. Abnormal uterine bleeding: surgical management-part III. J Am Assoc Gynecol Laparosc. 2000;7(4):18-47.

8. League DD. Endometrial ablation as an alternative to hysterectomy. AORN J. 2003;77(2):322-38.

9. Cameron LT. Menstrual disorders. In: Edmonds DK, editor. Dewhurst’s textbook of obstetrics and gynaecology for postgraduates. 6th ed. London: Blackwell Science Ltd; 1999. p. 410-9.

10. Baggish MS. Operative hysteroscopy. In: Rock AJ, Jones HW, editors. Te Linde’s operative gynecology. 9^th ed. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 379-411.

11. Carlson KJ, Schiff I. Alternatives to hysterectomy for menorrhagia. N Engl J Med. 1996;335(3):198-9.

12. Pinion SB, Parkin DE, Abramovich DR, Naji A, Alexander DA, Russell IT, et al. Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding. BMJ. 1994;309:979-83.

13. Daiter E. Advanced operative hysteroscopy and laparoscopy. [cited 2006 06/04]; Available from: http://www.obgyn.net

14. Julian TM. Hysteroscopic complications. Journal of Lower Genital Tract Disease. 2002;6(1):39-47.

15. Guido RS, Stovall DW. Hysteroscopy. [cited 2006 06/04]; Available from: http://www.isge.org

16. Chan SCS, Fraser IS. The role of diagnostic hysteroscopy in modern gynaecological practice. HKMJ. 1995;1(2):161-6.

17. Nagele F, Wieser F, Deery A, Hart R, Magos A. Endometrial cell dissemination at diagnostic hysteroscopy: a prospective randomized cross-over comparison of normal saline and carbon dioxide uterine distension. Human reproduction. 1999;14(11):2739-42.

18. Petrozza JC, Sikking E. Hysteroscopy. 2005 [cited 2006 03/04]; Available from: http://www.emedicine.com

19. Karci A, Erkin Y. Transient blindness following hysteroscopy. The Journal of International Medical Research. 2003;31:152-5.

20. Homer HA, Li TC, Cooke ID. The septate uterus: a review of management and reproductive outcome. Fertility and Sterility. 2000;73(1).

21. Indman PD, Brooks PG, Cooper JM, Loffler FD, Valle RF, Vancaillie TG. Complications of fluid overload from resectoscopic surgery. J Am Assoc Gynecol Laparosc. 1998;5(1):63-7.

22. Valle RF. Facilitating and implementing hysteroscpy for over a century. J Obstet Gynecol Ind. 2002;52(1):28-32.

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Eddy Hartono, Edmoon Liwan

Obstetrics and Gynecology Department

The Faculty of Medicine of the University of Hasanuddin

ABSTRACT

Objective : To report the success use of medical plastic bag as a replacement for endobag in the laparoscopic procedure of ovarian dermoid cyst.

Location : Dr. Wahidin Sudirohusodo General Hospital, Makassar

Study design : Case-report

Method : women, 39 years old, PIIIA0, with a preoperative diagnosis of ovarian cyst, a diagnostic laparoscopic was performed, we found a right ovarian dermoid cyst and endometriosis stage I, then we performed right salpingooforectomy through operative laparoscopic, as a replacement for endobag we used medical plastic bag (Zipack®). For the endometriosis stage I, we did bipolar coagulation. Sterilization was performed using bipolar destruction method.

Result : The use of medical plastic bag as a replacement for endobag in the laparoscopic procedure of ovarian dermoid cyst was quite effective in preventing spill of the cyst content to abdominal cavity.

Key words : laparoscopy, ovarian dermoid cyst.

I. INTRODUCTION

There were two types of ovarian tumors; neoplastic and non-neoplastic (e.g. tumors caused by inflammation and functional ones). As for neoplastic tumor, it was divided as benign and malignant, in a cystic or solid forms. Dudley (1992) stated the forms of ovarian cyst were:

1. Teratoma-dermoid 40%

2. Functional cyst 30%

3. Epithelial tumor 20%

4. Paraovarial tumor 6%

5. Endometrioma 5%

6. Malignant ovarian tumor 2%

One of the study of ovarian tumor found dermoid cysts in 62% of all ovarian neoplasm in young women aged less than 40 years old. Malignant transformation occurs in less than 2% of all dermoid cysts, and usually in post menopausal women. The risk of torsion of dermoid cyst was around 15%.^3,4

The surgical management of ovarian dermoid cyst can be performed through laparotomy or laparoscopy procedure.^5,6

Laparoscopy procedure was recommended for ovarian cyst management, if the cyst sized more than 5 cm, it contained a solid part, persistent of worsening symptoms, it was found in more than 2 or 3 menstrual cycles.⁵

In laparoscopic procedure of ovarian dermoid cyst, in order to prevent spilling of the cyst content when we take the cyst out from the abdominal cavity, we could use endobag, however this function of endobag may be replaced with the use of medical plastic bag.

II. CASE

A woman, PIIIA0, aged 36 years old, referred from a gynecologist with lower abdominal mass which has been diagnosed since one month ago and a complaint of lower abdominal discomfort which has been experienced since one year ago.

She had regular menstruation, without dysmenorrheal. From physical examination, we palpated a mass in the right hypochondriac area, sized 8 x 5 cm², sharp demarcation, mobile, no tenderness. From vaginal touché, we found no abnormalities in the vulva, vagina, nor portio, closed internal and external ostia of the uterus which was anteflexed and normal in size, at right adnexal area we palpated a cyst mass sized 8 x 6 x 5 cm³, sharp demarcation, regular surface, mobile, no tenderness.

The results of laboratory examination of urine and blood were within normal limit. Pregnancy test negative. Abdominal ultrasonography found a normal size uterus, a hipoechoic mass in the adnexal sized 8,3 cm x 6,8 cm, with a conclusion of adnexal tumor.

Patient was diagnosed with adnexal tumor, she was planned to underdo diagnostic laparoscopic procedure followed by operative laparoscopic. After counseling this 36 year old woman on contraception and the fact that she has already had enough offspring, we also planned a laparoscopic sterilization.

Figure 1 : Abdominal USG

After we completed preoperative evaluation, laparoscopy was performed on December 12th 2007 at 10:30-12:00 PM. We performed asepsis and antisepsis to the whole operation field, continued by uterine manipulator insertion. Insert verres neddle to the umbilicus and flow carbon dioxide until a pressure of 25 mmHg than insert a 10-mm optical trocar. Insert a 5-mm trocar to left and right abdominal wall for instruments used. Sustained carbon dioxide pressure at 10-12 mmHg.

After we explored the abdominal cavity, we found omental adhesion to the peritoneum which was then lysed, it was followed by observation for futher bleeding.

From identification of the uterus and bilateral adnexa, we found that they were within normal limit. In the right adnexal, we found a cystic mass sized 8 x 6 x 5 cm, having greyish border, regular surface, free of adhesion, giving the impression of right ovarian dermoid cyst (Figure 2).

Figure 2 : Right ovarian dermoid cyst

In the sacrouterine area, there is a endometriosis patch stage I, we performed a bipolar coagulation, which was continued by unilateral tubal sterilization per laparoscopic (Figure 3).

Figure 3 : endometriosis patch stage I and laparoscopic tubal sterilization

This was followed by right salpingooforectomy, and hemmorhage control (Figure 4) and reducing cyst through vacuum aspiration so that we got smaller mass which could be put in the medical plastic bag (Zipack®). It was pull out from the abdominal cavity through a 3 cm insision at 2 fingers above pubical symphisis (Figure 5).

Figure 4 : right salpingooforectomy

Figure 5 : right ovarian dermoid cyst inside medical plastic bag

Afterward, we performed bleeding control, and it was ascertained that no bleeding (Figure 6). Operation done, samples was taken to the histopathological examination. We gave post operative antibiotic and analgetik.

Figure 6 : right salpingooforectomy, without bleeding complication

III. RESULT

The use of medical plastic bag as a replacement to endobag in laparoscopic prosedure of dermoid cyst of the ovaries was quite effective in preventing spilling of the cyst content to the abdominal cavity. In the first day post laparoscopic, patient went home with a good general condition, the histopatological result showed ovarian dermoid cyst (Histopathological examination was performed at Wahidin Sudirohusodo General Hospital Registration number 1.07.P.0702).

IV. DISCUSSION

Dermoid cyst was a benign cystic teratoma in which ectodermal structures were completely differentiated, such as dermal epithelium, hair, tooth, and sebasea gland product which was yellowish resembling fat were more dominant than entodermal and mesodermal elements. Transformation to malignancy of all dermoid cysts was less than 2% and it usually happened to post menopausal women.^2-6

Similar to the other ovarian tumors, dermoid cysts gave unspecific signs and symptoms, i.e. abdominal distention, abdominal pain or discomfort, pressure sensation on the lower abdomen, urinary and gastrointestinal symptoms.^2,5-7

In this case, patient with dermoid cyst also gave unspecific symptoms i.e. discomfort in the lower abdomen since 1 year ago, this complaint makes the patient visit a gynecologist. After history taking, physical examination, and vaginal toucher, we got the impression of anteflexed uterus with normal size, we also palpated a cystic mass sized 8 x 6 x 5 cm, with distinct border, reguler surface, mobile, with no tenderness. From laboratory and abdominal ultrasound examination, we obtained a diagnosis of adnexal tumor.

Patel et.al. showed that the use of ultrasound to support a diagnosis of ovarian dermoid cyst has a positive predictive value of 98% and a sensitivity of 85%. Mais et.al. stated that transvaginal ultrasound has a sensitivity and specificity of 84.6% and 98.2%.⁶

From abdominal ultrasound, we identify a normal uterus with a hypoechoic mass sized 8.3 x 6.8 cm, giving the impression of adnexal tumor. Not giving an impression of ovarian dermoid cyst. In this case, the content of ovarian dermoid cyst was a prosuct of sebacea glands and hair, therefore we only found a hipoechoic image; if there were any mesodermal elements such as bone, cartilage, etc, it may gave a mixed echogenicity image; with this ultrasound, we can temporarily diagnose this as an ovarian dermoid cyst.

Diagnosis of dermoid cyst was confirm after diagnostic laparoscopy, we observe a grayish cystic mass with thin wall (Figure 2).

The management of ovarian dermoid cyst can be performed through laparotomy and laparoscopy.^5,6

From a study comparing laparoscopy and laparotomy procedure for ovarian dermoid cyst by Benezra V et.al., it was concluded that laparoscopic gave less bleeding, shorter hospital stay, and minimal complications. Therefore, laparoscopic procedure for dermoid cyst was quite safe.⁸

Surgical management of ovarian dermoid cyst may easily caused complications such as chemical peritonitis or wide spread infection and these were main complications of laparoscopic procedure. The incidence of chemical peritonitis in the laparoscopic procedure performed for ovarian dermoid cyst was 0.2%.⁷

The uptake of cyst using endobag will significantly reduce the operation time nor cyst’s content spill, however a spill which was well controlled will not increase morbidity as long as we wash the abdominal cavity thoroughly.⁹

The use of medical plastic bag as a replacement for endobag with the consideration that it was more economical and easier to be obtained compared to endobag, however the possibility of rupture during the uptake was higher than that of endobag.

The management of dermoid cyst in this case, using laparoscopy, was by performing a right salpingectomy (Figure 4) continued with cyst fluid aspiration. Cyst mass was inserted to the medical plastic bag (Figure 5), that it was taken out through a 3-cm insisional wound above the level of symphisis of pubic. If there is a spill of the cyst content, this may caused complication such as chemical peritonitis.

Before usage, the medical plastic bag will be rinsed for 20 minutes in glutaraldehyde solution (Cidex ®).

Figure 7 : Medical plastic bag (Zipack®)

Figure 8 : Endobag

Endometriosis is confirmed using laparoscopy, through laparoscopy, all types of endometriosis lesions can be seen including the minimal ones. To all lesions which were easily reached and seen, not near the ureter or bowel, a coagulation may be performed.¹⁰

In this patient, we observe an endometriosis lesion in the left sacrouterine area (Figure 3), since it was a minimal one, there were no sign or symptoms and the management was only bipolar coagulation of the lesion.

Considering the patient’s age and parity, a counseling on family planning, followed by tubal sterilization through laparoscopy using bipolar destruction method (Figure 3) were performed.

V. CONCLUSION

Similar to the other ovarian tumor, dermoid cyst gave unspecific sign and symptoms. Further diagnostic examination such as ultrasonography was needed.

The use of medical plastic bag as a replacement for endobag was quite effective in preventing spilling of the dermoid cyst content to the abdominal cavity.

Laparoscopic surgery on an ovarian dermoid cyst was a safe procedure with less bleeding, shorter hospital stay, and minimal complication.

REFERENCE

<!–[if supportFields]> ADDIN EN.REFLIST <![endif]–>1. Sutoto MSJ. Tumor jinak pada alat genitalia. In: Ilmu kandungan. 3 ed. Jakarta: Yayasan Bina Pustaka Sarwono; 2002. p. 328-66.

2. Hillard PJA. Benign diseases of the female reproductive tract : symptoms and signs. In: Berek JS, editor. Novak’ s Gynecology 13 ed. Los Angles, California: Lippicott Williams & Wilkins; 2002. p. 351-420.

3. Manuaba IBG. Operasi ginekologi transabdominal. In: Dasar – dasar teknik operasi ginekologi. 1 ed. Jakarta: Penerbit Buku Kedokteran EGC; 2005. p. 190-229.

4. Sutoto MSJ. Tumor Jinak Pada Alat Genitalia. In: Wiknjosaatro H, editor. Ilmu kandungan. 3 ed. Jakarta: Yayasan Bina Pustaka Sarwono; 2005. p. 328-66.

5. Malpani. Ovarian cysts and infertilty. Available at: URL: http://www.drmalpani.com/ovarian-cyst-and-infertility.htm. Accessed February, 07, 2007.

6. Hamilton CA. Teratoma, cystic. Available at: URL: http://www.emedicine.com/med/topic2248.htm. Accessed February 07, 2007.

7. Osama Shawaki IS, Alaa Ebrashy, Mustafa EL sadek, Abeer Bahnassy. Laparoscopic management of ovarian dermoid cysts. Middle East Fertility Society Journal 2004;9:58-65.

8. Victor Benezra UV, R. wayne Whitted. Comparison of laparoscopy versus laparotomy for the surgical treatment of ovarian dermoid cysts. Miami, USA: Departmen of Obstertics and Gynecology, Jackson Memorial Hospital; 2004.

9. Campo S GN. Laparoscopic conservative excision of ovarian dermoid cysts with and without an endobag. J Am Assoc Gynecol Laparosc 1998;2:165-70.

10. Baziad A. Endometriosis. In: Endokrinologi ginekologi. Jakarta: Media Aesculapius; 2003. p. 1-25.

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Eddy Hartono, Imam D Mulyawan,Telly Tessy

Department of Obstetric and Gynecology, Faculty of Medicine, Hasanuddin University Makassar-Indonesia

ABSTRACT

Background: The use of different agents for induction of ovulation, mainly clomiphene citrate and gonadotropins, is associated with various problems and drawbacks. This study introduces aromatase inhibition anastrozole as an oral method of ovulation induction that could eliminate problems due to clomiphene citrate.

Objective: To compare between clomiphene citrate and anastrozole as an ovulation induction.

Design: Randomized clinical trial study with statistical analysis by using Independent T test

Setting: Women of infertile couple who would be stimulated ovulation in outpatient clinic Wahidin Sudirohusodo Hospital Makassar South Sulawesi in the periods of twelve months from January to December 2005. They were randomly allocated into clomiphene citrate group (clomiphene citrate 50 mg for 5 days start at third day to seventh day of menstrual cycle) and anastrozole group (anastrozole 1 mg for 5 days start at third day to seventh day of menstrual cycle). The dependent variables are number of follicle and endometrial thickness.

Participants: Sixty-six cases are divided into 33 cases as clomiphene citrate group and 33 cases as anastrozole group fulfilling the inclusion criteria (infertile women with uterine and ovary normal).

Outcome measured: number of follicle and endometrial thickness

Results: There was significant different between both of sample according to number of follicle which clomiphene citrate group have mean 2,82 ± 0,769 (SD) and anastrozole group have mean 1,15 ± 0,364 (SD). There was significant different between both of sample according to endometrial thickness which clomiphene citrate group have mean 5,64 ± 0.929 (SD) and anastrozole group have mean 8,94 ± 1,694 (SD).

Conclusion: The study concluded anastrozole group tends to produce single follicle otherwise in clomiphene citrate group tends to preduce multiple follicles

and endometrial thickncss i n a nastrololc group was thicker than clomiphene citrate group.

Key words: anastrozole, clomiphene citrate, number of follicle, endometrial thickness

PERBANDINGAN KLOMIFEN SITRAT DAN ANASTROZOLE

SEBAGAI PEMICU OVULASI

Eddy Hartono ,Imam D.Mulyawan, , Telly Tessy

Subbagian Fertilitas Endokrin dan Reproduksi Bagian Obstetri dan Ginekologi Fakultas Kedokteran Universitas Hasanuddin Makassar

PENDAHULUAN

Latar belakang

Proses terjadinya ovulasi secara fisiologis perlu diketahui dengan baik, terutama dalam penanganan pasangan infertil yang memerlukan obat-obat pemicu ovulasi. Infertilitas karena gangguan ovulasi dengan penyebab endokrinologis hanya meliputi 20-36% dari keseluruhan kejadian infertilitas. Proses terjadinya ovulasi hingga kini belum seluruhnya terungkap dengan jelas.¹

Gangguan fertilitas diperkirakan mempengaruhi 10 -15 % pasangan tetapi presentase tersebut bisa dibawah perkiraan, karena ketidakmampuan untuk hamil menyebabkan stigma memalukan yang disembunyikan dan sesuatu yang dirahasiakan untuk sebagian pasangan. Sebagian yang lain tidak pemah tercatat karena mereka tidak mampu untuk mencari pengobatan secara medis. Kegagalan untuk memperoleh pemeriksaan dan berbagai pengobatan menambah kejadian yang menyedihkan pada kasus infertilitas karena sebenamya sederhana saja, dengan pilihan pemakaian obat yang tepat dan tidak terlalu mahal maka pada infertilitas yang anovulasi atau bahkan pada penanganan infertilitas yang tidak diketahui penyebabnya {unexplained infertility) bisa diatasi. ^2-4

Diantara pasangan perkawinan di Amerika Serikat yang berumur 15-44 tahun,, dilaporkan kira-kira 13% merupakan pasangan infertil menurut survey tahun 1965 dan 1985. Pada akhir tahun 80-an diperkirakan terdapat 5 juta pasangan infertil.^2,3

Stimulasi ovarium pada penanganan infertilitas bisa dilakukan sendirian atau dilanjutkan dengan inseminasi intrauterin dan teknologi reproduksi bantu. Saat ini terdapat dua pengobatan utama yang digunakan untuk memicu ovarium yaitu antiestrogen oral klomifen sitrat dan gonadotropin injeksi.^2-8

Penggunaan obat yang berbeda-beda untuk induksi ovulasi terutama klomifen sitrat dan gonadotropin berhubungan dengan bermacam-macam masalah dan terdapat beberapa kekurangannya. Masalah dan kekurangan yang berhubungan dengan penggunaan obat untuk induksi ovulasi saat ini antara lain :

· Risiko bahaya pada sindroma hiperstimulasi ovarium

· Kejadian kehamilan multipel yang tinggi

· Angka kehamilan yang rendah meskipun angka ovulasi tinggi (khusunya pada klomifen sitrat)

· Hasil luaran obstetrik yang jelek

· Membutuhkan monitoring yang ketat, khususnya pada pengobatan FSH

· Sangat mahal (pengunaan FSH)

· Pemberian parenteral (FSH)

• Kemungkinan risiko keganasan ovarium.^2-4

Telah diketahui bahwa klomifen sitrat secara luas dipergunakan sebagai pemicu ovulasi pada wanita infertil. Meskipun pada awalnya diberikan pada sindroma ovarium polikistik, klomifen sitrat kerap kali dipakai dalam rejimen tunggal atau kombinasi dengan sediaan gonadotropin. Klomifen sitrat sebagai bagian dari prosedur pemicu ovulasi, tidak jarang pula diindikasikan pada kasus infertilitas yang tidak diketahui penyebabnya. Sebagai obat pemicu ovulasi, klomifen sitrat memperlihatkan angka ovulasi dan kehamilan sebesar 60 – 85% dan 10 – 20%. Akibat antagonis di perifer (khususnya pada lapisan endometrium dan lendir servik), maka seringkali ditemukan penurunan 40-50% angka implantasi, meskipun diperoleh angka ovulasi yang tinggi. Penjelasannya adalah ketika anti estrogen terjadi begitu lama, maka akan terjadi penipisan lapisan endometrium (tebal endometrium < 8mm).^4-10

Penggunaan penghambat aromatase dalam bidang infertilitas telah diperkenalkan pada dekade akhir ini. Sediaan penghambat aromatase nir-steroid, pertama kali diperkenalkan dalam pengobatan kanker payudara wanita pascamenopause. Dengan menghambat aktifitas aromatase, akan terjadi penurunan massa tumor dan produksi estrogen secara sistemik.³‘⁵‘⁶‘¹¹

Penghambat aromatase menghambat konversi dari androgen menjadi estrogen Dengan pemberian penghambat aromatase terjadi penurunan kadar estrogen pada sirkulasi yang dihasilkan oleh ovarium dan produk estrogen lokal yang dihasilkan otak dimana hal in menyebabkan negatif feedback sehingga melepaskan gonadotropin. Dari hipotesis ini penghambat aromatase menyebabkan blocking produksi estrogen dari semua sumber dengan menghambat aromatisasi, hal ini akan menyebabkan rangsangan axis hipotalamik hipofisis dari estrogen negatif feedback, sehingga menghasilkan peningkatan sekresi gonadotropin dan menyebabkan stimulasi folikel ovarium. Keunggulan penghambat aromatase dari klomifen sitratsebagai pemicu ovulasi antara lain penghambat aromatase tidak menimbulkan deplesi reseptor estrogen khususnya jaringan endometrium dan mucus serviks, sehingga meningkatkan laju implantasi. Penghambat aromatase mampu memperkuat sensitifitas pulsasi FSH terhadap pematangan folikel, karena akumulasi androgen pada awal fase proliferasi akan meningkatkan ekspresi reseptor FSH. Penghambat aromatase merupakan sediaan penghambat aromatase nir steroid reversibel yang mempunyai waktu paruh singkat (± 48 jam) sehingga tidak mengganggu ovulasi dan embriogenesis dini. Angka kehamilan ganda pada pemberian penghambat aromatase akan menurun karena kebanyakan akan mengalami ovulasi tunggal.^11-20

Adapun keuntungan-keuntungan dari penghambat aromatase generasi ketiga, yaitu :

· Penghambat enzim aromatase yang paling kuat

· Sangat spesifik menghambat enzim aromatase tanpa hambatan yang bermakna terhadap enzim steroidogenesis yang lain

· Pemberiannya secara oral

· Bioavailabilitasnya 100% setelah pemberian secara oral

· Pengeluaran yang cepat dari tubuh (waktu paruh yang pendek ~45 jam)

· Tidak terjadi akumulasi obat atau metabolitnya

· Tidak ada metabolit aktif yang bermakna

· Toleransinya baik pada pemberian oral bertahun-tahun

· Efek samping yang sedikit dengan tolerabilitas yang tinggi

· Sangat aman tanpa kontraindikasi yang bermakna

· Relatif tidak mahal.^2-9,12-19

Rumusan Masalah

1. Apakah ada perbedaan jumlah folikel antara pemberian anastrozole dan klomifen sitrat.

2. Apakah ada perbedaan ketebalan endometrium antara pemberian anastrozole dan klomifen sitrat.

Tujuan Penelitian

a.Tujuan Umum

Untuk membandingkan antara penggunaan anastrozole dan klomifen sitrat sebagai pemicu ovulasi pada pasien infertil.

b. Tujuan Khusus

1. Membandingkan jumlah folikel yang dihasilkan antara pemberian anastrozole dan klomifen sitrat.

2. Membandingkan ketebalan endometrium pada pemberian anastrozole dan klomifen sitrat.

Manfaat Penelitian

1. Memberikan altematif penggunaan obat pemicu ovulasi pada pasien infertil.

2. Sebagai data dasar untuk penelitian selanjutnya.

BAHAN DAN CARA

Rancangan Penelitian

Penelitian ini merupakan penelitian dengan rancangan randomized clinical trial.

Tempat Penelitian

Penelitian ini dilaksanakan di poliklinik reproduksi RSUP Perjan dr. Wahidin Sudirohusodo Makassar dan dokter praktek klinik swasta di Makassar.

Populasi dan Sampel

a. Populasi

Populasi pada penelitian ini adalah pasangan infertil yang telah diskrining untuk pemberian pemicu ovulasi untuk mendapatkan kehamilan.

b. Sampel

Sampel pada penelitian ini adalah wanita pasangan infertil. Pemilihan sampel dilaksanakan secara consecutive sampling yaitu semua wanita pasangan infertil yang akan dilakukan pemicu ovulasi yang memenuhi kriteria inklusi akan diambil sebagai sampel.

a. Kriteria inklusi:

1. Wanita infertil primer atau sekunder yang menginginkan kehamilan

2. Kedua tuba paten dari hasil pemeriksaan histerosalpingografi

3. Uterus dan ovarium normal

b. Kriteria eksklusi :

Penderita yang megalami putus obat dalam penelitian ini

c. Besar sampel

Pada penelitian ini dari hasil perhitungan statistik didapatkan jumlah sampel 33 kasus untuk masing-masing subyek penelitian

Pengelolahan dan Penyajian Data

Data diolah dengan menggunakan program komputer SPSS (Statistical Package for Social Science} for window versi 11.5. Uji statistik dengan menggunakan uji Chi Square untuk mengetahui hubungan antara dua variabel dan uji T Dua Sampel untuk membandingkan antara dua variabel. Selanjutnya hasil penelitian akan disajikan dalam bentuk label dan grafik yang disertai dengan penjelasan.

Aspek Etis

Sebelum penelitian dilaksanakan peneliti meminta keterangan kelayakan etik {Ethical Clearence) dari Komisi Etik Penelitian Biomedis pada Manusia Fakultas Kedokteran Unhas. Semua penderita diberi penjelasan secara lisan dan menandatangani lembar persetujuan untuk ikut dalam penelitian secara sukarela.

HASIL PENELITIAN DAN PEMBAHASAN

Pada penelitian ini kami ingin membandingkan penggunaan klomifen sitrat dan anastrozole sebagai pemicu ovulasi. Sebagaimana kita ketahui bahwa penggunaan obat pemicu ovulasi yang biasanya kita gunakan saat ini adalah klomifen sitrat dan gonadotropin injeksi. Penggunaannya bisa digunakan klomifen sitrat saja atau digunakan bersama-sama dengan pemberian gonadotropin injeksi. Pada pengobatan pemicu ovulasi ini tentunya kita harus melakukan skrining terhadap pasien-pasien yang akan dilakukan pemberian obat-obat pemicu ovulasi. Oleh karena itu pemeriksaan yang seksama terhadap pasangan pasutri tersebut harus benar-benar dilakukan dengan baik untuk menentukan pengobatan yang mana yang tepat untuk pasangan pasutri tersebut.

Adapun langkah-langkah penting yang akan dilakukan sebelum melakukan pemberian obat pemicu ovulasi yaitu :

· Melakukan diagnosis yang tepat dan menyeluruh serta melakukan pemeriksaan pada pasien untuk menegakkan diagnosis banding untuk menyingkirkan penyakit-penyakit lain yang kemungkinan menyebabkan anovulasi dan infertilitas serta mengatasi penyakit yang mendasari jika ada

· Mengoptimalkan keadaan kesehatan pasien sebelum dilakukan pemicuan ovulasi Ketentuan pengobatan yang tepat untuk memicu 1 telur atau ovum untuk dimatangkan

· Pengamatan yang cermat dan hati-hati pada pengobatan siklus (dengan USG atau tes biokimia) untuk memeriksa respon ovarium

· Dosis obat yang tepat untuk mencegah adanya efek samping dan komplikasi

· Penatalaksanakan saat terjadinya ovulasi (kapan melakukan USG berkenaan dengan ukuran danjumlah folikel yang berkembang)

· Kapan saat yang tepat untuk pematangan dan melepaskan satu sel telur

· Melakukan hubungan seksual pada saat yang tepat

· Tes kehamilan untuk mengetahui hasil dari stimulasi ovarium.^2-6,19

Selama periode bulan Januari sampai dengan Desember 2005 telah dilakukan penelitian terhadap 66 wanita dari pasangan infertil yang menjalani pengobatan dengan pemakaian obat-obat pemicu ovulasi pada poliklinik reproduksi RSUP Perjan dr. Wahidin Sudirohusodo Makassar dan dokter praktek klinik swasta di Makassar yang telah memenuhi kriteria inklusi. Dari 66 sampel yang dilakukan penelitian terdiri dari 33 sampel yang diberikan obat pemicu ovulasi dengan memakai klomifen sitrat 50 mg dan 33 sampel yang diberikan obat pemicu ovulasi anastrozole 1 mg.

Pada tabel 1 menunjukkan bahwa analisis statistik dari karakteristik sampel yang diambil dalam penelitian ini menghasilkan nilai p > 0,05 yang berarti tidak bermakna. Sehingga karakteristik sampel yang kami gunakan dari analisis statistik ini adalah homogen sehingga selain telah diskrining dengan kriteria inklusi kemungkinan mempengaruhi dalam hal pemberian obat-obat pemicu ovulasi terhadap hasil penelitian ini bisa diminimalkan. Sampel yang digunakan merupakan kelompok wanita usia reproduktif dan pengambilan sampel dilakukan secara acak sehingga didapatkan sampel yang lebih homogen antara kedua kelompok sampel. Seperti halnya di Amerika Serikat kelompok infertil yang populasinya sebesar 10 sampai 15 % adalah pasangan yang berusia antara 15 – 44 tahun. Dari kelompok ini tidak semuanya yang datang untuk mendapatkan pengobatan terhadap infertilitasnya, karena berbagai macam alasan untuk tidak datang mendapatkan pertolongan pengobatan.^2-5

Pada penelitian ini perbandingan antara pemakaian obat klomifen sitrat dan anastrozole sebagai pemicu ovulasi kami bandingkan dengan pemeriksaan USG tranvaginal terhadap jumlah folikel dan ketebalan endometrium yang dihasilkan oleh kedua kelompok pengobatan pemicu ovulasi tersebut.

Pada tabel 2 dan grafik 1 menunjukkan gambaran dan jumlah folikel yang dihasilkan oleh pemberian kedua kelompok sampel. Pada tabel 2 didapatkan nilai rerata jumlah folikel dari kelompok klomifen sitrat adalah 2,82 ± 0,789 (SD) sedangkan nilai rerata jumlah folikel dari kelompok anastrozole adalah 1,15 ± 0,364 (SD). Uji statistik dengan Uji T Dua Sampel didapatkan nilai p < 0,05 yang berarti terdapat perbedaan yang bermakna antara kedua kelompok sampel.

Dalam hal ini bisa dikatakan bahwa dengan pemberian klomifen sitrat folikel yang dihasilkan cenderung menghasilkan folikel yang multipel yaitu sekitar 2-3 folikel matang. Dalam grafik 1 bisa dilihat dengan jelas perbedaan rerata jumlah folikel yang dihasilkan oleh kedua kelompok sampel tersebut. Sesuai dengan penelitian yang dilakukan oleh Mitwally dan Casper²‘³ bahwa masalah dan kekurangan dari pemakaian obat klomifen sitrat untiik pemicu ovulasi adalah suatu ovulasi yang multipel dan akhimya bisa terjadi kehamilan yang multipel pula. Bukan berarti bahwa klomifen sitrat tidak baik untuk dipakai sebagai obat pemicu ovulasi akan tetapi obat ini akan lebih baik digunakan sebagai obat pemicu ovulasi untuk menghasilkan beberapa folikel matang misalnya saat stimulasi ovarium terkontrol pada penanganan pasangan infertil dengan teknik reproduksi bantu.^2-6

Pada tabel 3 dan grafik 2 menunjukkan ketebalan endometrium yang dihasilkan oleh kedua kelompok sampel. Pada tabel 3 menunjukkan nilai rerata ketebalan endometrium dari kelompok klomifen sitrat adalah 5,64 ± 0,929 (SD) dan ketebalan endometrium dari kelompok anastrozole adalah 8,94 ± 1,694, dari hasil penelitian ini didapatkan bahwa kelompok anastrozole menyebabkan ketebalan endometrium lebih tebal dari pada kelompok klomifen sitrat. Dengan uji statistik menggunakan Uji T Dua Sampel didapatkan nilai p < 0.05 yang berarti terdapat perbedaan yang bermakna antara kedua kelompok sample.

Perbedaan tersebut akan lebih jelas terlihat pada grafik

Dari hasil penelitian yang dilakukan oleh Mitwally ^3,4 ketebalan endometrium pada pasien dengan siklus yang anovulasi pada PCOS dengan pemberian letrozol ketebalan endometrium pada saat pemberian akan diberikan injeksi HCG adalah 8,1 ± 2,4 (SD) sedangkan dengan pemberian klomifen sitrat ketebalan endometriumnya adalah 6,2 ± 2,5 (SD), sedangkan ketebalan endometrium pada pasien dengan siklus yang berovulasi dengan pemberian letrozol ketebalan endometrium yang didapatkan adalah 8,9 ±1,2 (SD) dan dengan pemberian klomifen sitrat ketebalan endometriumnya adalah 5,0 ± 1,0 (SD), dimana dengan analisis statistik nilai p < 0,001 yang berarti terdapat perbedaan yang bermakna antara pemberian letrozole dan klomifen sitrat terhadap ketebalan endometrium.²‘³

Yagel meneliti terhadap kelompok pemberian klomifen sitrat , ternyata terjadi penipisan endometrium sebesar 15-50 %, demikian hal yang dikemukakan oleh Gonen dan Casper² menyatakan bahwa tiadanya kehamilan (perlakuan dengan klomifen sitrat) pada kelompok dengan ketebalan endometrium < 6 mm pada pertengahan siklus.

Ketebalan endometrium yang kurang pada kelompok klomifen sitrat ini disebabkan oleh karena adanya deplesi reseptor estrogen sehingga menurunkan pertumbuhan 1apisan endometrium pada fase proliferasi, hal ini terjadi karena masih adanya pengaruh klomifen sitrat sampai pada pertengahan siklus menstruasi karena adanya zu-isomer dari klomifen sitrat yang masih menetap didalam tubuh karena waktu paruhnya yang panjang (beberapa minggu) dan pengeluarannya yang lambat hal ini akan menyebabkan akumulasi efek antiestrogenik pada pemberian obat pemicu ovulasi pada siklus berikutnya.^2-3 Pada penelitian ini kelompok anstrozole menghasilkan ketebalan endometrium yang kurang lebih normal atau lebih tebal dibandingkan dengan kelompok klomifen sitrat, hal ini karena anastrozole tidak menyebabkan deplesi reseptor estrogen pada pertengahan siklus sehingga pertumbuhan endometrium tidak dipengaruhi oleh anastrosole ini. Selain itu hal ini disebabkan karena waktu paruh anastrozole ± 45 jam sehingga setelah selesai pemberian obat, efek anastrozole akan segera hilang ^2-4

Dengan adanya efek pada ketebalan endometriurn ini pada pemberian obat pemicu ovulasi maka dengan pemberian klomifen sitrat angka kehamilannya akan menjadi rendah meskipun angka ovulasinya tinggi. Sedangkan dengan pemberian anastrozole angka kehamilannya akan lebih tinggi karena pertumbuhan endometrium pada fase proliferasi tidak akan terganggu sehingga pertumbuhan endometrium lebih tebal dan hal ini akan lebih baik untuk terjadinya implantasi hasil fertilisasi. Pada penelitian ini tidak dilakukan observasi sampai pasangan infertil tersebut bisa mencapai suatu kehamilan, yang seharusnya bisa dipantau pada sekitar hari ke 35 siklus haid setelah pasangan tersebut menjalani prosedur yang ditetapkan untuk mendapatkan suatu kehamilan. Hal ini karena keterbatasan waktu dari peneliti untuk melakukan pemantauan lebih lanjut terhadap sampel yang ada.

KESIMPULAN

1. Pada kelompok anastrozole cenderung menghasilkan jumlah folikel tunggal sedangkan kelompok klomifen sitrat cenderung menghasilkan jumlah folikel yang multipel.

2. Ketebalan endometrium pada kelompok anastrozole lebih tebal daripada kelompok

klomifensitrat

DAFTAR PUSTAKA

1. Baziad A. Pemakaian obat pemicu ovulasi. Dalam endokrinologi ginekologi. Edisi kedua. Media aesculapius FKUI. 2003. h.103

2. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Seminars in Reproductive Medicine. 2004. Volume 22.No 1; 61 – 73

3. Mitwally MF, Casper RF. Aromatase inhibition for ovarian stimulation : future avenues for infertility management. Current Opinion in Obstetrics and Gynecologiy. 2002. 14; 255-63.

4. Silva PD. Management of ovulatory dysfunction in the infertile couple. Gundersen Lutheran Medical Journal. 2004. Vol 3 number 1: p. 21-4

5. Putra ID. Penghambat aromatase sebagai alternatip pemicu ovulasi. Majalah obstetri dan ginekologi Indonesia. 2004. h. 178-183

6. Correa FJS. Use aromatase inhibitors for induction of ovulation. Femina. April 2004 ; Vol 32. No. 3; p.9

7. Silva PD. Management of ovulatory dysfunction in the infertile couple. Available from: http://www.gundluth.org/web/misc/MedicalJoumal.nsf/%24Images/lmage2/%24file/OvulatoryDysfunction.pdf+aromatase4-inhibitor.4- infertilitv.+induction+ovulation&hl=id Accessed on 20/1/2005

8. Mitwally MF. Use of an aromatase inhibitor for induction of ovulation in patients resistant to clomid. Available from: http://www.2ofus4now.org/ Article.asp?ArticleID=346 Accessed on 20/1/2005

9. ______ . Comparison of an aromatase inhibitor with Clomiphene Citrate forInduction of Ovulation. Available from: http: //www. royaninstitute. org /Award/ Abstracts/Aw Ab 01.htm Accessed on 20/1/2005

10. The practice committee of the American Society for reproductive medicine. Use of clomiphen citrate in women. Fertil Steril. 2003. vol. 80: p. 1302-8

11. MacReady N. Off-label use: Aromatase inhibitors show promise in fertility Tx. Available from: http://www.findarticles.com/p/articles/mi_mOCYD/is_17 39/ ai_n6212363 Accessed on 20/1/2005

12. Mitwally MF, Casper RF. Use of an aromatase inliibitor for induction of ovulation in patients with an inadequate response to cloiniphene citrate. Available from:

http://www.infertilityspecialist.com/letrozole.html Accessed on 20/1/2005

13. Sukcharoen N. Management of anovulatory infertility association with polycystic ovary syndrome (PCOS). J.Med Assoc Thai. 2004.p. 182-8

14. Conway SC. Aromatase inhibitor (Letrozole) shows promising results in fertility treatment. Available from: http://www.infertilitvspecialist.com/ letrozole.html Accessed on 20/1/2005

15. Sukcharoen N. Management of anovulatory infertility associated with polycystic ovary syndrome (PCOS). J Med Assoc Thai. 2004. Vol 87. p. 192-7

16. Lavery S. Drugs used in reproductive medicine. Current Obstetrics & Gynaecology. 2003. p.355-61. Available at: www.sciencedirect.com Accessed on 20/1/2005

17. Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women with unexplained infertility. Human Reproduction. 2003 : vol 18. no. 8: p. 1588-97

18. Goker ENT, Levi R, Kamar A, Tavmergen E. Aromatase inhibitors in ovulation

Induction. Turkish J. Fertil. 2003. vol.3; p. 21-6

19. Mitwally MF, Casper RF. Aromatase inhibitors for the treatment of infertility. Expert Opin Investig Drugs. 2003. Vol 12 353-72

Eddy Hartono

Reproductive Medicine.Medical Faculty University of Hasanuddin -Makassar

Introduction

Gonadotropin releasing hormone (GnRH) is a decapeptide produced by the hypothalamus. Hypothalamus is the highest center within the brain organizing several important functions, consisting of neuroendocrine cells producing five neurohormones. GnRH is one of those neurohormones, produced by arcuate nucleus.^1,2

Trials in rats showed that there are two centers within the hypothalamus having different functions. These are tonic center located in the ventromedial of arcuate nucleus and cyclic center located in the preoptical area near the suprachiamic center in the anterior part of the hypothalamus. Cyclic center functioned to control LH release in the mid-cycle, whereas tonic center is responsible to fulfill daily basal gonadotropin requirement.^1,2

Within the hypothalamic tissue, GnRH level is low, so that extraction is difficult and destruction by peptidase is more straightforward, therefore in favor of treatment GnRH analogue was made consisting of GnRH agonist and antagonist.

Gonadotropin releasing hormone (GnRH)

Natural GnRH is a peptide hormone consisting of 10 amino acids. Natural GnRH structure is piro-glutamine-histidine-triptofan-serine-tirosine-glisine-leusine-arginine-proline-glisine-(NH₂)-acid.^2-4

Figure 1. Gonadotropin releasing hormone (referred to reference 2)

GnRH has a short half-life, weak receptor binding and easily broken down by peptidase. The connection between 6^th and 7^th amino acid rings is the most fragile spot that may undergo nonactivation by peptidase known as L-Cystin-Aryl-Amidase (L-CARA) enzyme. Degeneration commonly occurs in the chains of ring 6-7 and 9-10. Second and third amino acid (histidine and triptophan) play an important role in activating the receptors within the pituitary. GnRH amino acid formations in all mammals are similar.^3,5

GnRH is synthesized mainly in the nuclei of the hypothalamic nerves. In a small amount, it is also synthesized in other part of the brain. From the hypothalamus, GnRH will enter the circulation under the influence of noradrenalin nerve conducting system, whereas dopamine, serotonin, and melatonin will inhibit the secretion of GnRH. The capillary vessel connects the basal part of the hypothalamus and the anterior pituitary. Through this path, the releasing hormone will reach the cells producing gonadotropin and travel through the shortest pathway, this hormone will induce the synthesis and secretion of LH and FSH.^2,3,5

GnRH is secreted through a pulsatile manner every 90 minutes. During these 90 minutes, pituitary not only secreted LH and FSH but also synthesized another LH and FSH, which commonly finished in one hour. Either repeated GnRH treatment in a pulsatile manner with a shorter interval or continuous GnRH treatment using dose greater than the regular dose, both could induce desensibility of the cells producing LH and FSH in the pituitary (down regulation).^2,3,5

GnRH analogue

In 1971, Schally and colleagues isolated, identified and synthesized GnRH. The synthetic GnRH is known as GnRH analogue (GnRHa). In order to obtain GnRHa, the amino acid structure of natural GnRH is replaced with other amino acids at chain 6 and 10. The synthetic GnRH is more durable to endopepticlase and is 80-100 times more active biologically than that of natural decapeptide.^2,3,5,6

Figure 2. GnRH agonist (referred from reference 2)

According to its mechanism of action, GnRH analogue is divided into 2 form ie. GnRH agonist and GnRH antagonist.^1-3 Lately, there are numerous variations of GnRH analogue that can be used for treatment, as seen on table:^2,6

GnRH Agonists in Clinical Use

a. GnRH agonist

Continuous GnRH agonist treatment (without pulse) causes the GnRH to bind with its receptor at the anterior pituitary; this will ultimately reduce the pituitary sensitivity to GnRH agonist stimulation and therefore reduce LH and FSH levels. This will cause a decrease in estrogen and progesterone production by the ovary (receptor down regulation).³

In the early stage of the treatment, there will be an overstimulation of the receptors that will induce over production of LH and FSH, therefore inducing high levels of estrogen and progesterone in the ovary (flare up). This GnRH agonist to receptor binding is very strong (having slow reversibility) that eventhough we have stopped the treatment, the effect will last for months. Normalization of menstrual cycle needs months also. Since its mechanism of action causing flare up and reduce anterior pituitary sensitivity, therefore this type of GnRH analogue is called pink type GnRH agonist.^2,3,4

Commonly, GnRH agonist is given through subcutaneous, intramuscular, or intranasal routes. Oral route is not effective since it will be degraded by endopeptidase enzyme within the bowel. Intranasal route is also not effective if the resipient is having cold or influenza.

b. GnRH antagonist

GnRH antagonist is obtained by replacing the amino acid structure of natural GnRH at chains 1,2,3,6, 8 and 10. The mechanism of action of GnRH antagonist is by binding to its receptor in the anterior pituitary without causing hyperstimulation to this receptor (flare up). It do not have a strong binding strength with its receptor, having rapid reversibility; so that when it is stopped, the function of anterior pituitary would promptly become normal again, quickly followed by the return of normal cycle.^2-4

Since GnRH antagonist could rapidly release itself from its receptor binding, therefore it must be given as often as possible (every each day or every single week) and the best route of treatment is by subcutaneous route.^2,3

In the past, experts have always been failed using the first and second generation of GnRH antagonist because of its histamine-release effect at the location of injection. However, at the moment the third generation of GnRH has been successfully reconstructed and this new generation do not inherit the aforementioned effect.³

The Role of GnRH Analogue in Gynecological Field

In practice, GnRHa treatment is aimed to prevent early LH surge in order to avoid ovary hyperstimulation syndrome in in vitro fertilisation treatment. In addition, GnRHa is also given in other gynecological disorders which growth is influenced by estrogen, such as uterine fibroid, adenomiosis, or endometriosis.¹

Endometriosis

Endometriosis is endometrial tissues located outside the uterine cavity eg. internal reproductive organs, bladder, bowel, peritoneum, lungs, umbilicus, up to the eyes and brain.^4,6

Endometriosis gives 3 basic symptoms, ie.:

1. Pain; such as pelvic pain, dismenorrhea, or dyspareunia.

2. Tumor in the ovary, an endometrioma that may give direct pressure effect to the surrounding organs.

3. Infertility, caused by internal reproductive organs attachment to the surrounding tissue or internal reproductive organs distorsion or immunological disorder causing defect in oocyte.¹

Up to now, the diagnosis of endometriosis is made through direct laparoscopic visualisation and may be supported by biopsy examination. No tumor marker commonly examined that has enough reliability to confirm the diagnosis or to be use as a standard evaluasion in the follow up.¹

Many trials have proven that GnRHa is an effective medical therapy for endometriosis. GnRHa strongly suppress estrogen production, so that its level mimics that of menopausal woman. A combination of operative measures and GnRHa are most commonly performed and having the lowest recurrence rate.^4,6

GnRHa is commonly use in severe endometriosis. Moderate to severe endometriosis needs reconstruction prosedure aimed to restore the distorsion, attachment, obstruction, drainage/cystectomy besides ablation/removal of visible endometrial pacthes. In these cases, GnRHa usually is given before and after surgery.¹

The advantage of GnRHa are: it makes operative prosedure simpler, reduced the diameter of the cyst, makes detachment easier.⁶ The cure rate of pelvic pain and menstrual pain reach a point of 80-90%, whereas pregnancy rate of 52%.^3,4,6 Nezhat (1997) gave treatment at 3 months before and after surgery for severe endometriosis. Then, he waited for 6-12 months, observing whether pregnancy occur or not.⁶ If pregnancy do not occur, In Vitro Fertilization and embryo transfer are carried out.¹

The side effects of GnRHa mainly caused by the low level of estrogen level in the circulation so that symptoms occuring mimicking estrogen deficient state in post menopausal woman, such as hot flushes, heavy sweating, headache, insomnia, bone ache, palpitation, and vaginal dryness. In treatment more than 6 months, it can caused a decrease in bone mineral density. In these symptoms occur during the time GnRH is given then an estrogen or progesterone tablet need to be given until there is no more symptoms (add back therapy). The tablets do not influence GnRHa action toward endometriosis.^4,6

GnRHa treatment before surgery is highly effective in reducing the size of endometriosis cyst. Based on several researches of 2000 cases, it is found that GnRHa treatment injected 12 weeks before laparoscopic surgery managed to reduce endometriosis nodules. The combined treatment is better than surgery only without adding GnRHa before.⁸

Several trials also proved that GnRHa treatment after laparoscopy gives excellent outcome and low recurrence rate.⁸

Lately, many have also used GnRH antagonist for endometriosis treatment. GnRH antagonist will bind to its receptor in the anterior pituitary without causing stimulation to the receptor, which means without any secretion of FSH nor LH at the onset of the treatment (without flare up); since its binding is not so strong, this rapid reversibility cause normal mestrual cycle to promptly occur after treatment is stopped. Moreover, GnRH antagonist seems to maintain basal estradiol concentration in women with endometriosis treated with GnRH antagonist. Therefore, GnRH antagonist must be given every single day or every week, subcutaneously.^2,1

Patients reports a symptom-free period with GnRH antagonist treatment for 8 weeks with cetrorelix 3 mg once a week without complaint of estradiol deficiency state. Estradiol level in these patients is approximately 50 pg/mL. However, laparoscopic control shows a decrease in endometriotic pacthes, from stage III before treatment to stage II after a 8-week treatment.¹⁰

Adenomyosis

Other form of endometriosis is nodules located in rectovaginal area, histologically different from endometriosis nodules. These nodules are hard and typically containing endometrial cells which are surrounded by hypoplastic involuntary muscle cells. Of these nodules, an adenomyosis knot is formed. In the process of adenomyosis knot formation, a release of marker such as vimentin and cytokeratin occurs, indicating that adenomyosis originated from Mullerian duct.⁴

Definitive therapy for adenomyosis is total hysterectomy. Hormonal treatment using GnRHa is aimed to decrease uterus size and eliminate symptoms such as abnormal uterine bleeding and dysmenorrhea. However these symptoms will recur and the uterus will return to the normal size after a 6-month treatment.⁸ Treatment using medication which inhibit certain enzymes activity is more useful than hormonal treatment.⁴

1. Decreases uterus and myoma volume so that ease microsurgery in women who still want to preserve their uterus and their reproductive function.
2. Reduce anemia cause by bleeding.
3. Ease the separation of fibroid tissue from normal miometrium.
4. Reduces bleeding during operation.
5. Allows vaginal approach in cases which need hysterectomy.
6. Ease operation prosedure using endoscopy.
7. Reduce the duration of operation and hospital-stay.
8. In uterine myoma cases, the dose of GnRH analogue only need to be given 3 times, with an interval of 4 weeks. GnRH analogue is best given in myoma which size mimics 14- to 18-week pregnancy. If the size mimics pregnancy age more than 18 week, then GnRH treatment is no longer relevant.

Dysfunctional Uterine Bleeding (DUB)

DUB is abnormal uterine bledding not caused by organic abnormalities.¹¹ Before a diagnosis of DUB is made, the clinician must exclude other causes such as: pregnancy, tumor, infection, coagulopathy, and pelvis or sistemic pain.¹²

The pathophysiology of DUB depends on the ovulation state. Anovulatoar DUB often found in perimenarch and perimenopausal period.¹² The DUB occur as a result of dysfunction of hypothalamic-pituitary-ovary axis. In perimenarch period, there is an inhibition in the positive feedback mechanism of LH surge, so that ovulation do not happen. Whereas, in perimenopausal period, there is a decrease in number of primordial follicles also a decrease in ovarian sensitivity to FSH and LH causing sub-optimal level to induce LH surge and ovulation. Follicles which do not undergo ovulation will continue to produce estrogen so that estrogen stimulation will keep on occuring to the endometrium, causing the endometrium to continue growing. Eventually, the estrogen levels drop and withdrawal bleeding occurs. Vascular tone, inhibition of vaso­pressin release, and disturbed angiogenesis also con­tribute to heavy bleeding.^11,12 Ovulatory DUB is thought to be secondary to defects in local hemostasis; no disturbance in the HPO axis occurs, nor are there abnormalities in the steroid hor­mone profiles. Eighty five percent DUB includes in anovulatoar DUB.¹²

The basic principle of ceasing bleeding in acute anovulatoar DUB (in a hemodynamically stable state) or chronic one is to convert proliferation to secretion phase of the endometrium.¹¹ GnRH agonist can be used in refractory DUB cases or in women who still want to preserve her reproductive function.¹² Gonadotropin releasing hormone (GnRH) blocks the release of the reproductive hormones LH (luteinizing hormone) and FSH (follicular-stimulating hormone). As a result, the ovaries stop ovulating and no longer produce estrogen. This will cause amenorrhea due to endometrial atrophy.^13-16 At least a 2-4 week therapy is needed before a supression effect and an adequate steroidogenesis inhibition state are reached.^16-18 The medication is relatively more expensive than other medication used in DUB treatment and having more side effects.¹² Commonly reported side effects (which can be severe in some women) include menopause-like symptoms that include hot flashes, night sweat, and changes in the vagina, weight change, and depression. The side effects vary in intensity depending on the GnRH agonist. They may be more intense with leuprolide and persist after the drug has been stopped. The most important concern is possible osteoporosis from estrogen loss. Women ordinarily should not take them for more than six months.^19-20

An alternative treatment for those who failed to respond to hormonal treatment is endometrial ablation prosedure. GnRHa treatment before ablation will decrease endometrial thickness, reduce swelling, and prevent pseudoresidual reactions which usually occur with other hormonal treatment. GnRHa treatment before surgery will ease the prosedure and reduce bleeding in ablation prosedure. Endometrial ablation is the best prosedure in women who do not wish to preserve her fertility however still want to keep their uterus.²¹

Referrences

1. Samsulhadi, Peran GnRHa pada pengobatan Endometriosis. Disampaikan pada simposium peranan GnRH analog dalam bidang endokrinologi reproduksi, Pertemuan Ilmiah Tahunan POGI XIV, Bandung 11-15 Juli 2004.

2. Baziad A. Endometriosis dalam : Endokrinologi Ginekologi edisi 2, Jakarta : Media Aesculapius Fakultas Kedokteran Universitas Indonesia. 2003, 1 – 22.

3. Subijanto S, Baziad A. Pemakain hormon pelepas Gonadotropin (GnRH) dalam kedokteran reproduksi. Disampaikan pada Temu Ilmiah I Fertilitas Endokrinologi Reproduksi, Bandung 4 – 6 Oktober 2002.

4. SperoffL, Glass RH, Kase MD. Endometriosis In Clinical Gynecologic Endocrinology, and Fertility. 6^th edition. Philadelphia : Lippincott Williams and Dilkens ; 1999. 1057-69.

5. Djuwantoro T, Terapi GnRH analog sebelum histerektomi atao miomektomi pada mioma uteri. Disampaikan pada Simposium Peranan GnRH analog dalam bidang endokrinologi reproduksi. Pertemuan Ilmiah Tahunan POGI XIV, Bandung 11 – 15 Juli 2004.

6. Baziad A. Pengobatan medikamentosa mioma uterus dengan analog GnRH. Dalam Endokrinologi Ginekologi Edisi 2. Jakarta : Media Aesculapius Fakultas Kedokteran Universitas Indonesia ; 2003. 151 – 7.

7. Baziad A, Surjana Ej, Rusdianto E. Gn-RH analog (Gn-RHa). Dalam : Baziad A, Affandi B. Editor Panduan Penanganan Endometriosis. 1^st ed. Jakarta : Balai Penerbit FK UI ; 1997. 34 – 41.

8. Endometriosis. Available from :

http://209.164.14.20/journalsisecure/grynecoI/secureiEndometriosis. htm

9. Center for uterine fibroids : Information about fibroids Adenomyosis. Available from http://www.fibroids.net/html/frameset.htm

10. Buffet NC. Olivennes F, Bouchard P. Antagonis GnRH Clinical Obstetrics and Gynecology. 2003 : 4 (2).p. 254-256.

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I. PENDAHULUAN

Pembentukan tulang dimulai dari dalam kandungan dan mencapai puncak pada dekade ketiga, dimana massa tulang pada pria lebih tinggi dari tulang wanita. Wanita akan mengalami kehilangan tulang yang lebih cepat dibanding pria.<!–[if supportFields]> ADDIN ENRfu <![endif]–>1<!–[if supportFields]><![endif]–> Metabolisme tulang diatur oleh aktivitas 2 sel tulang yang berhubungan dengan remodelling tulang yaitu sel-sel osteoblas yang bertugas melakukan formasi tulang dan sel osteoklas yang bertugas dalam resorpsi tulang. Hormon estrogen dalam keadaan normal memicu aktivitas osteoblas, tetapi menghambat aktivitas osteoklas sehingga tercapai keseimbangan pembentukan dan perusakan tulang. Memasuki usia 40 tahun dimana kadar estrogen yang mulai menurun secara normal, remodelling tulang mulai berubah kecepatan resorpsi tulang (osteoklas) lebih tinggi dari formasi tulang (osteoblas) sehingga proses osteopenia – osteoporosis dimulai.<!–[if supportFields]> ADDIN ENRfu <![endif]–>2<!–[if supportFields]><![endif]–>

Osteoporosis adalah penyakit tulang sistemik yang ditandai oleh rendahnya massa tulang dan kerusakan mikroarsitektur tulang yang mengakibatkan tulang menjadi rapuh dan mudah patah. Secara operasional diagnosis osteoporosis ditegakkan apabila terdapat densitas massa tulang berada di bawah -2,5 SD dari angka rata-rata pada orang dewasa muda normal.<!–[if supportFields]> ADDIN ENRfu <![endif]–>3,4

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