Treatment of endometriosis with danazol: report of a 6-year prospective study

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1 FERTILITY AND STERILITY Copyright < 1985 The American Fertility Society Vol. 43 No.3 March 1985 Printed In U.S.A. Treatment of endometriosis with danazol: report of a 6-year prospective study Veasy C Buttram Jr. M.D.*t Robert C. Reiter M.D.:j: Susanne Ward R.N.* Baylor College of Medicine Houston Texas and Naval Regional Medical Center San Diego California Presented are the results of a 6-year prospective study designed to evaluate the effec.tiveness of danazol for the treatment of endometriosis. Ninety-six patients completed 6 months of therapy at a dosage of 8 mg daily and 17 patients completed therapy with 4 mg daily. No difference was reported in the incidence of side effects regardless of dosage. Gross resolution of disease (as determined by second-look laparotomy or laparoscopy) was evaluated in 11 patients and found to be similar regardless of dosage. Ovarian endometriosis> 1 cm was observed to respond significantly less well to danazol than peritoneal or ovarian disease < 1 cm. Pregnancy rates for 157 patients with no other discernible causes of infertility were slightly higher for the 8-mg danazol regimen than for the 4-mg regimen. In patients with mild disease the use of danazol alone resulted in pregnancy rates lower than those achieved with conservative surgery alone. Its use preoperatively for all stages of disease resulted in slightly higher pregnancy rates than when conservative surgery alone was employed. Danazol was less effective when used postoperatively. No differences were observed between three classification schemes in their ability to predict subsequent prognosis for conception. Fertil Steril43: Conservative surgery has been utilized for the treatment of infertility associated with endometriosis for more than 5 years. In 1973 and 1979 we reported on the effectiveness of surgery in enhancing chances of conception relative to the severity of the disease. I 2 Treatment of endometriosis with danazol a 17-ethinyl-testosterone de- Received November ; revised and accepted January *Department of Obstetrics and Gynecology Baylor College of Medicine. treprint requests: Veasy C. Buttram Jr. M.D. Professor and Director Endocrinology-Fertility Division Department of Obstetrics and Gynecology Baylor College of Medicine Texas Medical Center Houston Texas 773. :j:naval Regional Medical Center. Vol. 43 No.3 March 1985 rivative was first reported by Greenblatt et al. in It was subsequently approved for this use by the Food and Drug Administration in In 1978 we initiated a prospective study designed to evaluate the effectiveness of this agent for the treatment of endometriosis. Preliminary results describing the side effects of danazol and its impact on gross resolution (regression) of endometriosis have been reported previously.4 Despite encouraging results with both medical and surgical modalities controversy persists regarding optimal therapy for infertility secondary to endometriosis. The purpose of this report is multifold: (1) to compare an 8-mg regimen of danazol with a 4-mg regimen with regard to side effects reso- Buttram et al. Treatment of endometriosis with danazol 353

2 Table 1. Danazol Study 8mg 4mg Total Patients enrolled Age 28.7 ± 3.6 Parity.1 ±.32 Treatment regimen Danazol only Preoperative Postoperative Discontinued Completed questionnaire Second-look procedure Endometriosis only lution of disease and enhancement of conception rates; (2) to compare pregnancy rates in patients receiving danazol alone or in conjunction with surgery to pregnancy rates in patients receiving conservative surgery only; and (3) to evaluate the Acostal American Fertility Society (AFS)5 and revised American Fertility Society (R-AFS)6 classifications of endometriosis in predicting the success of therapy. MATERIALS AND METHODS Two hundred twenty infertile patients with laparoscopically confirmed endometriosis were enrolled between January 1978 and March 1983 (Table 1). Patients were classified according to severity of disease as determined by the Acosta 1 AFS5 and R-AFS6 classifications of endometriosis. Ninety-six patients were treated with 8 mg of danazol daily (2 mg four times daily) prior to May 1981; 124 patients enrolled in the study thereafter received 4 mg daily (2 mg twice daily). All patients completing therapy were treated for a total of 6 months beginning on day 1 of the first menstrual period following laparoscopy or laparotomy. One hundred ninety patients including 71 receiving 8 mg daily and 119 receiving 4 mg daily completed a detailed questionnaire regarding side effects associated with the medication. Weight gain was monitored closely in these patients. In order to assess gross resolution (regression) of endometriosis following danazol therapy a to- Table 2. Historical Controls Age Parity Endometriosis only Acosta classification Mild Moderate Severe an total number of patients ± ± Pregnant/Na /34 % Pregnant / Buttram et al. Treatment of endometriosis with danazol tal of 128 patients (including 45 patients receiving 8 mg daily and 82 receiving 4 mg daily) were reevaluated by "second-look" laparoscopy or laparotomy. Resolution of both peritoneal and ovarian disease was determined by the same observer (V. C. B.) and recorded as % to 25% 25% to 5% 5% to 75% and 75% to 1% based upon the decrease in number and size of endometrial implants plaques nodules and/or cysts. Although this method is subjective increments of 25% were considered discriminable. Mean percent resolution was calculated for peritoneal and ovarian disease as a simple weighted average using the means of the four resolution ranges (i.e. 12.5%37.5%62.5% and 87.5%). Patients were assigned to one of three treatment regimens including danazol alone danazol for 6 months followed by surgery or danazol for 6 months postoperatively. Selection was nonrandomized and based upon multiple factors including severity and location of disease associated pathology patients' ages and their desires and fears regarding surgery or medication. In addition treatment was in several instances influenced by degree of resolution of endometriosis observed at second-look laparoscopy. That is patients in whom little or no improvement was noted after danazol therapy were more likely to undergo subsequent conservative surgery than were patients with marked improvement. Finally logistical constraints or presence of a large adnexal mass occasionally led to the decision to perform conservative surgery prior to danazol therapy. A total of 86 patients received danazol alone including 24 on the 8-mg regimen and 62 on the 4-mg regimen. Ninety patients received the Table 3. Side Effects Necessitating Discontinuation 8 mg (1 patients) 4 mg (5 patients) 1. Arthralgia 1. Rash 2. Rash 2. Myalgia 3. Rash hemoptysis 3. Weight gain acne voice 4. Myalgia change decreased libido 5. Depression 4. Depression fatigue 6. Depression 5. Weight gain depression 7. Depression fatigue myalalgia decreased libido 8. Depression fatigue myalgia headache 9. Depression flushing myalgia decreased libido acne 1. Nausea breakthrough bleeding decreased breast size Fertility and Sterility

3 Table 4. Side Effects Weight gain Muscle cramps Decreased breast size Flushing Oily skin/hair Depression Acne Hirsutism Deepening of voice Skin rash 8 mg 4 mg (71 patients) (119 patients) % % bers of patients were available chi-square analysis was performed. In addition the data were analyzed to determine where and how frequently the various classification schemes differed. RESULTS The mean age (27.2 ± 3.3) and parity (.3 ±.45) of the "historical controls" were similar to the mean age (28.7 ± 3.6) and parity (.1 ±.32) of the patients in the present study. drug preoperatively including 52 patients who received 8 mg daily and 38 who received 4 mg daily. Conservative surgery following danazol therapy was performed in the sixth month oftherapy. Twenty-nine patients were treated postoperatively 1 at a dosage of 8 mg daily and 19 at a dosage of 4 mg daily. Of the 22 patients initially enrolled 15 discontinued the medication because of side effects. Pregnancies and interval to conception were recorded for the remaining 25 patients 157 of whom had no other associated causes of infertility including 66 patients who received 8 mg daily and 91 patients who received 4 mg daily. Follow-up for a minimum of 15 months after therapy has been achieved for all patients. Pregnancy rates for these patients were recorded according to the severity of disease (Acostal AFS5 and R AFS 6 classifications) as well as the mode of the therapy used. These results were further compared with pregnancy rates for 137 previously reported patients with endometriosis and no other apparent cause of infertility all of whom were treated with conservative surgery alone by the senior author (V. C. B.) between 1973 and These patients comprised the group referred to as "historical controls" (Table 2). Pregnancy rates relative to severity of disease also were analyzed according to the three different classification schemes. When adequate num- Table 5. Weight Gain Pounds 8 mg (71 patients) 4 mg (119 patients) % % > 2 5 SIDE EFFECTS Side effects necessitating discontinuation of medication are demonstrated in Table 3. Fifteen of 22 patients (7%) discontinued the medication because of side effects. Depression and muscle cramps were the most frequently reported causes. Weight gain muscle cramps decreased breast size and vasomotor symptoms were the most frequently reported side effects among patients completing therapy in both dosage groups and each was noted by 5% or more of the total respondents (Table 4). A generalized maculopapular skin rash was observed in 21 (9%) of the 22 patients. Three patients discontinued the drug because of this side effect. Weight gain was observed in 85% of the 19 monitored patients completing therapy (Table 5). Although weight gain was less than 1 pounds in most patients an impressive number of patients experienced weight gain in excess of 1 pounds including 41% of the patients receiving 8 mg daily and 21% of the patients receiving 4 mg daily (P <.5)..~ & ~J!! ~c ::::J III E ~ ::::J III CJ~ I " " ~ 1Il- _."" "- I.. I' mg - 4mg Month of Conception Figure 1 Cumulative pregnancy rates for the BOO-mg and 4-mg danazol regimens. Vol. 43 No.3 March 1985 Buttram et al. Treatment of endometriosis with danazol 355

4 Table 6. Peritoneal Resolution Pretreatment severity No. of patients /-25'* 8 mg (44 patients) < 1 em em 16 2 > 3 em mg (7 patients) < 1 em em 19 4 > 3 em /-5% 5/-75% 75/-1% Mean % resolution RESOLUTION OF DISEASE One hundred twenty-seven patients underwent a second-look laparoscopy or laparotomy after danazol therapy. However in some patients evaluation for resolution of peritoneal and/or ovarian disease was impossible because of adhesions and! or ovarian enlargement which prevented adequate visualization. Resolution of peritoneal disease was evaluated in 44 patients treated with 8 mg daily and 7 treated with 4 mg daily (Table 6). No difference in resolution was observed regardless of the dosage of danazol or whether there was < 1 cm 1 to 3 cm or > 3 cm of disease. The overall mean percent resolution (both regimens) for peritoneal endometriosis was 61%. The response of ovarian disease was evaluated in 26 patients (39 ovaries) who had completed therapy with 8 mg daily and 33 patients (55 ovaries) who received 4 mg daily (Table 7). No difference was observed in ovarian resolution between the two dosage groups. The overall mean percent resolution (both regimens) for ovarian disease was 51%. However ovarian endometriosis < 1 cm did appear to respond better (7% mean percent resolution both groups) than ovarian disease initially judged to be > 1 cm (33% in both groups). A wide variation in response of both ovarian and peritoneal endometriosis was noted in the two treatment groups. For example resolution of peritoneal disease in the 114 patients varied from the % to 25% response of 14 patients to the 75% to 1% response of 44 patients (Table 7). Resolution in the 94 evaluated adnexa ranged from % to 25% resolution in 29 to the 75% to 1% resolution in 26 (Table 7). Correlation of mean percent resolution in subsequent fertility was not possible primarily because the number of patients was so small after distribution among multiple treatment regimens and resolution ranges. Numbers were further reduced by the ~xclusion of patients with pelvic adhesions which might decrease the possibility of conception but were not observed to be altered by danazol therapy. The number of variables also presented difficulties. It was not possible to arrive at an estimate of overall resolution in individual patients because in some instances each ovary and the peritoneum responded differently. PREGNANCY RATES (R AFS CLASSIFICATION)6 Of the 157 patients with no other discernible causes of infertility 53% conceived within 15 months after therapy 61% of those receiving 8 mg daily and 47% of those receiving 4 mg daily. The cumulative pregnancy rate was similar for both the 8-mg and 4-mg regimens (Fig. 1). Sixty-nine percent of patients conceiving did so within 6 months of therapy. Seven percent of the patients aborted. There were two fetal deaths in utero and one ectopic pregnancy. Eighty-seven Table 7. Ovarian Resolution Pretreatment severity No. of ovaries /--25'* 8 mg (26 patients 39 ovaries) < 1 em em 17 6 > 3 em mg (33 patients 55 ovaries) < 1 em em 16 9 > 3 em /-5'* 5/--75% 75/-1% Mean % resolution Buttram et at. Treatment of endometriosis with danazol Fertility and Sterility

5 Table 8. Pregnancy Rates-Danazol Alone Severity of disease 8 mg (14 patients) 4 mg (44 patients) Both regimens (58 patients) Acosta AFS R AFS Acosta AFS R AFS Acosta AFS R AFS Minimal 2/3 Mild 6/12 6/11 5/1 9/25 Moderate /1 8/16 Severe 3/3 Extensive 1/27 1/17 6/13 8/23 3/5 3/3 15/37 (41%) 9/18 (5%) 3/3 16/38 (42%) 11/2 (55%) o 8/16 (5%) 13/33 (39%) 3/6 3/3 percent of the pregnancies resulted in viable fullterm infants. DANAZOL ALONE Fifty percent of the 16 patients with minimal disease and 39% of the 33 patients with mild disease conceived following the 8-mg and 4-mg regimens (Table 8). No significant difference was observed in conception rates regardless of the dosage of danazol. Only six patients with moderate and three with severe disease were treated with danazol alone (both regimens): 67% conceived (Table 8). Of interest is that all three patients with severe disease treated with danazol alone (4 mg) had complete posterior cul-de-sac obliteration with no ovarian endometriosis or adnexal adhesions. POSTOPERATIVE DANAZOL Thirty percent of 24 patients treated postoperatively with the 8-mg and 4-mg regimens conceived (Table 1). Again no significant difference in conception rates was observed regardless of the danazol regimen utilized. DANAZOL COMBINED WITH SURGERY VERSUS SURGERY ONLY (ACOSTA CLASSIFICATION)' Pregnancy rates for patients with mild moderate and severe disease who were treated with conservative surgery alone were 73% 56% and 4% respectively as compared with 85% 69% and 53% for patients with disease of similar severity treated with preoperative danazol (Tables 2 and 9). Only 32% of patients with severe disease treated with postoperative danazol (both regimens) ultimately conceived (Table 1). PREOPERATIVE DANAZOL Eighty-three percent of 18 patients with mild 67% of 27 patients with moderate and 5% of 3 patients with severe disease treated preoperatively with the 8-mg and 4-mg regimens conceived (Table 9). The combined pregnancy rate for patients with mild disease treated preoperatively (both regimens) was significantly higher (83%) than that observed among patients with mild endometriosis treated with danazol alone (39%) (P <.1). Pregnancy rates were similar for both danazol treatment regimens. EVALUATION OF THE CLASSIFICATION SCHEMES Pregnancy rates for 137 surgically treated "historical controls" classified according to the Acosta classification 1 were statistically different for the three classes of disease (P <.1). For the 157 current study cases six different regimens of therapy were used. The largest number of patients in any of these treatment regimens was 44. When groups of patients in the current study receiving 8 mg and 4 mg of danazol preoperatively were combined conception rates were observed to vary inversely with severity of disease Table 9. Pregnancy Rates-Preoperative Danazol Severity of disease 8 mg (43 patients) 4 mg (32 patients) Both regimens (75 patients) Acosta AFS R AFS Acosta AFS R AFS Acosta AFS R AFS Minimal o Mild 9/11 7/ /2 2/2 4/ (85%) 9/11 (82%) 15/18 (83%) Moderate 12/16 14/ /1 1/15 7/13 18/26 (69%) 24/33 (73%) 18/27 (67%) Severe 9/16 8/15 8/15 1/2 6/15 7/15 19/36 (53%) 14/27 (52%) 15/3 (5%) Extensive P =.96 a P =.11a P =.62a achi-square analysis of correlation between severity of endometriosis and prognosis for conception. Vol. 43 No.3 March 1985 Buttram et al. Treatment of endometriosis with danazol 357

6 Table 1. Pregnancy Rates-Postoperative Danazol Severity of disease 8 mg (9 patients) 4 mg (15 patients) Both regimens (24 patients) Acosta AFS R AFS Acosta AFS R-AFS Acosta AFS R AFS Minimal Mild 111 Moderate 11 /2 113 Severe 3/ /6 4/14 Extensive Oil /22 (32%) 7117 (41%) 6/2 (3%) /2 /2 regardless of whether the Acosta 1 AFS 5 or R AFS6 classification was utilized (Table 9). When this relationship was examined by chi-square analysis the R-AFS classification6 was observed to correlate most successfully severity of endometriosis with prognosis for conception although the statistical difference was minimal (Table 9). Among patients treated with danazol alone a trend toward a higher pregnancy rate was noted in patients with minimal disease (5%) than in those with mild disease (39%) when classified according to the R-AFS6 scheme (Table 8). Several patients classified as having mild and even moderate endometriosis according to the Acosta 1 or AFS 5 schemes had mild and even minimal disease according to the R-AFS classification.6 Table 11 reflects the differences in staging depending on whether the Acosta 1 the AFS 5 or the R-AFS6 classification was used. The Acosta l and AFS 5 classifications tended to result in staging more severe than suggested by the R-AFS classification6 although there were instances in which the disease was classified as less severe by the AFS classification. 5 The latter usually was attributable to the presence of cul-de-sac obliteration which is classified as severe with the R-AFS classification6 but mild or moderate by the AFS scheme. 5 DISCUSSION The problems inherent in conducting a study of this magnitude are myriad. In all 357 patients including 137 surgically treated "historical controls" have been considered. Two hundred ninetyfour patients had no apparent cause of infertility other than endometriosis. In addition to the errors incurred in comparing "historical controls" with the study groups in a nonrandomized manner choice of therapy frequently was influenced by variables such as resolution of disease and patient's age or fears regarding surgery or medication. Selection of the dosage of danazol was randomized only insofar as all patients treated prior to May 1981 received 8 mg daily. All patients enrolled after May 1981 received 4 mg daily as the result of an effort to determine whether cost and side effects could be reduced without compromising effectiveness. Despite such problems these data are subject to meaningful comparisons and provide a basis for some tentative conclusions regarding the treatment of endometriosis with danazol. SIDE EFFECTS Early collaborative studies suggested that the incidence of side effects associated with danazol was < 1%.7 Side effects were far more prevalent among our study population although they precluded completion of therapy in only 7%. Initially it was hoped that many of the untoward side effects of the drug were dose-related and that use of a lower dosage would improve patient acceptance. However there was little difference in the incidence of side effects reported by respondents in either dosage group. Interestingly the percentage of selected side effects was slightly higher among patients in the lower dosage group which may have reflected more thorough pretreatment counseling in the latter group. This may also have been responsible for fewer patients gaining more than 1 pounds on the lower dosage regimen. The generalized maculopapular skin rash which developed in 21 patients resolved in the 18 Table 11. Staging of Severity According to the Three Classification Schemes R-AFS Minimal-16 Mild-52 Moderate-36 Severe-53 Acosta Mild-14 Moderate-2 Mild-37 Moderate-15 Moderate-28 Severe-8 Severe-53 AFS Mild~33 Moderate-18 Severe-I Moderate-33 Severe-3 Moderate-8 Severe-39 Extensive Buttram et al. Treatment of endometriosis with danazol Fertility and Sterility

7 patients who continued with the therapy by ingesting only the contents of the capsule. This suggests an allergy to the dye in the capsule. RESOLUTION OF DISEASE Resolution of peritoneal and ovarian endometriosis was similar regardless of the dosage regimen (8 mg versus 4 mg) although a wide variability of individual response to danazol was observed. Peritoneal and superficial ovarian disease (i.e. < 1 cm) regressed similarly with a mean percent resolution of 61 % and 7% respectively. Ovarian disease> 1 cm (typically invasive endometrioma) responded less well with a mean percent resolution of 33%. These data suggest that surgical removal of invasive ovarian endometriosis may be more appropriate than medical suppressive therapy. The classification schemes (Acosta1 AFS5 and R-AFS6) were not helpful in documenting resolution of disease following danazol therapy. They are based upon the total area of endometriosis involving the peritoneum and/or ovaries; frequently the total amount of peritoneal disease was similar following danazol therapy even though the implants may have appeared less active. In addition ovarian endometriomas> 1 cm in size did not typically decrease in size although they may have been less bioactive. Filmy adhesions occasionally regressed but dense adhesions did not. Unfortunately insufficient data were accumulated in this study to determine whether gross resolution of endometriosis correlated with prognosis for conception. PREGNANCY RATES In terms of pregnancy rates use of danazol alone (8 mg or 4 mg) clearly was not as effective as the preoperative danazollsurgery regimen (8 mg or 4 mg). Only 5% of patients with minimal disease (R-AFS6) and 39% of patients with mild disease (R-AFS6) conceived after danazol alone (both regimens)-a combined pregnancy rate of 41%. However the fact that 41% of patients with minimal or mild disease did conceive with danazol therapy alone suggests that this form of therapy may be considered particularly for patients younger than 3 or in instances in which circumstances preclude adequate laser treatment or cautery at the time of initial laparoscopy. The 8-mg regimen may be slightly more effective than the 4-mg regimen. Vol. 43 No.3 March 1985 Preoperative danazol appears to improve pregnancy rates regardless of the severity of disease. The 8-mg regimen may be more effective than the 4-mg regimen although even in this large study insufficient data were accumulated to demonstrate this statistically. When pregnancy rates of patients treated with preoperative danazol (both 8 mg and 4 mg) for disease classified by the Acosta 1 scheme were compared with those for the "historical controls" treated with surgery alone there was a 12% 11% and 1% improvement for mild moderate and severe disease respectively. (These percentages were 8%19% and 16% for mild moderate and severe disease respectively if only the preoperative regimen of 8 mg of danazol is considered.) Although it is possible that this improvement reflects better surgical technique suture material instrumentation and so forth it may represent an enhancing effect of preoperative danazol upon conception rates. We previously reported the observation that preoperative danazol therapy results in a reduction of pelvic vascularity and inflammation. 4 We suggested that this improved pelvic environment might reduce the risk of postoperative adhesion formation and thus improve the prognosis. If the improvement in conception rates is due principally to this mechanism a shorter preoperative treatment period (i.e. 1 to 2 months) may be as effective as the 6-month period used in the study. It may be appropriate for patients with endometriosis that can be eradicated at the time of surgery but would seem inappropriate in patients with cul-de-sac obliteration for example because the disease generally cannot be surgically removed without the risk of damage to the colon. In the present study the use of danazol preoperatively resulted in a higher pregnancy rate than its use postoperatively. In addition the 32% pregnancy rate in 22 patients with severe disease (Acosta classification 1) treated postoperatively with danazol (8 mg or 4 mg) was lower than the 4% rate when surgery alone was used ("historical controls"). This low pregnancy rate may reflect a bias in patient selection or it may serve to amplify the beneficial effect of preoperative danazol. Whether this form of therapy should be prescribed for 6 months postoperatively is ques" tionable. CLASSIFICATION SCHEMES The differences in the Acosta1 AFS5 and R AFS6 classifications are outlined in the accom- Buttram et al. Treatment of endometriosis with danazol 359

8 r panying article "Evolution of the Revised American Fertility Society Classification of Endometriosis."s The purpose of a scheme for classification is that it provides a means of separating patients into various groups defined by the severity of their disease and suggests their prognosis for conception after a particular treatment. The Acosta classification! fulfilled this obligation in 137 "historical control" patients treated with surgery alone. Similarly the Acosta! AFS5 and R-AFS6 classifications appeared to correlate severity of disease and prognosis for conception among patients in the current study treated with preoperative danazol although the degree of correlation was less statistically significant than that observed among the "historical controls." None of the classification schemes was found to be demonstrably better than the others. Nevertheless all the classifications have been needed and useful and have improved as they evolved. It is our opinion that utilization of the R-AFS scheme6 will provide greater uniformity in the reporting of results and more precise documentation of the severity of endometriosis. Acknowledgments. We wish to express our appreciation to Jon M. R. Rawson M.D. Ph.D. and Carolyn Schum M.A. for their editorial assistance. REFERENCES 1. Acosta AA Buttram VC Franklin RR Besch PK: A proposed classification of pelvic endometriosis. Obstet Gynecol 42: Buttram VC Jr: Conservative surgery for endometriosis in the infertile female: a study of 26 patients with implications for both medical and surgical therapy. Fertil Steril31: Greenblatt RB Dmowski WP Mahesh VB Scholer HFL: Clinical studies with an antigonadotropin-danazol. Fertil Steril 22: Buttram VC Jr Belue JB Reiter R: Interim report of a study of danazol for the treatment of endometriosis. Fertil Stei'il 37: American Fertility Society: Classification of endometriosis. Fertil Steril 32: American Fertility Society: Revised American Fertility Society Classification of Endometriosis: Fertil Steril 43: Young MD Blackmore WP: The use of danazol in the management of endometriosis. J Int Med Res (Suppl 3) 5: Buttram VC Jr: Evolution of the Revised American Fertility Society Classification of Endometriosis. Fertil Steril 43: Buttram et ai. Treatment of endometriosis with danazol Fertility and Sterility