Danazol: Endocrine pharmacology and therapeutic applications

01: Endocrine pharmacology and therqmstic i3ppliCatiOnS

ROBERT

L. BARBIERI,

KENNETH

J. RYAN,

Boston,

M.D. M.D.

Massachusetts

.” (AM.

J. 08s~~~.

GYNECOL.

THE PAST DECADE three major new agents entered the armamentarium of the gynecologic noIogi& bromocriptine, danazol, and luteinizrmone-releasing hormone (LHRH). The endercrine pharmacology of bromocriptine and LHRH is

DURING

Fran the Department Hospital Women.

I$ Obstetrics

for

and Gpecologv,

Supported in part by United S&.&s Public He& Grant HD 079-23-04 and Rocltefelkr Founai&n RF 65040. Receiued for publication Revised

October

Accef~ted November

Service Grant

July 15, 1980.

7,198O.

f991.)

well characterized at both the molecular level and the level of the whole organism. In contrast the endocrine pharmacokgy of danazol is not well understood. It has been repeatedly stated that danazol has “strong antigonadotropic properties and mild androgenic effects, with no other hormonal properties.“’ However, substantial evidence exists to suggest that the pharmacology of danazol is significantly more complex. In this review we will emphasize the molecular phumacology of danazol, especially as it relates to understanding the efficacy of danazol in the treatment of endometriosis. iem

28,198O.

Reprint rspests: Km&h Obstetis and Gynecology, Massachusetts 02115. 2-9378/81/200453+11$01.10/0

Boston

141:453,

J. Ryan, M.D., De$mtment 75 Francis Street, Boston,

0

1981

The

C. V. Mosby

Co.

of

Danazol is an isoxazule derivative of the synthetic steroid 17~ethinyhestosterone (ethisterone) (Fig. 1). 453

454

Barbieri and Ryan

Table

I. Summary

of gonadotropin

concentrations

during

danazol

therapy Pre-dxznazol

Investigator PTeP?l#U@USd

No. of patients

Danuzol dose Owlday)

Days of administration

4 20 47 11 6 5 21 7 5

50-200 200-800 400-800 ii: 600 200 800 800

20-40 60-180 14-42 180 6 6 100 28 180

5 4

600 400

5 3 5

200 600

FSH (milJlmi)

WOme71:

Colle and Greenblattts Floyd’@ Goebel and RjoskzO Lauersen and Wilsonzl Lieberman et al.22 Stillman et al.*s van Dijk et al.24 Went2 et al.z” Wood et al.z6 Postmeai$ausal women: Franchimont and Cramilion’5 Fraser and ThorburnrG

15 7

8 9.5

10 13

Not reported 8 6.3 1.97 rig/ml 41 nglml 5.2 6.12 25 8 220 ngimi 200 rig/ml 8 10 50 61

15.6 39

Men:

Franchimont and CramilorG5 Sherins et al.27

Danazoi is chemically related to azastene and cyanoketone, two potent inhibitors of 3/&hydroxysteroid dehydrogenase.2 Danazol is well absorbed by the oral route and is metabolized to approximately 60 different products.3 Certain authors have stated that of the five metabolites of danazol which have been structurally identified, none is hormonally active.” 4 However, 17a-ethinyltestosterone (ethisterone) is a major metabolite of danazops 4 and it is -known to be a progestational and a mild androgenic agent.j Ethisterone has no estrogenic effects, minimally suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and does not inhibit ovulation5 The circulating half-life of danazol in women is approximately 15 hours.6 In addition to the long circulating half-life, the tissue half-life of some isoxazole derivatives is relatively long (days).‘Therefore, twice daily administration of the drug will provide relatively stable circulating and tissue concentrations. In the rat and monkey, danazol is highly concentrated in the liver, adrenals, and kidneys3 In the monkey, danazol is excreted in the feces and urine.3

Endoche pharmecdogy of danarol The evaluation of the endocrine pharmacology of a sex steroid can be conceptually divided into at least four major areas of investigation: (1) the effects of the sex steroid on hypothaksmic-pituitq function, (2) the effects of the sex steroid on various “end” organs and the interaction of the drug with intracellular steroid receptors in these tissues, (3) the direct effects of the drug on gonadal function, and (4) the alteration of endogenous steroid metabolism by the drug. Interestingly, danazol has

15 100 100

7.4 7 8.8

4.6 -

major effects on each of these systems and its thetapeutic efficacy can be traced to its multipotent acti&. In the past the endocrine pharmacology of a sex steroid wasp defined by various bioassays emphasizing &istologic and weight changes as endpoints. One of the dramatic advances in reproductive endocrinology over the past 10 years has been the definition of many reproductive mechanisms at the molecular level. Con&quently, direct measurement of hormone levels and analysis of drug-protein binding have become the bases for defining the endocrine pharmacology of a sex steroid. In the following discussion we will review the effects of danazol on each of the aforementioned.systemswith an emphasis on studies which use direct measurement of hormone levels and analysis of drugprotein binding.

Danmeludh

trryg-

The effects of danazol on the hypothalamic-pituitrsry axis depend in large part on the model chosen examination. Differences in sex, age, gonadal sta; and species of the subjects can lead to major diff&ences in experimental results. The original reports that danazol was a selective “antigonadotropin” were based on experiments in rodents which did not in&&e direct meusurelnent of serum go+nadotropin concentration. For example, Dmowski and’&sociate? reported that the subcutaneous administration of 4 to 20 mg danazollkgtday for 14 days to hemicastrated immature male and female rats prevented the gonadal hypertrophy that would otherwise normally have occurred in these animals. Sim Potts and associates9 reported that the oral adminiasra-

Volume Number

Danazol 455

141 4

&wing danuwl therapy FSH (mIU/nd) 13 18

7 11.3 Not reported 9 7.3 2.11 rig/ml 38 rig/ml 7.12 5.4 32 12 180 @ml 200 rig/ml 10 4 10 37

3.5 5

4.2

24 53

Change in LH or FSH No No No No No No No No No

significant significant significant significant significant significant significant significant significant

change change change change change change change change change

Significant decrease LH, FSH Significant decrease LH, FSH

2.4 -

-

Significant decrease LH, FSH No significant change No significant change

tion of danazol at 50 to 400 mgikg to hemicastrated matatrefemale rats prevented the ovarian hypertrophy ti would normally have occurred. These authors that their results demonstrated the “anepic” properties of danazol. However, these im&$gators failed to measure serum gonadotropin rations directly. Their results could be exby other hypothetical mechanisms, one of is a direct effect of danazol on the remaining gowd. Siakcethese original reports, attempts have been to directly measureLH and FSH in animals redanazol. In castrated rats1*13and monkeys,14 1 hasbeen demonstrated to lower LH and FSH cmtrations. In postmenopausalwomen, small but decreasesin LH and FSH occur during dainistration’j* I6 (Table I). These studiesindianimalswithout functional gonadsdanazol cstn iower circulating LH and FSH. In animalswith intact gonads the effects of danazol 1 LH and FSH are significantly more complex. on For example, in the male rat with intact gonads,a subcrr&eous dose of 5 mgtkg results in a decrease in xr testtosterone and an increasein serumLB. l7This otiation suggeststhat at a doseof 5 mg/kg, danazol actsst a site other than the hypothalamic-pituitary system to reduce serum testosterone, resulting in a compensstory increasein serum LH. A review of all available literature concerning LH and FSH levels in ~naenopausal women and men treated with danazol ststhat dmzzol does not alter basal gonadotropin conc#&&n (Table I).‘“” One possiblecriticism of this mterpretation of thesestudiesis that it is often difficult

Fig. I. Structureof danazol. to differentiate between “normal” LH and “low” LH with available radioimmunoassaytechniques.Although this is a problem, iit is possibleto show that the combined estrogen-progestogenoral contraceptive significantly and dramatically reduces basal gonadotropin concentrations to low or undetectable levelsZRThis would suggest that the combined oral contraceptive and danazol may produce anovulation by different mechanisms.From the data presented in Table I it would be wrong to conclude that danazol hasno effect on the hypothalamic-pituitary axis. A significant percentage of premenopausal women receiving danazol develop symptomsand signsof hypoestrogenism,’ but their LH and FSH concentrations are not in the postmenopausal range. This would suggest that danazol blocks the compensatory increasein LW and FSH that should normally occur in a hypoestrogenic state. Although danazol does not alter basalgonadotropin concentrations in premenopausalwomen, it can eliminate the “midcycle” LH and FSH surge in doses as small as 200 mg per day. I*, 2s*3oLittle experimental evidence is available concerning the mechanismsof danazol inhibition of the midcycle surge. It is possible that danazol has a selective effect on hypothalamicpituitary control of cyclic gonadotropin secretion or that danazol directly inhibits follicular maturation and blocks the preovulatory estradiol surge that is responsible for the midcycle gonadotropin surge. The results of LHRH stimulation tests in subjects receiving danazol remain controversial. Some authors claim that LHRH aldministration to subjectsreceiving danazol resultsin normal LH and FSH responses.“,13,l4 These investigators have concluded that danazol has important biologic .actionsat the hypothalamic level. Others have reported that danazol blunts the LH and FSH responsesto LHRH.‘“, I5 Danazol appears to have little or no effect on the nongonadotropic anterior pituitary hormones. Franchimont and Cramilion’j reported that danazol did not change basallevelsof thyrotropin, thyroid-stimulating hormone (TSH). or prolactin or modify their response

466

Barbleri and Ryan

Table

II. Danazol

binding

to intracellular

and circulating

steroid-binding

proteins Afjnity

Receptor

Tissue

Androgen

Rat Rat Rat Rat Rat Rat

Progesterone Glucocorticoid Estrogen Sex hormone-binding Corticosteroid-binding

globulin globulin

prostates* uterus= brait?’ utert# utert@ brains4

Binding

Yes (8s) Yes Yes Yes (8s) Yes Yes

Rat IiveP

Yes

Human endometrium% Rat uterus32,33 Rat brainM

No No No

Human

Yes

serum37.38,77

Human serum3’+”

to thyrotropin-releasing hormone. Danazol does not modify basal cortisol levels’ja 23, 31 or block pituitary response to metyrapone.31

DerymJ and steroid receptors Danazol has been described as a “selective androgen.“’ However, recent reports suggest that danazol binds to multiple classes of steroid receptors (Table II). Danazol binds to rat prostate,32 uterus,33 and brain34 androgen receptors, and the danazol-androgen receptor complex can translocate into the nucleus.% These findings are consistent with the observed androgenic effects of danazol in castrated male rats (maintenance of ventral prostate, seminal vesicle, and levator ani weight)*, g and in women (facial hair growth, acne, and voice changes).’ Danazol binds to rat uterus3*s 33* 35 and brain progesterone” receptors. The danazol-progesterone receptor complex translocates into the nucleus at a very slow rate35 and it is unable to stimulate ribonucleic acid (RNA) synthesis .35 The effect of danazol in progesterone bioassays remains controversial. Potts and associatess have reported that danazol has no progestational activity in the Clauberg assay (test substance given to estrogen-primed immature rabbits and endometrial histology examined for progestational effects). In contrast, Dmowski and associates8 observed atypical progestational effects in the endometrium of rabbits receiving danazol. In support of the findings of Dmowski’s group, Wentz and associates25 reported secretory changes in the endometrium of women receiving danazol. In discordance with all of the above findings, other investigators have reported that danazol is antiprogestational.36 This conclusion was based on the observation that danazol in doses of 25 and 50 mg/kg/day prevented the endometrial response to progesterone in the Clauberg assay. Although the bioassay data are confusing, danazol clearly binds to progesterone receptors from various tissues. It is likely that danazol itself has mixed

Yes

constant, Ki CM)

9 x 10” 1 x 10-a 0.5 x 10-a 2.7 x lo-*

10.0 x 10-e 2.0 x 10-s 5 x 10-B

-

-1 -2

x 10-S x 10-r

Danarol receptor tramlocation to nU&l‘%.S

Yes Yes Unknown Low

No Unknown Unknown

-

agonist-antagonist effects with respect to the progesterone receptor system. The fact that one of the metabolites of danazol, ethisterone, is progestationa15 ma); account for some of the discrepancies noted in the above studies. For example, experimental systems in which large amounts of the metabolite ethisterone are present may result in data suggestive of a~progestational effect of danazol. Experimental systems where the ethisterone metabolite is not present may result in data that suggest that danazol is antiprogestational. Danazol does not bind to estrogen receptors in human endometrium,26 rat utertq3** s or rat brain3* These findings are consistent with the observation that danazol has no estrogenic effects in various bioassay systems.“* y Of great interest is the observation that danazol can displace testosterone and estradiol from human sex hormone-binding globulin (SHBG) and progesterone and cortisol from human corticosteroid-binding globulin (CBG) in vitro.37 Schwarz and associates3s reported that in men, danazol dramatically increases the free testosterone index at the same time that it lowers total testosterone concentration. These authors suggest that danazol is androgenic because although it decreases total testosterone concentration it increases the biologically active fraction of testosterone (free fraction) available to target tissues. The observation that danazol can bind to circulating steroid-binding proteins significantly complicates the interpretation of serum total steroid hormone concentrations measured in patients receiving this drug. Further research will be needed to define the importance of these observations.

DanaW and steroida In in vitro experiments, danazol has been shown to inhibit multiple enzymes of steroidogenesis, including cholesterol cleavage enzyme,34 S/3-hydroxysteroid dehydrogenase, “, 39 17&hydroxysteroid dehydrogenase,17* * 17cu-hydroxylase, I’* 39 17,20-lyase, 17, 39 1 lp-hydroxy-

Volume 141 Number4

TaUe

III.

Danazol

Danazol

inhibition

of enzymes of steroidogenesis

Cholesterol cleavage SP-Hydroxysteroid dehydrogenase

17&Hydroxysteroid 17a-Hydroxylase 17,20-Lyase

1 l/3-Hydroxylase 2 1-Hydroxylase Aromatase

457

dehydroxylase

Rat adrenalRat testis”*SB Rat ova@ Rat adrenal” Human corpus luteurns Rat testis’7*sg Human corpus luteurn” Rat testis”“’ Rat ovary’* Human corpus luteurn” Rat testis17*s9 Rat ovaryI Human corpus luteum5’ Human adrenal& Rat adrenal” Human adrenal’O Rat adrenal” Placenta% Human corpus luteum3’

bse,17’ 40 and Pl-hydroxylase 17,40 (Table III). Biochemieal analysis suggests that danazol competitively inhibits the previously mentioned enzymes by binding to the alive site for the steroid substrate.39, 4o The enzymatic inhibition constants for danazol inhibition of the aforementioned enzyme systems are similar to the serum amcentration of danawl obtained in women taking 400 to 800 mg danazol daily.6* 23, 41, 42 In cell culture experiments, danazol has been demonstrated to inhibit gonadotropin-induced steroidogenesis in the rat,“* * porcine,” and hamster% granulosa and luteal cell and in the rat Leidig celLW In the rat luteal cell, danazol &es not interfere with binding of human chorionic pnadotropin (hCG) to the gonadotropin receptor or with hCG stimulation of cyclic adenosine monophospirate. It is likely that danazol modifies ovarian stetidogenesis either by inhibiting the aforementioned enzymes or by binding to ovarian androgen receptors and blocking the synthesis of proteins essential to ster&dogenesis. Although most of the data demonstrating that danazol inhibits steroidogenesis have been obtained in vtro, two important studies suggest that the in vitro data are applicable in vivo. In a beautifully designed and executed study, Asch and associates45 showed that danazol shortens the luteal phase and decreases proe@sterone production in intact monkeys via a direct effect on the ovary. In their critical experiment, danazol was administered to monkeys starting with the first postovulatory day. Compared to control animals, danazoltreated monkeys could not respond to exogenously administered hCG with a normal rise in progesterone prod*Iction. StlTdies by Stillman and associatesz3 suggest that dana-

Unknown Competitive

20 5.8

Competitive

4.4

Competitive

2.4

Competitive

1.9

Competitive

0.8

Competitive

3

No inhibition No inhibition

-

zol may partially inhibit human adrenal 3@-hydroxysteroid dehydrogenase and 1 I@-hydroxylase in vivo. Stillman and associatesZ3 measured the effect of danazol on the serum concentration of various steroids before and after adrenocorticotropic hormone (AC?IXi) stimulation. Five normally menstruating women were studied on the sixth day of two consecutive menstrual cycles; once as a pretreatment control and again after the administration of danazol, 600 mg orally/day, for 6 days. Danazol administration resulted in no significant change in baseline cortisol concentration, but resulted in a significant in’crease in progesterone, dehydroepiandrosterone, and androstenedione concentrations. The administration of ACTH during the danazol treatment period resulted in greater increments in pregnenolone and 1 1-deoxycortisol and smaller increments in progesterone and cortisol than those seen in the control period. These fin&ngs suggest that danazol produces a partial inhibition of 3@-hydroxysteroid dehydrogenase and 1 I&hydroxylase in vivo. The studies by Asch and associates45 and Stillman and associatesa prlovide the first experimental evidence that danazol can inhibit steroidogenesis in the primate ovary and adrenal in vivo.

At the present time, no published data are available concerning the effects of danazol on the met&olic clearance rate (MCR) of endogenous steroids. However, the observation that danazol can displace endogenous steroids from CBG and SHBG suggese~ that it might affect the MCR of various steroids.37* a$ Preliminary experiments in rodents suggest that danazol can

458

Barbieri

October 15, 1981 Am. J. Obstet. Gynecol.

and Ryan

Table IV. Results of four large studies testing the efficacy of danazol No. of

Investigator

patients

FriedlandeP Greenblatt and Tzingounix5’ Dmowski and Cohensz~53 Lauersen et als4 Barbieri et als5

39 t: 32

100

Dana.zol dose

@&W

Mean duration of therapy (SW.)

800

800 800 800 800

increase the metabolic clearance rate of progesterone.34 In summary: (1) danazol prevents the midcycle surge of LH and FSH; (2) danazol does not significantly suppress basal LH or FSH in gonadally intact human beings; (3) in castrated animals danazol can prevent the compensatory increase in LH and FSH; (4) danazol binds to androgen, progesterone, and glucocorticoid receptors; (5) the danazol-androgen receptor complex can translocate into the nucleus and initiate androgenspecific RNA synthesis; (6) the danazol-progesterone receptor complex translocates poorly and can initiate minimal, if any, RNA synthesis; (7) danazol does not bind to intracellular estrogen receptors; (8) danazol binds to SHBG and CBG; (9) danazol inhibits cholesterol cleavage, enzyme, 3@-hydroxysteroid dehydrogenase, l’l@hydroxysteroid dehydrogenase, 17,20-lyase, I7a-hydroxylase, 1 lb-hydroxylase, and 2 l-hydroxylase; (10) danazol does not inhibit aromatase; (11) danazol increases the MCR of progesterone; and (12) metabolites of danazol are hormonally active. For example, one of the metabolites of danazol, ethisterone, is progestational and mildly androgenic. The endocrine pharmacology of danazol, as outlined above, has direct implications for understanding the efficacy of danazol in the treatment of endometriosis. Although little experimental evidence is available concerning the hormonal requirements of the endometrial implants of endometriosis, clinical observations suggest that endometriosis is rare prior to menarche and uncommon after menopause. These clinical observations imply that ovarian hormones are the major regulators of growth of the endometrial implants of endometriosis. It is known that normal endometrium and the implants of endometriosis contain estrogen, androgen, and progesterone receptors? It is likely that the endometriotic implants retain patterns of hormonal responsiveness similar to those of normal endometrial cells. The following are true in normal endometrium: (1) Estrogen in physiologic doses stimulates endometrial hyperplasia in a dose-dependent fashion if unopposed by progesterone; 47 (2) androgens produce atrophy of the endometrium; and (3) progestational agents produce a decidual reaction when adequate es-

6 6 6 6 4

Symptowwtic im~vement (%) 72 86 100 88 89

in the treatment Laparoscvpic irnpncyt 0 95

of endometriosis Uncorrected fertility rate (%)

Recurrence rate--symptoms or signs %

Unavailable

85

41 50 46

Unavailable

Unavailable

mo.) Unavailable

94

46

33 (49 mo.)

Unavailable

33 (78 39 (37

mo.)

trogen is present and atrophy when a hypoestrogenic environment exists. 48 To test the hypothesis that implants of endometriosis retain hormonal responses similar to those of normal endometrium, DiZerega and associates4g studied the effects of estrogen, progesterone, or no hormone replacement on the growth of peritoneal endometriotic implants in castrated monkeys. Estrogen alone was able to support the growth of the endometriotic tissue in the peritoneal cavity. In a hypoestrogenic, hypoprogestational environment the endometrial tissue atrophied. Surprisingly, progesterone alone was also able to support the growth of the endometriotic tissue. Given the hormonal responses of endometrial tissue and the pharmacologic properties of danazol, it is not surprising that this drug is effective in the treatment of endometriosis. The multiple pharmacologic properties of danazol produce an endocrine environment intensely hostile to the growth of endometriosis. By direct androgenic and antiprogestationul effects on the endometriotic implants danazol can produce atrophy. By inhibiting follicular function through hypothalamicpituitary and ovarian mechanisms dunarol produces a hypoestrogenic-hy~oprogestatiowl state. This hypoestrogenie-hypoprogestational state also produces atrophy of the endometriotic implants. Furthermore, by producing amenorrhea, danazol prevents “reseeding” of the peritoneum with endometrial tissue. The complex pharmacology of danazol makes it difficult to accept the statement that danazol is a “selective antigonadotropin with minimal androgenic effects and no other hormonal properties.” The term antigonadotropin has always been ambiguous and should probably be avoided. It may be more suitable to refer to danazol as a synthetic steroid with androgenic and mixed progestational-antiprogestational effects which produces anovulation and low levels of circulating estrogen and progesterone by actions at the hypothalamic, pituitary, and ovarian levels.

DenazQlend~thB~tof

%s Danazol has been shown to be effective in the treatment of endometriosis, benign breast disease, angio-

Volume Number

Dana201 459

141 4

edema, and precocious puberty, and as a contraceptive agent. It is in the treatment of endometriosis that danazol has achieved the widest clinical use. In Table IV, the results of five large studies testing the efficacy of danazol in the treatment of endometriosis are summarized.s0-55 All five groups prescribed 800 mg of danazol per day for an average duration of 4 to 6 months. Dramatic improvement was noted, in terms of both symptoms and signs (72% to 100%) and laparoscopic findings (85% to 95%). The uncorrected fertility rate ranged between 41% and 50%. Recurrences were common after completion of treatment and the rates ranged between 5% and 15% of treated patients per year. These studies suggest that danazol is an effective drug in the treatment of endometrosis. Interestingly, there is little consensuson the specificsof the clinical application of danazol. The following discussionhigh&hts the areas of consensusand the breadth of disagreement concerning the use of danazol. Selection of patients for danazol therapy. Most chniciansagree that patients with a suspecteddiagnosis of endometriosis must have confirmation of the diagnosisby laparoscopy or laparotomy prior to initiation of therapy. Other than this one caveat, the indications for danazol therapy are controversial and discussedin more detail below. Initiation of danazd therapy. When administered to pregnant females, danazol and related isoxazole compounds can produce urogenital abnormalities in the offspring. ‘356Consequently great care must be taken to ensure that patients initiating danazol therapy are not pregnant. In mostcasestherapy with danazol should be initiated during menstruation. Otherwise, appropriate testsshould be done to demonstrate that the patient is not pregnant. In patients with poor drug compliance, on a regimen of low dosesof danazol, careful monitoring of the patient for a possibleunsuspectedintervening pregnancy must be maintained. Dosage.The patient packageinsert for danazol suggestsa doseof 800 mg per day. However, many experienced clinicians now suggestthat all patients start on a dose of 400 mg per day.57,5sIn most patients this dose produces rapid relief of symptoms, cessationof menses,and objective regression of disease.In those patients who do not respond to 400 mg of danazol per day, the dose can be increased to 600 or 800 mg per day. In those patients requiring 600 or 800 mg of dalkazol per day to obtain a clinical response,the dosage can often be reduced after 2 to 3 months of therapy without precipitating a return of symptomsand physical findings. Ihwation of therapy. Initial trials investigating the efficacy of danazol evaluated a 6-month therapy regi-

men. This therapy interval need not be rigidly followed. Individualization of care is important when danazol is used to treat endometriosis. For example, in the patient with advanced endometriosiswho is scheduled for conservative laparotomy, a 12- to 24-week preoperative course of danazol might be appropriate. For the patient with painful endometriosis who does not desire fertility and who is adamantly opposed to surgery, a 52- to 78-week course of danazol is not unreasonableif side effects are carefully monitored. Side effects. The major sideeffects seenwith danazol therapy are (in decreasingorder of frequency): weight gain, edema, decreasedbreast size, acne, oily skin, hirsutism, deepening of voice, headache, hot flashes, changes in libido, and muscle cramps.“” Significant weight gain (2 to 10 kg) is not uncommon. In our experience more than three quarters of patients receiving danazol will complain of one or more sicleeffects; however, discontinuation of the drug becauseof side effects is uncommon. Contraindications to danaaol. In the nonpregnant, non-breast-feeding patient with documented endometriosis, relatively few absolute contraindications to danazol therapy exist. Danazol ismetabolized largely via hepatic mechanismsand hasbeen reported to produce mild to moderate hepatocellular damage in some patients (elevated serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase).“” Therefore, in patients with hepatic dysfunction, danazol is relatively contraindicated. Since danazol can induce marked fluid retention, patientswith severehypertension,*0congestive heart failure, or borderline renal function may experience deterioration of their medical condition after danazol is begun. Timing of attempts at conception after completion of danazol therapy. Dmowski and Cohen”” have re-

ported a high number of second-and third-trimester intrauterine fetal deathsin patients who conceivedwithin the first three cyclesafter discontinuation ofdanazol. They suggestthat this degree of fetal wastagemay be secondary to implantation in an atrophic endometrium and that following a course of danazol one full menstrual cycle of normal flow and duration be observed prior to any attempts to conceive. In contrast to these observations, Daniel1 and ChristiansonG observed no increasein fetal wastagein patients conceiving within 3 months of completing a course of danazol. Further information is needed to resolve these discrepancies.In our practice we have followed the suggestions of Dmowski and Cohenj3 and have urged our patients to wait one full menstrual cycle of normal flow and duration prior to attempting conception. Use of danazol without surgery the infertility of endometriosis.

in the treatment

of

Endometriosis is a

460

Bafbieri and Ryan

heterogeneous disease and the stage of the disease is one of the most important factors in planning therapy. Patients with infertility and severe endometriosis with marked anatomic abnormalities of the fallopian tubes, ovaries, and cul-de-sac will usually require surgery to enhance fertility. However, patients with infertility and mild endometriosis often have no major anatomic abnormalities. In these patients prostaglandins produced by the endometriotic implants have been postulated to be important biochemical mediators of tubal dysfunction and altered steroidogenesis.‘j2 Recent studies that a course of danazol,alome might be able to enhance fertility in patients with mild endometriosis. Van Zyl and associates63 studied 20 infertility patients with mild to moderate endometriosis (staging system of Acosta and associate?*, and eight conceptions were obtained by using danazol without surgery. In 38 infertility patients with Stage I and Stage II endometriosis (staging system of Kistner and colleague@), a course of danazol without surgery resulted in a 50% uncorrected fertility rate.“j Use of danazol with surgery in the treatment of the infertility of endometriosis. In patients with infertility and advanced stages of endometriosis, surgery is usually necessary to repair anatomic abnormalities and to remove implants of endometriosis. Little experimental data are available concerning the value of danazol in the preoperative or postoperative management of endometriosis. Some experienced clinicians suggest that danazol has little value in the preoperative management of endometriosis.66 Others believe that danazol may improve the prognosis for infertile women with endometriosis by decreasing the number and size of endometriotic areas, thereby minimizing the extent of surgery.67 In addition, the preoperative use of danazol eliminates the chance of traumatizing a corpus luteum. Use of danazol in the postoperative management of the infertile patient with endometriosis is even more controversial. Most conceptions following surgical therapy occur within the first 6 months after surgery .6* Therefore, by treating the surgical patient with danazol for a prolonged period postoperatively, the time interval with the highest fertility potential will be passed over. It is our belief that danazol should be used in most patients preoperatively but that postoperative danazol therapy in infertility patients should be minimized. Use of dauazol in the treatment of endometriosis in patients not desiring fertility. For the patient over 40 with symptomatic endometriosis who has completed her family, the definitive therapy is total abdominal hysterectomy and bilateral oophorectomy. However, some patients may want to postpone or avoid major surgery. For these patients a trial of danazol may be reasonable. For the young symptomatic patient with endometriosis

October Am. J. Obstet.

15, 1981 Gynecol.

who intends to delay pregnancy, danazol therapy is highly effective in relieving symptoms and physical findngs.5’f-5s Dauazol in the treatment of endometriomas. No systematic study assessing the effect of danazol onendometriomas has been reported. Clinical experience suggests that danazol can often reduce the size of endometriomas, but that it is unusual for danazol to cause complete regression of an endometrioma.s3. 55,58 In generai, danazol is more effective in causing regression of peritoneal endometriotic implants of small diameter. Use of danaeol in metastatic endometriosis. For the majority of patients with endometriosis involving organs outside the pelvis, total abdominal hysterectomy and bilateral oophorectomy are necessary. However, certain patients will refuse surgery and others are extremely poor operative risks. In these patients, danazol therapy is an alternative of last resort. Danazol has been successful in the treatment of pulmonary endometriosis 76g bowel obstruction 734 and ureteral obstructionti caused by endometriosis. Recurrence rates after danazol thwy for enduretriosis. A major problem in the treatment of endometriosis is that the disease tends to recur unless definitive surgical therapy is performed. Following a course of danazol therapy the recurrence of symptoms and physical findings is approximately 5% to 20% per year.“O-“” A second course of danazol therapy is often successful in inducing a remission of disease symptoms and physical findings.j” An important point to emphazise is that in no clinical study examining the efficacy of danazol have the investigators routinely performed relaparoscopy of aA1 patients with recurrence of symptoms and/or physical findings. It has been our experience that a few patients who have completed a course of danazol and have recurrence of symptoms and physical findings have no evident endometriosis on a “third-look” laparoscopy.“” It is possible that microscopic endometriosis is present and cannot be identified by gross examination. Alternatively, other causes of the symptoms may be present. Dana& versus pseudupregnancy. Very little data are available which directly compare the efficacy of danazol versus a pseudopregnancy regimen in the treatment of endometriosis. The results of one small, prospective, randomized trial of danazol versus mestranoh norethynodrel have been reported by Noble and Letchworth.” A total of 86% of the patients treated with danazol reported improvement in their symptoms. Only 30% of the pseudopregnancy group reported symptomatic improvement. Improvement in objective findings was demonstrated in 84% of patients treated with dan-. azol compared to only 18% of patients on the pseudopregnancy regimen. Side effects were a major problem

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for patients receiving both therapeutic regimens. Only 4% of the danazol group but 41% of the pseudopregnancy group discontinued therapy becauseof side effects. In a retrospective study of 438 patients, Mettler and Semm72found that patients with endometriosis treated medically had a higher fertility rate when treated with danazol (45%) than when treated with lynestrenoi (32%). However, it is difficult to assess the validity of the results of either study becauseof several deficienciesin design. The clinical impressionof those who have used danazol extensively is that it is more effective than pseudopregnancyin the treatment of endometriosis.53,35The major factor which has inhibited the widespread useof danazol is its high cost (approximately $1.OOper 200 mg). Effect of danazol on thyroid function tests. Oral administration of danazol exposes the liver to very high concentrations of the drug via the portal circulation. Since the synthesis of many of the circulating proteins secreted by the liver is regulated by sex steroids, the

administration of an attenuated androgen, suchasdanazol, will change the pattern of liver protein synthesis.73

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For example, when women are administered danazol the circulating concentration of thyroid-binding globulin (TBG) dramatically decreases.73 The decrease in TBG will result in a decrease in thyroxine (T,) but free T, and TSH will remain norma1.74* 7sTherefore, in a patient receiving danazol, a decreased total T, value in the presence of a normal TSH value should not lead to a diagnosis of primary hypothyroidism.“’ It is difficult to outline a specific protocol or flow diagram for the treatment of endometriosis. Each case presents its own &agnostic and therapeutic challenges to the clinician. The introduction of the synthetic steroid danazol has significantly advanced the medical management of endornetriosis. As outlined above, danazol has many theoretical advantages over other hormonal therapies for endometriosis. Further clinical studies will amplify our understanding of danazol’s mechanism of action and its appropriate clinical application. We would like to thank Dr. K. Elkind-Hirsch viewing the manuscript.

for re-

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endometriosis, Contemp. Obstet. Gynecol. 15:121, 1980. 68. Buttram, V. C.: Conservative surgery for endometriosis in the infertile female: a studv of 206 natients with imnhcanons for both medical and surgical therapy, Fe&l. Steril. 31:117, 1979. 69. Ronnberg, L., and Ylostalo, P.: Treatment of pulmonary endometriosis with danazol, Acta Obstet. Gynecol. Stand. 60:77, 1981. 70. Gardner, B., and Whitaker, R. H.: The use of danazol for ureteral ostruction caused by endometriosis, J. Urol. 125:117, 1981. 71. Noble, A. D., and Letchworth, A. T.: Medical treatment of endometriosis: a comparative trial, Postgrad. Med. J. (Suppl. 5) 55:37, 1979. 72. Mettler, L., and Semm, K.: Clinical and biochemical experiences with danazol in the treatment of endometriosis in cases with infertility, Postgrad. Med. J. (Suppl. 5) 55:27, 1979.

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73. Laurell, C. B., and Rannevik, G.: A comparison of plasma protein charges induced by danazal, pregnancy, and estrogen, J. Clin. Endocrinol. Metab. -719, 1979. 74. Thorell, J. I., Dymling, J., and Rannevik, G.: Effect of danazol on thyroid function in women, Postgrad. Med. J. (Suppl. 5) 55:33, 1979. 75. Graham, R. L., and Gambrell, R. D.: Changes in thyroid function tests during danazol therapy, Obstet. Gynecol. 55:395, 1980. 76. Barbieri, R. L.: Danazol and thyroid function, Ann. Intern. Med. 92:133, 1980. 77. Pugeat, M. M., Dunn, J. F., and Nisula, 3. C.: Transport of steroid hormones: Interaction of 70 drugs with testosterone binding lobulin and corticosteroid binding globulin, J Clin. En bfocrinol. Metab. 53:69, 1981.