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Effects of cancer chemotherapy on gonadal function of patients
Cancer Treatment Reviews (1980) 7, 14I- 1"52
Effects o f c a n c e r c h e m o t h e r a p y o n g o n a d a l f u n c t i o n of patients
S. M . S h a l e t
Department of Endocrinology, Christie Hospital and Holt Radium Institute, Manchester, U.K.
Introduction
T h e r e have been an increasing n u m b e r of reports in recent years of go~iadal d a m a g e follgwing cytotoxic drug therapy for the treatment of m a l i g n a n t an d n o n - m a l i g n a n t conditions. In view of the m a r k e d cytotoxicity of most anti-cancer drugs, in particular the alkylating agents, it is not surprising that these drugs exert adverse effects on h u m a n fertility. G o n a d a l d a m a g e has been a t t r i b u t e d to chlorambucil (14, 19, 27, 31, 47, 56), cyclophosphamide (35, 41, 43, 48, 54, 76, 79), b u s u l p h a n (2, 2 9 , 46) (and other alkylating agents), vinblastine (78) a n d cytosine arabinoside (43). W h e n this complication occurs after the use of a c o mb in atio n of cytotoxic drugs, several of which ma3/ d a m a g e the gonad when used as single agents, then it m a y p r o v e impossible to estimate the contribution of any one single d r u g to the collective adverse effect. Procarbazine, a m e t h y l h y d r a z i n e derivative, m a y be taken as an example to'illustrate this point. This drug is k n o w n to be capable of i n d u c i n g complete germinal aplasia in the rat (36, 42) and the n o n - h u m a n primate (69). G e r m i n a l aplasia has also been described in pubertal boys treated for Hodgkin's disease with procarbazine, mustine, vincristine a n d prednisone (65), however, the contribution of the procarbazine to this testicular d a m a g e cannot be accurately estimated although it is likely that mustine a n d procarbazine are the most likely of the 4 drugs to induce such d a m a g e . Thus assessment of the adverse effects of individual cytotoxic drugs on the h u m a n gonad has been m a d e more difficult by the advent of combination c h e m o t h e r a p y . I t should also be r e m e m b e r e d that the specific disease state, w h i c h necessitates the use ofcytotoxic drugs, m a y have a deleterious effect on gonadal function (53). 0305-7372180/030141+ 12 $02.00/0
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C y t o t o x i c - i n d u c e d gonadal d a m a g e in the adult m a l e T h e effects ofcytotoxic drugs on the testis have been studied by testicular biopsy, semen analysis and endocrine assessment of the hypothalamic-pituitary-testicular axis. T h e r e is no doubt that the cytotoxic drugs which damage the testis, predominantly affect the germinal epithelium. Indeed it has been suggested that the aikylating agents and vinblastine do not interfere with Leydig cell fimction (68, 78). Light microscopy of testicular biopsies obtained from patients treated with cyclophosphamide (18) and chlorambucil (56) revealed normal-looking Leydig cells despite germinal aplasia; furthermore tile plasma testosterone levels of patients with cytotoxic-induced azoospermia or germinal aplasia were nearly always within the normal range (31, 77). More recently, however, the concept that the Leydig cell is resistant to cytotoxic-indueed d a m a g e has been challenged. C h a p m a n et al. (13) studied 74 men who had received cyclical combination chemotherapy with M V P P (mustine, vinblastine, procarbazine and prednisolone) for advanced or recurrent Hodgkin's disease. All patients received 6 or more cycles of M V P P and 11 men received additional combination chemotherapy. These men had finished their chemotherapy between 1 and 62 months (median 27 months) earlier. Follicle stimulating hormone (FSH) levels were consistently raised after therapy at all periods of study. Median luteinising h o r m o n e (LH) levels were at, or just above, the upper limit of normal, and median testosterone levels were no,'mal. C h a p m a n et al. (I3) suggested that tile persistent increase in FSH concentrations reflected the d a m a g e d germinal epithelium and the high normal LH concentrations in tile presence of normal testosterone concentrations indicated a degree of Leydig cell damage due to the cytotoxic therapy. Using similar criteria De Kretser et al. (17) have suggested that isolated germinal epithelial damag,, is rare and that Leydig cell function is nearly always impaired as well, irrespective of the testicular pathogenesis. An alternative interpretation of the data of C h a p m a n et al. (13) is that the high normal LH levels reflect damage to the tubular system rather than the Leydig ceil. Thus although it is believed that the elevation in serum FSH level associated with various disorders ofspermatogenesis (7, 17, 25, 34, 59) is due to a decreased negative feedback, at the hypothalamic-pituitary level of inhibin, the postulated FSH-suppressing h o r m o n e produced by the Sertoli cells (73) ; it has been shown that in higher concentrations than those required for FSH-suppression, inhibinlike preparations may affect L H secretion (26). This would mean that the lowered inhibin concentrations associated with tubular damage would result in a marked rise in FSH levels and a much more modest rise in the LH levels. Decreased libido and sexual performance during cflemotherapy was reported by 74% of the males studied by C h a p m a n et al. (13). Impotence only occurred in 8 % although it may be that this symptom was not reported reliably. Impotence associated with a low plasma testosterone level was even less common~ and only occurred in 2 out of 74 men. There is no known method of correcting cytotoxic-induced tubular damage once it has occurred, however the effects of androgen deficiency due to Leydig cell damage may be ameliorated by androgen replacement therapy. Unfortunately it would seem that in the men studied by C h a p m a n et al. (13) the sexual dysfunction was rarely due to androgen deficiency. Therefore, irrespective of whether or not subtle changes in Leydig cell function have occurred, treatment with a n d r o g e n s i s ~ery seldom indicated in these patients. Gynaecomastia has been described as a complication of chemotherapy since it has been associated with the use of busulphan (29), vincristine (71), bischloronitrosourea
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(61) as well as combination c h e m o t h e r a p y (65) with mustine, vincristine, procarbazine a nd prednisone ( M O P P ) . It has been interpreted as a clinical manifestation of Leydig cell dysfunction although tile exact mechanism is unclear. In the study o f S h e r i n s et al. (65) 9 out of 13 pubertal boys developed gynaecomastia after their combination chemotherapy but no prepubertal boy showed this complication after the same treatment. T h e y suggested that the gynaecomastia was an accentuation of the transient breast enlargement observed normally in early puberty but e n h a n c e d by a relative decrease in serum testosterone. T h e r e was no indication that these boys failed to progress normally through puberty a nd therefore hormonal treatment was unnecessary. Most of the d a t a pertaining to single cytotoxic agents have been concerned with the variable effects on fertility of cyclophosphamide an d chlorambucil. Studies (31, 56) have shown t h a t the degree of d a m a g e to the germinal epithelium of adult, p r e p u b e r t a l and pubertal, males is related to the dose of chlorambucil received: the min imal total dose necessary for azoospermia was 400 mg (56). Chlorambucil and presumably other alkylating agents m a y cause qualitative changes in the biochemical nature of h u m a n semen as well as a reduction of the sperm count. C a l a m e r a et al. (9) studied 6 patients treated for i y m p h o m a s with chlorambucii. During treatment, severe oligospermia or azoospermia developed but, in addition, the seminal fructose and citric acid concentrations increased. After w i t h d r a w a l of the drug recovery of the germinal epithelium preceded the return to normal of the seminal fructose an d citric acid concentrations. Tile practical relevance of these observations is u n k n o w n , but w h e n the seminal fruc'tose a nd citric acid concentrations were restored to normal, by treatment with androgens or H C G , this }lad no effect on the azoospermia. Cyclophosphamide-induced testicular d a m a g e is also dose-dependent (43, 54), but it is less cleat" w h e t h e r the degree of d a m a g e is related to the duration of the treatment. Buchanan et al. (8) in a follow-up of 96 male patients, who developed azoospermia within 6 months of starting cyclophosphamide therapy, showed that, in 12 patients, spermatogenesis r e t u r n e d within 15-49 months after stopping the drug. T h e r e t u r n of spermatogenesis was not significantly related to the d u r a t i o n of therapy, total dose or length of follow-up after stopping treatment. H o w e v e r the n u m b e r of patients studied was small. Lendon et al. (43) did find a significant i m p r o v e m e n t in testicular tubular morphology with increasing time after complet!on of c o m b i n a t i o n c h e m o t h e r a p y for acute lymphatic leukaemia in childhood. However, there were obvious differences in the cytotoxic d r u g t r e a t m e nt and the ages of tile patients studied by these 9 groups. Thus difficulty in separating tile contribution of t}ie duration of treatment from the total dose of the d r u g receivdd, studies performed with small numbers, follow-up of patients invariably less than 4-5 years after therapy ceased an d the advent of c o m b i n a t i o n c h e m o t h e r a p y have all obscured the definition of the precise factors which d eterm i n e w h e t h e r d a m a g e d germinal epithelium is capable o f r e c o v e r y or not. It might be th o u g h t that such data could be more easily derived from animal experiments using single cytotoxic drugs r a t h e r than a combination but species variation m a y be. an i m p o r t a n t variable (15). In a small study of 16 patients who had completed their combination c h e m o t h e r a p y for d i s s e m i n a t e d / l y m p h o m a , Roeser a al. (57) suggested that serial measurements of the serum F S H level were useful in predicting likely recovery of spermatogenesis. However, they provided no evidence to suggest that tile previously elevated F S H level declined before the sperm count returned to normal, therefore there would a p p e a r to be no a d v a n t a g e in m e a s ur i ng the serum F S H level r a t h e r than the sperm count after
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s t o p p i n g c h e n m t h e r a p y . C h a p m a n et al. (13"., stated that t h e y c o u l d not s u b s t a n t i a t e this f i n d i n g o f a decline in the s e r u m F S H level, w h i c h is har.dl.v very surprising as so few of their patients r e g a i n e d s p e r m a t o g e n e s i s (4 out o f 64~. T h e r e p o r t s of recover)' 0f" s p e r m a t o g e n e s i s in m a n y ot" the p a t i e n t s p r e v i o u s l y t r e a t e d w i t h single cvtotoxie a g e n t s (8', or a c o m b i n a t i c m of 2 or 3 d r u g s (57~ is e n c o u r a g i n g b u t the o u t l o o k for thc H o d g k i n ' s p a t i e n t s t r e a t e d w i t h M V P P (13~ or M O P P (57) a p p e a r s poor. C e r t a i n l y tbr u p to 4 years after t h e cessaxion of such t h e r a p y tot H o d g k i n ' s disease a z o o s p e r m i a is a n e x t r e m e l y c o m m o n c o n s e q u e n c e . It is not k n o w n i!" the a z o o s p e r m i a is irreversible; Sherins a n d l)e Vita (64:, described 2 p a t i e n t s w h o received M O P P t h e r a p y for H o d g k i n ' s disease a n d wire s h o w e d n o r m a l s p e r m a t o g e n e s i s 4 a n d 7 years af~er the e n d of t r e a t m e n t , h o w e v e r , the m a j o r i t y o f such p a t i e n t s have not been followed for longer t h a n 5 years p o s t - t r e a t m e n t . L o n g - t e r m studies are badly n e e d e d a n d as t h e n u m b e r a n d f r e q u e n c y o f a d m i n i s t r a t i o n of'courses of M V P P or M O t ' P m a y v a r y b e t w e e n R e g i o n a l O n e o l o g i c a l centres, i n d i v i d u a l centres will need. l,'J o b t a i n their o w n d a t a o n testicular f u n c t i o n after such t r e a t m e n t . I n t h e m e a n t i m e , it iew of the g u a r a n t e e d inli:rtility, d u r i n g t r e a t m e n t (13, 57~. the tow f r e q u e n c y a n d u n p r e d i c t a b i l i t y of recover), of s p e r m a t o g e n e s i s after t r e a t m e n t , s p e r m s t o r a g e s h o u l d be available for m a l e p a t i e n t s u n d e r g o i n g MX,'PP or M ( ) P t ' t h e r a p y , since m a n y of" these p a t i e n t s m a y enjoy p r o l o n g e d survival, U n t i l 1979 there h a d been no r e p o r t in the l i t e r a t u r e o f s e r u m p r o l a c t i n e s t i m a t i o n s in p a t i e n t s with c y t o t o x i e - i n d u c e d g o n a d a l failure. C h a p m a n et al. (13) then m a d e the interesting o b s e r v a t i o n that 18 o f tht:ir 74 m e n treated w i t h M V P P t h e r a p y tbr H o d g k i n ' s disease h a d u n e x p l a i n e d h y p e r p r o l a c t i n a e m i a . H y p e r p r o l a c t i n a e m i a is a recognised cause of m a l e h y p o g o n a d i s m b u t this is usually m a n i f e s t e d by i m p o t e n c e arid d e c r e a s e d libido; s p e r m a t o g e n e s i s m a y be i n f l u e n c e d bv raised p r o l a c t i n levels, but a z o o s p e r m i a is a most u n l i k e l y c o n s e q u e n c e ( t 1, 21 ). T h u s the consistent a z o o s p e r m i a d u r i n g M V P P t h e r a p y in the m e n s t u d i e d by C h a p m a n el al. ( 1 3 ) must be d u e to the direct effect o f t h e cytotoxic d r u g s on the g e r m i n a l e p i t h e l i u m . It is also u n l i k e l y t h a t the u n e x p l a i n e d h y p e r p r o l a c t i n a e m i a was significantly a l t e r i n g sexual activity as only 6 m e n were imp o t e n t f o l l o w i n g cessation o f c h e m o t h e r a p y a n d in 3 o f these the s y m p t o m a n t e d a t e d their illness. T h e cause o f t h e m o d e r a t e l y raised p r o l a e t i n levels in these m e n is u n k n o w n a n d f u r t h e r studies ark n e e d e d to c o n f i r m this g'roup's findings.
Cytotoxic-induced t e s t i c u l a r d a m a g e in the pre-pubertal and pubertal m a l e Despite i n c r e a s i n g e v i d e n c e of c y t o t o x i c - i n d u c e d g o n a d a l d a m a g e in the a d u l t , r e p o r t s c o n c e r n i n g the effects o f ey~moxic d r u g s on t h e g o n a d a l f u n c t i o n o f c h i l d r e n a r e s c a n t y a n d controversial. I n 1972 Berry et al. (4) r e p o r t e d n o r m a l testicular histologs, in a 6year-old boy vcho h a d received a total o f 7790 m g o f c y c l o p h o s p h a m i d e i n t e r m i t t e n t l y over 180 days. A little later Arneil (1) o b s e r v e d n o r m a l testicular histology in 7 prep u b e r t a l boys w h o r e c e i v e d c y c l o p h o s p h a m i d e for m a l i g n a n t disease. T h e d o s a g e level varied from 3 to 24 rng/d a n d d u r a t i o n o f t h e r a p y from less t h a n 50 to 400 d. R a p o l a et al. (55) s t u d i e d 4 m a l e s w h o h a d r e c e i v e d c y c l o p h o s p h a m i d e d u r i n g p u b e r t y / o r k i d n e y disease. T h e 2 p a t i e n t s w h o w e r e m o r e a d v a n c e d in p u b e r t a l m a t u r a t i o n w h e n they received c y c l o p h o s p h a m i d e s u b s e q u e n t l y s h o w e d n o r m a l tcsticular histology whilst t h e 2 patients, r e p o r t e d to be " b i o l o g i c a l l y y o u n g e r " w h e n t r e a t e d , s h o w e d c o m p l e t e a b s e n c e of s p e r m a t o g e n e s i s on biopsy. T h e s e a u t h o r s (55) w e n t o n to s p e c u l a t e t h a t t h e v u l n e r a b i l i t y of t h e g e r m i n a l e p i t h e l i u m to c y t o t o x i c - i n d u c e d d a m a g e v a r i e d w i t h t h e d e g r e e o f p u b e r t a l m a t u r a t i o n . H o w e v e r , the total dose o f c y c l o p h o s p h a m i d e r e c e i v e d
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was h i g h e r in the a s p e r m a t o g e n i c patients t h a n in the 2 with n o r m a l s p e r m a t o g e n e s i s a n d the n u m b e r of patients studied was very small. T h e c o n c e p t of v a r i a b i l i t y o f sensitivity of the testis to cytotoxic d a m a g e was g r a d u a l l y e x t e n d e d to i n c o r p o r a t e the view that the p r e - p u b e r t a l testis was relatively insensitive to such an insult. T h e earlier histological reports ( 1 . 4 ) were reinforced by h o r m o n a l studies (16, 39. 50.51 ) w h i c h s h o w e d no a b n o r m a l i t i e s in s e r u m FSH, L H a n d testosterone c o n c e n t r a t i o n s in p r e p u b e r t a l boys who, h a d received c y c l o p h o s p h a m i d e s o m e years earlier. Similarly Sherins et aZ. (65j found g e r m i n a l aplasia a n d very high s e r u m F S H levels ill boys w h o h a d received M O P P t h e r a p y for H o d g k i n ' s disease w h e n p u b e r t a l : they also - t u d i e d 6 boys w h o received the s a m e t r e a t m e n t but w h o w e r e p r e - p u b e r t a l w h e n the 5- received their c h e m o t h e r a p y a n d at the time of study. S e r u m F S H , L H a n d testosterone c o n c e n t r a t i o n s were a p p r o p r i a t e for their age in these 6. A m o r e recent r e p o r t by L e n d o n et aL (43) has m a d e it quite clear that the p r e - p u b e r t a l testis m a y be d a m a g e d by cytotoxic d r u g s . T h e y studied t e s t i c u l a r histology in 44 boys treated with c o m b i n a t i o n c h e m o t h e r a p y for a c u t e l y m p h a t i c leukaemia. Nearly all o f their patients h a d received their c h e m o t h e r a p y w h e n p r e - p u b e r t a l a n d the m e a n t u b u l a r fertility index ( p e r c e n t a g c o f seminiferous tubules c o n t a i n i n g identifiable s p e r m a t o g o n i a ) was 50°/i~ o f that in a g e - m a t c h e d controls. E i g h t e e n o f the testicular biopsies h a d a severely depressed t u b u l a r fertility index of 4 0 % or less. T h e c o n c l u s i o n from this histological s t u d y (43) has been reinforced by t h e studies o f p o s t - p u b e r t a l patients with a b n o r m a l i t i e s o f g o n a d o t r o p h i n secretion a n d a m a r k e d r e d u c t i o n in their s p e r m counts tbllowing the a d m i n i s t r a t i o n of c y c l o p h o s p h a m i d e (44, 52) a n d c h l o r a m b u c i l (31) d u r i n g p r e - p u b e r t a l life. S o m e o f the confusion in t h e l i t e r a t u r e c o n c e r n i n g the v u l n e r a b i l i t y o f the p r e - p u b e r t a l testis to cytotoxic d a m a g e has arisen because of the reliance on h o r m o n a l tests of testicular f u n c t i o n to define w h e t h e r such d a m a g e has occurred. Shalet et al. (63) have n o w s h o w n in an e n d o c r i n e s t u d y of t h e 44 boys whose testicular histologies w e r e earlier r e p o r t e d by L e n d o n et al. (43), that m o d e r a t e l y severe d a m a g e to t h e t u b u l a r system o f the testis unassociated with L e y d i g cell i m p a i r m e n t m a y not be d e t e c t e d in the p r e - p u b e r t a l boy using c u r r e n t tests ot" testieular function. It is this co-existence of a b n o r m a l m o r p h o l o g y a n d n o r m a l testicular tianction test-s, w h i c h has c o n t r i b u t e d to the c o n c e p t t h a t the p r e - p u b e r t a l testis m a y be less susceptible to eytotoxic d a m a g e t h a n the p u b e r t a l testis; this c o n c e p t r e m a i n s to be p r o v e n . A t t e m p t s have been m a d e to define the dose o f c h l o r a m b u c i l (31) or c y c l o p h o s p h a m i d e (44) r e q u i r e d in a boy to cause testicular d a m a g e b u t these h a v e been t h w a r t e d by the lack of an a d e q u a t e dosage range, small n u m b e r s a n d the v a r i a t i o n in the p u b e r t a l status of the patients studied. T h e i m p r o v e d prognosis o f c h i l d r e n t r e a t e d for a c u t e l y m p h a t i c l e u k a e m i a a n d H o d g k i n ' s disease has m e a n t that i n c r e a s i n g a t t e n t i o n m u s t be paid to the q u a l i t y o f life a t t a i n e d by t h e survivors. L o n g t e r m follow-up o f s u c h patients is m a n d a t o r y so that it can bc established w h e t h e r or not the c y t o t o x i c - i n d u c e d d a m a g e to the g e r m i n a l e p i t h e l i u m sustained by such a high p r o p o r t i o n of these patients, proves reversible or not. At t h e present time only single-case reports (33, 45) exist a n d t h e r e f o r e firm advice c o n c e r n i n g f u t u r e fertility c a n n o t be given to these y o u n g males or their parents. P
Cytotoxic-induced gonadal d a m a g e in the adult feznale T h e clinical m a n i f e s t a t i o n s o f c y t o t o x i c - i n d u c e d g o n a d a l d a m a g e in t h e female i n c l u d e a m e n o r r h o e a or o l i g o m e n o r r h o e a a n d m e n o p a u s a l s y m p t o m s such as flushing a n d d y s p a r e u n i a . As in the male, the early studies r e p o r t e d g o n a d a l failure after single
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cytotoxic d r u g t h e r a p y with one o f the fi)llowi~lg 3 a l k y l a l i n g a g c n t s - - c h l o r a m b u c i l (19, 27), b u s u l p h a n (2, 2(.), 4(3) a n d c y c l o p h o s p h a m i d c (10, 22., 24, 21~, 41, 48, 76, 79, 20). Most i n t o r m a t i o n is a v a i l a b l e oil t h e effects o f c y c l o p h o s p h a m i d e on female r e p r o d u c t i v c f u n c t i o n . Uldall e t a / . (76) s t u d i e d 34 w o m e n with g i o m c r u l o n e p h r i t i s t r e a t e d with d a i l y c y c l o p h o s p h a n f i d e lor an a v e r a g e of 18 n l o n t h s . E i g h t e e n w()mcn d e v e l o p e d a m e n o r r h o e a a n d on a v e r a g e this c o m p l i c a t i o n o c c u r r e d w i t h i n 7 m o n t h s o f s t a r t i n g cycle)p h o s p h a m i d e . T h e periods olfly r e t u r n e d in 1 o u t o f the 9 p a t i e n t s w h o d i s c o n t i n u e d the d r u g an average, o f 12 m o n t h s previously. U r i n a r y ocstrogcns were low a n d u r i n a r y g o n a d o t r o p h i n s elevated suggesting t h a t the a m e n o r r h o e a was d u e to c y c l o p h o s p h a m i d e i n d u c e d d a m a g e at a n o v a r i a n r a t h e r t h a n h y p o t h a l a n f i c - p i t u i t a r y level. W a r n e e/ al. (79) s t u d i e d the o v a r i a n m o r p h o l o g y in 6 w o m e n w h o h a d received c y c l o p h o s p h a r n i d e for g l o m e r u l o n c p h r i t i s o r r h e u m a t o i d arthritis. N o n e s h o w e d e v i d e n c e o f follicular m a t u r a t i o n a n d ova were only seen in 2. T h e s e ova were a b n o r m a l in a p p e a r a n c e a n d n o n e gave. e v i d e n c e o f d e v e l o p m e n t into p r i m o r d i a l follicles. T h e s e a u t h o r s (79) s u g g e s t e d tha~ c y c l o p h o s p h a n f i d e p r e v e n t e d the swelling or prolili:ration of thecal cells to form tbllicle:~ a n d in g r e a t e r c u m u l a t i v e doses or over l o n g e r periods, c y c i o p h o s p h a m i d e m a y also acl directly on the ovary to d e p l e t e the n u m b e r of ova. F r e c k m a n et al. (27) d e s c r i b e d similar histological c h a n g e s in the ovaries o f w o m e n w h o h a d received e h l o r a m b u c i l tbr breast c a r c i n o m a . In the studies o f U l d a l l et al. (76) a n d W a r n e et al. (79) r e c o v e r y o f o v a r i a n f u n c t i o n after cessation o f c y c l o p h o s p h a m i d e was rare, h o w e v e r , K u m a r et al. (41) r e p o r t e d 6 o u t o f 8 w o m e n to h a v e h a d a r e t u r n o f m e n s t r u a l f u n c t i o n after cyclop h o s p h a m i d e - i n d u c e d o v a r i a n ' f a i l u r e . T h e w o m e n h a d been t r e a t e d |or less t h a n 9 m o n t h s w h i c h m a y explain the l a r g e r n u m b e r o f reversible cases. H o w e v e r a h h o u g h wc c a n bc c e r t a i n t h a t the m e a n d u r a t i o n o f c h e m o t h e r a p y was less in the s t u d y o f K u m a r et al. (41) thz'.n t h e o t h e r 2 studies (76, 79), it is m o r e difficult to k n o w if the total dose o f c y c l o p h o s p h a m i d c received by t h e p a t i e n t s was significantly diflerent in the 3 studies, as is likely; n e i t h e r K u m a r et al. (41) n o r U l d a l l et al. (76) m e n t i o n the total dose o f the d r u g received by their patients. N o n e t h e l e s s it is very likely that the total dose of cyclop h o s p h a m i d e received is an i m p o r t a n t d e t e r m i n a n t o f the reversibility of this c o m p l i c a t i o n : Belohorsky et al. (2) ~nacle t h e a d d i t i o n a l o b s e r v a t i o n t h a t the dose Of the d r u g , i.e. b u s u l p h a n , received by their l e u k a e m i c p a t i e n ts, d e t e r m i n e d h o w soon after initiation o f t r e a t m e n t the a m e n o r r h o e a d e v e l o p e d . T h e difficulties in establishing w h e t h e r the d u r a t i o n o f c h e m o t h e r a p y is a n i m p o r t a n t factor in the reversibility of g o n a d a l d a m a g e in the malt- exist just as s t r o n g l y in the t~male. O n t h r o t h e r h a n d a g e - r e l a t e d susceptibility to such d a m a g e in the a d u h female is an established v a r i a b l e . T h u s a h h o u g h t h e d u r a t i o n of t r e a t m e n t is likely to be i m p o r t a n t , proof" is lacking. J a c o x (37) in a stud), of" the efl~cCs o f e x t e r n a l i r r a d i a t i o n on o v a r m n f u n c t i o n , stated that after a single dose of 500 r a d s to t h e ovaries, 6 to 8 m o n t h s o f a m e n o r r h o e a c o u l d be e x p e c t e d in y o u n g w o m e n , a n d p e r m a n e n t sterility in the m a j o r i t y o f w o m e n o v e r the age o f 40. I n c o n t r a s t W a r n e et al. (79) f o u n d n o a g e - r e l a t e d susceptibility in their p a t i e n t s with c y c l o p h o s p h a m i d e - i n d u c e d o v a r i a n failure. T h i s is c u r i o u s in ~,iew o f t h e studies (40, 58, 66), t h a t w e r e s u b s e q u e n t l y to a p p e a r , r e p o r t i n g t h a t there was a n a g e - r e l a t e d susceptibility to c y t o t o x i c - i n d u c e d o v a r i a n failure. W a r n e et at. (79) o n l y s t u d i e d a small n u m b e r o f w o m e n over t h e age o f 35 years a n d t h e y c o m m e n t e d in their article that a m c n o r r h o e a d e v e l o p e d in the first 4 m o n t h s o f t r e a t m e n t in 4 patients, 35 years o f age or older. T h e latter is a p o i n t f u r t h e r e x a m i n e d by K o y a m a et al. (4.0) w h o s t u d i e d w o m e n w i t h breast c a r c i n o m a t r e a t e d w i t h d i f f e r e n t c y t o t o x i c d r u g s i n c l u d i n g cyclo-
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p h o s p h a m i d e . T h e a v e r a g e dose' o f e y c l o p h o s p h a m i d e given betbre the onset o f a m e n o r r h o e a in p a t i e n t s in their 40s, 30s a n d 20s was 5.2 g, 9.3 a n d 20.4 g respectively. S h e r m a n et al. (66) r e i n | b r e e d this v i e w in their s t u d y o f breast c a n c e r p a t i e n t s in an a d j u v a n t trial w h o received m c l p h a l a n a n d 5-fluorouracil, Sixty-four p e r cent of" w o m e n , 40 years o r over, d e v e l o p e d i r r e g u l a r m e n s e s or a m e n o r r h o c a . By c o n t r a s t only 12 °A~o f those w o m e n 39 years a n d y o u n g e r r e p o r t e d a c h a n g e in m e n s t r u a l p a t t e r n . It c o u l d h a v e b e e n pred i c t e d that a g e - r e l a t e d susceptibility was likely to be an i m p o r t a n t v a r i a b l e as it has b e e n well k n o w n lor m a n y years that the n u m b e r o f o o c y t e s decreases steadily with i n c r e a s i n g age (5), t h e r e l o r e o v a r i a n f i m c t i o n in o l d e r w o m e n , w h o h a v e fewer r e m a i n i n g oocytes, is mort: v u l n e r a b l e to the efl~.cts o f b o t h e x t e r n a l i r r a d i a t i o n a n d c h e m o t h e r a p y . I nitial studies o f l b m a l e p a t i e n t s , w h o h a d d e v e l o p e d a m e n o r r h o e a or o l i g o m e n o r r h o e a d u r i n g t r e a t m e n t w i t h a l k y l a t i n g a g e n t s , were based on c h a n g e s in t h e u r i n a r y o e s t r o g e n a n d total g o n a d o t r o p h i n levels (76, 79) a n d histological e x a m i n a t i o n o f o v a r i a n biopsies (27. 79). T h e typical h o r m o n a l findings in p a t i e n t s w i t n c y t o t o x i c - i n ~ u c e d o v a r i a n d a m a g e were e l e v a t e d u r i n a r y g o n a d o t r o p h i n levels a n d low u r i n a r y o e s t r o g e n levels. Not surprisingly, in m o r e r e c e n t p u b l i c a t i o n s (58, 60) e l e v a t e d s e r u m F S H a n d L H levels a n d low s e r u m oestradiol levels h a v e been t b u n d in f e m a l e breast c a n c e r p a t i e n t s w h o d e v e l o p e d o v a r i a n failure following e i t h e r c y c l o p h o s p h a m i d c or m e l p h a l a n as p a r t o f their a d j u v a n t c h e m o t h e r a p y . If p r i m a r y o v a r i a n d a m a g e is s u s p e c t e d then tile single most i m p o r t a n t h o r m o n e e s t i m a t i o n is the s e r u m F S H c o n c e n t r a t i o n (3, 30). T h e o b s e r v a t i o n t h a t a m c n o r r h o e a o c c u r r e d in s o m e w o m e n w h o h a d n o r m a l m e n s e s at t h e start o f t h e t h e r a p y (40, 58), has led to a suggestion t h a t the p r o l o n g e d disease-free interval observed in breast c a n c e r p a t i e n t s giver, a d j u v a n t t h e r a p y m i g h t be a t t r i b u t a b l e to t r e a t m e n t - i n d u c e d a l t e r a t i o n in e n d o c r i n e f u n c t i o n . T o test this hypothesis F i s h e r el at. (23) s t u d i e d the r e l a t i o n s h i p b e t w e e n disease-free survival a n d d e p r e s s i o n o f o v a r i a n f u n c t i o n in p r o - m e n o p a u s a l p a t i e n t s with p r i m a r y breast c a n c e r w h o received a d j u v a n t c h e m o t h e r a p y w i t h m e l p h a l a n a l o n e o r in a d d i t i o n to 5 - f l u o r o u r a c i l . T h e result i n d i c a t e d t h a t Iooth the y o u n g e r p a t i e n t s (~< 39 years) a n d the o l d e r p a t i e n t s ( 4 0 - 4 9 years) w i t h positive axillary n o d e s w h o r e c e i v e d p r o l o n g e d m e l p h a l a n t r e a t m e n t as a n a d j u v a n t to m a s t e c t o m y c o n t i n u e d to d e m o n s t r a t e a significantly g r e a t e r disease-free survival t h a n d i d p a t i e n t s w h o received p l a c e b o . T h o s e in the y o u n g e r a g e g r o u p s h o w e d a g r e a t e r i m p r o v e m e n t ill disease-fi'ee survival at 4 years relative to their c o n t r o l s t h a n d i d those in t h e o l d e r a g e g r o u p . In c o n t r a s t to t h e findings relative to disease-free survival, o v a r i a n f u n c t i o n was m o s t affected in t h e o l d e r a g e g r o u p . T h e r e f o r e it w o u l d a p p e a r t h a t w h i l e suppression o f o v a r i a n f u n c t i o n m a y a c c o u n t for s o m e o f t h e a d j u v a n t c h e m o t h e r a p e u t i c effect in p r e - m e n o p a u s a l w o m e n , o t h e r factors w e r e also responsible. S h e r m a n et al. (67) looked m o r e closely at the h o r m o n a l features o f the m e n s t r u a l cycle in t h e prem ~ n o p a u s a l breast c a n c e r p a t i e n t s , w h o m a ; . n t a i n e d r e g u l a r menses, h a v i n g r e c e i v e d t h e s a m e a d j u v a n t c h e m o t h e r a p y as in the s t u d y o f F i s h e r et al. (23). I n this w a y t h e y h o p e d to d e t e c t subtle h o r m o n a l c h a n g e s w h i c h m i g h t reflect failure to o v u l a t e or a defect in t h e follicular or luteal p h a s e o f t h e cycle. T h e h o r m o n a l c h a r a c t e r i s t i c s w e r e c o m p l e t e l y n o r m a l after 3 to 14- courses o f c h e m o t h e r a p y so t h a t n o t o n l y w e r e t h e m e n s t r u a l cycles r e g u l a r , t h e y were also o v u l a t o r y . A p u z z l i n g o b s e r v a t i o n , w h i c h h a s n o t yet b e e n e x p l a i n e d , c o n c e r n s t h e re-establishm e n t o f m e n s e s in 2 4 % o f t h e p r e - m e n o p a u s a l p a t i e n t s w h o d e v e l o p e d a m e n o r r J a o e a d u e to their c y t o t o x i c t h e r a p y (6). T h e s e w e r e p a t i e n t s t r e a t e d for b r e a s t c a n c e r w i t h cyclop h o s p h a m i d e , m e t h o t r e x a t e a n d 5-fluorouracil a n d t h e p e r i o d s in this g r o u p o f p a t i e n t s returned despite continued chemotherapy.
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Apart from breast cancer, the other majo r malignancy in which the abnormalities of reproductive function following c h e m o t h e r a p y have been studied, is Hodgkin's disease. Sobrinho et at. (72) studied l0 t-Iodgkin's disease patients'who developed amenorrhoe'a or oligomenorrhoea shortly after c h e m o t h e r a p y was started. A variety of d r u g combinations were used and every patie,:t received at least one alkylating agent but no more than 4 patients received the same d r u g combination. Menstruation returned in only 1 patient 2 months after the end of a 14 m o n t h course of vinblastine an d another patient b e c a m e pregnant d u r i n g treatment with m e c h l o r e t h a m i n e and chlorambucil a n d underwent a therapeutic abortion. A not h er small group of 13 patients with Hodgkin's disease were studie8 by Morgenfield et al. (49). These patients were treated with ch lo ramb uci l , vinblastine and a m e t h y l h y d r a z i n e derivative, some also received cyclophosphamide. T h e women were divided into 2 groups; those who developed a m e n o r r h o e a and those who did not. T h e latter group received markedly lower doses of the drugs. T h e first large study was reported by C h a p m a n et al. (12) w h o studied'~'epr~.luctive function in 41 w o m e n with a d v a n c e d Hodgkin's disease. All except 1 had received standard M V P P c h e m o t h e r a p y (74) an d 21 had additional M V P P as m a i n t e n a n c e therapy or other drugs if the disease relapsed after M V P P . At the beginning of the study, 7 w o m e n were still receiving c h e m o t h e r a p y and 34 had finished their treatment. T h e patients were observed over a 16-month period, at the end of which, the age rarrge was 20-51 years (median 30 years), and the group had been off c h e m o t h e r a p y from 10-78 m o n t h s (median 36 months). At the end of the study 12t~ had regular ovulatory menstrual cycles, 2 6 % ha d oligomenorrhoea and 62 g~, had complete a m e n o r r h o e a with biochemical evidence of p r i m a r y ovarian failure. It was interesting to note that over the 16 months of the study ovarian function deteriorated rather than improved. D u r i n g this time the menstrual pattern in 6 w o m e n ch an g ed from oligomenorrhoea to a m e n o r r h o e a . This deterioration in ovarian function, after c h e m o t h e r a p y has been completed, contrasts sharply with the earlier observation of B o n n a d o n n a et al. (6) that the menstrual cycle was re-established in 2 4 % of pre-menopausal breast cancer patients despite continued c he mot he ra py. O v a r i a n biopsies were obtained from 6 patients of C h a p m a n et al- ( 1 2 ) and there was a reduction in the primordial follicles in all cases. Where such a gross depletion of primordial follicles occurs, recovery ofovarian function would be unexpected but if the major manifestation of the cytotoxic-induced ovarian d a m a g e is impaired follicular m a t u r a t i o n then restoration of ovarian function is more likely. I n sharp contrast to the 24% incidence of unexplained hyperprolactinaemia in m e n with Hodgkin's disease, C h a p m a n et al. (12) only tbund 1 such case in the female study. This group (12, 13) further suggested that 3 of the 74 males and 3 of the 41 females had a prolactin-secreting pituitary m i c r o a d e n o m a . This view is based on a radiological rather than a tissue diagnosis; such radiology is notoriously difficult to interpret (75) and, if true, would suggest a relationship between Hodgkin's disease or its treatmen t an d prolactin-secreting pituitary tumours. M a n y of the females treated for Hodgkin's disease (12) lost interest in sexual interco~rse; libido diminished progressively d u r i n g therapy a n d this appeared to correlate well with the progressive loss of ovarian function. At the end of the study 4 6 % of the wome n reported no sexual activity an d menopausal symptoms such as flushing and dyspareunia were common. Separation a n d divorce were m u c h more frequent in these women than in the general population a n d C h a p m a n et al. (12) suggested that the u n d e r lying cause for this disruption in their personal relationships was the cytotoxic-induced ovarian failure, however, proof was lacking. T h erap eu tically there can be no d o u b t that
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patients distressed by the menopausal symptoms associated with ovarian failure w~Ii benefit from cyclical oestrogen and progesterone therapy. It is not yet clear how long such patients S'hould be treated or whether all patients with biochemical evidence of ovarian failure should receive steroid replacement therapy. Occasional pregnancies have been described in women (12, 38) with previous evidence of impaired ovarian function following chemotherapy for Hodgkin's disease. T h e suggestion (38) that hormonal therapy may help such women to conceive is unsubstantiated, similarly there is no evidence to indicate that hormone manipulation during chemotherapy may protect ovarian function.
C y t o t o x i c - i n d u e e d ovarian failure in the p r e - p u b e r t a l a n d pubertal female There have been relatively few studies on the effects o f cytotoxic drugs on gonadal function in the pre-pubertal and pubertal female. Tile reports of Pcnnisi et al. (51), Etteldorf et al. (18) and Lentz et al. (44) found no evidence of menstrual dysfunction in women, who had received cyclophosphamide for renal disease during childhood. Each of these 3 reports described successful pregnancies amongst their patients. Less encouraging was the morphological study of Miller et al. (48) in which the autopsy findings in a 13-year-old girl, who had received cyclosphosphamide for 29 months, revealed ovaries totally lacking in follicles. Siris et al. (70) examined the'effects of childhood leukaemia and chemotherapy on puberty and reproductive function in 35 girls and women. Twenty-eight patients had normal pubertal maturation during a median time of 74 months after diagnosis of Ieukaemia and 49 months of chemotherapy. Seven patients were abnormal, 4 exhibited hypothalamic-pituitary dysfunction and 3 had evidence of primary ovarian dysfunction. None of these 3 latter patients had received cyclophosphamide and intereslingly only 9 out of the 35 females had received this drug. T h e main drugs used were vincristine, methotrexate, 6-mercaptopurine and steroids although 1 of the 3 girls with primary ovarian dysfunction had also received busulphan. Shalet et al. (62) found definite biochemical evidence of ovarian failure in 2 out of 7 pre-pubertal girls who had received combination chemotherapy for acute lymphatic leukaemia. A further 5 pre-pubertal girls were studied by Shalet (unpublished data) and 1 had a very high FSH concentration consistent with primary ovarian damage. These 3 girls with biochemical evidence of ovarian failure had all received cyclophosphamide and some 3 Years after that study still show abnormalities of FSH secretion. O n e girl is still pre-pubertal, one has completed her pubertal maturation quite normally but still has oligomenorrhoea some 2 years after menarche and the third is now aged 14½, has progressed through puberty but has not yet had a period. Clearly longer follow-up is necessary to assess the clinical significance of the impaired ovarian function. In the pre-pubertal and pubertal female there are insufficient data to c o m m e n t on the relationship between cytotoxic-induced ovarian d a m a g e and the total drug dosage, duration of treatment and potential reversibility of such d a m a g e after treatment has finished. T h e morphological evidence that such gonadal damage occurs is, however, just as convincing in the female as in the male. HimelsteinBraw et al. (32) studied the ovaries of 31 leukaemic girls obtained at autopsy. Follicle development was inhibited in nearly all. In the ovaries in which follicle development
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occurred, the n u m b e r and size of antral follicles was reduced compared to the controls. All girls had been treated with cytotoxic drugs. T h e ovaries of those girls treated for less than 1 week were normal, whereas all ovaries from girls treated for more than 2 months showed inhibition oftbllicle growth. This suggested that it was the treatment and not the disease that had inhibited follicle development. Prolonged treatment (1-2 years) caused a reduction in the n u m b e r ofsmall non-growing follicles in 2 cases. T h e impaired follicular m a t u r a t i o n in such patients may prove reversible but ira serious depletion of primordial follicles has occurred tbllowing exposure to cytotoxic drugs in.childhood then a prcmature menopause may be a long-term sequel. It is quite likely that the age-related susceptil3illty to cytotoxic-induced ovarian thilure in the a du l t female may bc extended to the pre-pubertal female, however, other irnportant variables such as drug metabolism and clearance may also depend on the age and pubertal status of the subject.
Conclusions 1. Tile ma j or group of drugs responsible tbr cytotoxm-induced gonadal d a m a g e are the alkylating agents such as cyclophosphamide, busulphan, chiorambucil and melphalan. O t h e r drugs such as vinblastine an d cytosine arabinoside have also been incriminated. 2. With the advent of combination c h e m o t h e r a p y it has become increasingly difficult to estimate the precise thctors w h ich determine the degree of cytotoxic-induced gonadal d a m a g e or the capability of recovery from such damage. Gonadal damage is certainly dependent on the total dose of the d r u g received but there is no conclusive evidence that the duration of c h e m o t h e r a p y is an important variable. Age-related susceptibility is another d e t e r m i n a n t of cytotoxic-induced gonadal d a m a g e in the a dul t female but not in the adult male. 3. T h e pre-pubertal and pubertal gonad may be d amag ed by cytotoxie c h e m o t h e r a p y but the concept that the pre-pubertal testis is less susceptible to such d a m a g e than the pubertal testis remains unproven. 4. In the male the cytotoxic drugs capable of d a m a g i n g the testis, primarily affect the germinal epithelium. However, there is increasing evidence that Leydig cell function ma y not be as resistant to cytotoxic-induced d a m a g e as previously believed. 5. Recovery of gonadal function after cytotoxic-induced d a m a g e is well recognised following treatment with single alkylating agents. It is likely that the duration of time after cessation of c h e m o t h e r a p y is an important d e t e r m i n a n t of such recovery. However, the outlook for patients treated with combination c h e m o t h e r a p y such as M V P P or M O P P appears poor, although there are no large studies which have assessed gonadal function in such patients more than 5 years after the che]notherapy finished. 6. In the male undergoing M V P P or M O P P therapy, sperm storage should bc available before such treatment is initiated. I n the symptomatic female with cytotoxic-indueed ovarian failure, treatment with an oestrogen an d a progesterone preparation should b e offered if there is no specific contra-indication. 7. Long-term follow-up studies are badly needed and as the n u m b e r of courses and frequency of administration of these cytotoxic drug combinations m a y vary between different centres, individual centres will need to obtain their own data on the incidence Of this complication a n d the possibility of recovery in their o w n patients.
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R e c e n t studies h a v e c o n c e n t r a t e d on a d u l t patients t r e a t e d for breast c a n c e r or H o d g k i n ' s disease. S i m i l a r stvdics are r e q u i r e d in patients t r e a t e d fi)r o t h e r m a l i g n a n t a n d n o n - m a l i g n a n t conditions.
References 1. 2. 3. 4. 5. 6.
Arneil, G.C:. (1972) Lancet ii: 12.'59. 13elohorsky, B., Siracky, J . , Sandor, I,. & Klaubcr, E. (1960) Neoplasma 7" 397. Bergh, T., Nillius, S. J. & Wide, I.. (1978) Br..7. Obstet. Gynaecol. 85: 945. Berry, C. L., Cameron, J . S., Ogg, C. S., Trounce, D. Q . & Turner, 1). R. (1972) Lancet ii: 1033, Block, E. (1952) Acta Anat. 14- 108. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, G., De Lena, NI., Tancini, G., Bajetta, E., Musumeci, R. & Veroncsi, U. (1976) .N'. Engl. 07. ~1.led. 294: 405. 7. Bramble, F . J . , Houghton, A. 1,., Eccles, S., O'She~, A. & Jacobs, H. S. (1974) Lancet |i: 311. 8. Buchanan, J. i)., Fairley, K. F. & Barrie, J. kl. (1975) lancet ii-" 156. 9. Calamera, J. C., l~4orgenfield, M. (2., Ma**cini, R. E. & Vilar, O. (1979) Andrologio I 1 - 43. 10. Cameron, J. S. & Ogg, C. S. (1972) lancet i: 1174. 11. Carter, J. N., Tyson, J. E., Tolis, G., Van Vliet, S., Faiman, C. & Frieserl, H. G. (1978) aV. Engl. ,7. Med. 299: 847. 12. Chapmun, R. M., Sutcliffe, S. B. & Malpas, J. S. (1979)07. Am. Afed. Assoc. 242- 1877. 13. C h a p m a n , R. M., Suteliffe, S. B., Rees, 1.. H., Edwards, G. R. W. & Malpas, J. S. (1979) Lancet i- 285. 14. Cheviakoff, S., C a l a m e r a , J. C., Morgenfield, 1~,~. & N,lancini, R. E. (1973).7. Reprod. Fertil. 33: 155. 15. I)a Cunha, M., Meistric.t-.; M. L., Reid, H. L. & Powel[, M. L. (1979) Pioc. Am. Assoc. Cancer Res. 20: ! 00. 16. De Groot, G. %~/., Falman, C. & W i n t e r , J. 19. S. (1974) 07. Pediat~. 84: 123. 17. De Kretser, 1). M., Burger, H. G., Fortune, 1)., Hudson, B., l,ong, A. R., Paulsen, G. A. & Taft, H. P. (1972) .7- Clin. Endocrinol. Metab. 35: 392. 18. l:~tteldorf,.J.N., West, G. D., Pitcock, J . A. & Williams, D. 1.. (1976) 07. Pediatr. 88: 206. 19. Ezdinili, E. Z. & Sttltzman, L. (1965)07. Am. A.Ied. "Assoc. 191:-144. 20. Fairlcy, K. F., Barrie, J. U. & Johnson, W. (1972) Lancet i: .568. 21. Fala.schi, P., ]:rajese, (;.,.l~.occo, A., th~sser, G. M. & Rees, L. H. (1979) l, ancet i: 667. 22. Feng, P. H. (1972)Lancet i: 840. 23. Fisher, IL, Sherman, B. M., Rockette, H., R e d m o n d , C., Margolt~e, R. & Fisher, E. R. (1979) Cancer 44 : 847. 24. Fosdick, W. M., Parsons, 3. L. & Hill, D. F. (1968) Arthritis Rheum. 11: 151. 25. Franchimont, P. (1972).7. Roy. Coll. Phys. (London) 6: 283. 26. Franchimont, P., l)emoulin, A., Hazee-Hagelstein, M. T., Vel~traelen-Proyard, 3. & Bourgignon, 3. P- (1979) Acta Endocrinol. 91, suppl. 225: 469. 27. Fr.eekman, H. A., Fry, H. L., Mendez, F. L. & M a u r e r , E. R. (1964) 07. :Int. Med. Assoc. 189: 23. 28. l'~ri6s, 3. F., Sharp, G. G., MeDevitt, H. O. & 14olman, H. R. (1970) Clin. Res. 18: 134. 29. Gahon, D. A. G., Tilt, M. & Wiltshire, W. (1958) Ann. At.Y. :lead. Sci. 68: 967. 30. Goldenberg, R. L.. Grodin, J. M., Rodbard, D. & Ross G. T . (1973) Am. 07. Ob.~t. GynecoL 116: 1003. 31. Gueary, P., Lenoir, G. & Broyer, M. (1978) 07. Pediatr. 92: 299. 32. Himelstein-Braw, R., Peters, H. & Faber, M. (1978) Br..7. Cancer 38: 82. 33. Hinkes, E. & Plotkin, D. (1973) ,7. Am. A1ed. Assoc. 223: 1490. 34. tiunter, W. 1M., Edmdr,M. P., Watson, G. S. & M c L e a n , N. (1974) 07. Clin. EndocrinoL Metab. 39: 740. 35. Hsu, A. C., Folami, A. O., Bain, J. & Phillips-Rance, G. (1979) Fertil. Steril. 31: 173. 36. Jackson, H., Fox, B. W. & Craig, A. W. (1961) .7- Reprod. Fertil. 2- 447. 37. Jaeox, H. W., (1939) Radiology 32: 538. 38. Johnson, S. A., G o l d m a n , 3. M. & Hawkins, D. F. (1979) Lancet ii: 93. 39. Kirkland, R. T., Bongiovanni, A. M., Cornfield, D., McCormick, J. B., Parks, J . S. & Tenore, A. (1976) `7. Pediatr. 89 : 941. 40. K o y a m a , H., W a d a , T., Nishizawa, Y., lwanaga, T., Aoki, Y., "l'eresawa, T., Kosaki, G., Y a m a m o t n "F. & Wada, A. (1977) Cancer 39: 1403. 4 1 . . K u m a r , R., Biggart, 3- D., McEvoy, 3. & Mcgeown, M. G. (1972) lancet i: 1212. 42. Lee, I. P. & Dixon, R. L. (1972),7. Pharmacol. "Exp. Ther. 181: 219.
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43. i.endon, M., Harm, t. M., Palmer, M. K., Shalet, S. M. & Morris Jones, p. H. (1978) Lancet ii: 439. 44. la.ntz, R. 1)., Bergstein, J., Stelli's, M. W.. Brown, I). R., l'rcm, K., Michael, A. F. & Vernier, R. I,. (1977) ,7. Pediatr. 91: 385. 45. l.illeyman, J. S. (1979) Lancet ii: il25. 46. l.ouis, J., Limarzi, l.. R. & Best. W. (19561 Arch. Intern. Med. 97: 299. 47. Miller, D. (';. (1971),7. Am. Med...h~or. 217: 1662. 48. Miller, J. J.. Williams, G. F. & l,eissring, j. c. (1971) Am..7. Med. 50: 530. 49. Mnrgenfiekt, M. C., (';oldberg, V., Parisivr, tl., Bugnard, S. (:. & Bur, G. E. (1972; Surg. (;ynecol. Obstet. 134: 826. ."~0. Parra, A., Santos. D., Cervantes, C., Sojo, I.. Carraneo, A. & Cortes-Gallegos, V. (1978) 07. Pediatr. 92: 117. 51. Pennisl, A.J., Grushkin, C. M. & l,ieberman, F. (1975) Am. ,7. Dis. Child. 129: 315. 52. Penso, J., l,ippe, B., Ehrlich, R. & Smith F. G. (1974)J. Pediatr. 84: 831. 53. t'hadke, A., Mackinnon, K. & Dossetor, J. (1970) Can. Med. Assoc.,7. 102: 607. 54. Qureshi, M. S. A., Goldsmith, 1I. J., Penningttm, J. H. & Cox, P. E. (1972) Lancet ii: 1290. 55. Rapola, J.. Koskimies, O., 1~luttunen, N. P., Floman, P., Vilska, J. & Hallman, N. (1973) Lancet i: 98. 56. Richter, P.. Calamera, J. C., Morgerlfield, M. C., Kierszenbaum, A. I,., l,avicri, J. C. & Mancini, R. E. (1970) Cancer 25: 1026. 57. Roeser, H. P., Stocks. A. E. & Smith, A.J. (1978) Aust. N . ~ . J . Med. 8: 250. 58. Rose, D. P. & Davie.s, T. E. (1977) lancet i: 1174. 59. R.osen, S. W. & Weintraub, B. 1). (1971)..7. Clin, Endo~vinol. Metab. 32: 410. 60. Samaan, N. A., De Asis, D. N., Buzdar, A. U. & Blumenschein, G. R. (1978) Cancer 41: 2084. 61. Schorer, A. E., ()ken, M. M. & Johnson, G.J. (1978) Cancer Treat. Rep. 62: 574. 62. Shalet, S. M., Beardwell, C. G., Twomey, J. A., Morris Jot~e.~, P. H. & Pearson, D. (1977)07. Pediatr. 90: 920. 63. Shalet, S. M., Harm, I. M., Lendon, M., Morrisjo:~es, P. H. & ,Beardwell, C. G. (1980) Arch. Dis. Child. (in press). 64. Sherins, R.J. & De Vita, V. T. (1973) Ann. Intern. Med. 79: 216. 65. Sherins, R.j., Olweny, C. L. M. & Ziegler, J. L. (1978) J¢. t'.'ngl. 07. Med. 299: 12. 66. Sherman, B. M., Fisher, B., Rockette, H., Redmond, C., Such, E., & West,J. (1978) Clin. Res. 26: 442. 67. Sherman, B. M., Wallace, R. B. & Jochimsen, P. R. (1979) Clin. Endocrinol. 10: 287. 68. Sieber, S. M. & Adamson, R. H. (1975) Adv. Cancer Res. 22: 57. 69. Sieber, S. M., Correa, P., Dalgard, D. W. & Adamson, R. H. (1978) Cancer Res. 38: 2t25. 70. Siris, E. S,, Leventhal, B. G. & Vaitukaitis, J. I.. (1976) N. EngL `7. Med. 294: 1143. 71. Smith, R. H. & Barrett, O. (1967) Calif. Med.`7. 107: 3't7. 72. Sobrinho, I,., I.evine, R. & De Conti, R. (1971) Am. ft. Obstet. G)'necol. 109: 135. 73. Steinberger, A. & Steinberger, E. (1976) Endocrinol. 99: 918. 74. Sutcliffe, S. B., Wrigley, P. F. M., Peto, j., Lister, T. A., Stansfield, A. G., Whitehouse, J. M. A., Crowther, D. & Malpas, J. S. (1978) Br. Med.`7. i: 679. 75. Swanson, H. A. & Du Boulay, G. (1975) Br.,7. Radiol. 48: 366. 76. Uldall, P. R., Kerr, D. N. S. & Taechi, D. (1972) Lancet i: 693. 77. Van Thiel, D. H., Sherins, R.J., Myers, G. H. & De Vita, V. T. (1972),7. Clin. Invest. 5I: 1009. 78. Vilar, O. (1975) In (Mancini, R. E. & Martini, L., eds) Male Fertility and Sterility. New York: Academic Press. 79. Warne, G. L., Fairley, K. F., Hobbs, J. B. & Martin, F. I. R. (1973) At. Engl. ,7. Med. 289: 1159.
Effects o f c a n c e r c h e m o t h e r a p y o n g o n a d a l f u n c t i o n of patients
S. M . S h a l e t
Department of Endocrinology, Christie Hospital and Holt Radium Institute, Manchester, U.K.
Introduction
T h e r e have been an increasing n u m b e r of reports in recent years of go~iadal d a m a g e follgwing cytotoxic drug therapy for the treatment of m a l i g n a n t an d n o n - m a l i g n a n t conditions. In view of the m a r k e d cytotoxicity of most anti-cancer drugs, in particular the alkylating agents, it is not surprising that these drugs exert adverse effects on h u m a n fertility. G o n a d a l d a m a g e has been a t t r i b u t e d to chlorambucil (14, 19, 27, 31, 47, 56), cyclophosphamide (35, 41, 43, 48, 54, 76, 79), b u s u l p h a n (2, 2 9 , 46) (and other alkylating agents), vinblastine (78) a n d cytosine arabinoside (43). W h e n this complication occurs after the use of a c o mb in atio n of cytotoxic drugs, several of which ma3/ d a m a g e the gonad when used as single agents, then it m a y p r o v e impossible to estimate the contribution of any one single d r u g to the collective adverse effect. Procarbazine, a m e t h y l h y d r a z i n e derivative, m a y be taken as an example to'illustrate this point. This drug is k n o w n to be capable of i n d u c i n g complete germinal aplasia in the rat (36, 42) and the n o n - h u m a n primate (69). G e r m i n a l aplasia has also been described in pubertal boys treated for Hodgkin's disease with procarbazine, mustine, vincristine a n d prednisone (65), however, the contribution of the procarbazine to this testicular d a m a g e cannot be accurately estimated although it is likely that mustine a n d procarbazine are the most likely of the 4 drugs to induce such d a m a g e . Thus assessment of the adverse effects of individual cytotoxic drugs on the h u m a n gonad has been m a d e more difficult by the advent of combination c h e m o t h e r a p y . I t should also be r e m e m b e r e d that the specific disease state, w h i c h necessitates the use ofcytotoxic drugs, m a y have a deleterious effect on gonadal function (53). 0305-7372180/030141+ 12 $02.00/0
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S. M. SHALET
C y t o t o x i c - i n d u c e d gonadal d a m a g e in the adult m a l e T h e effects ofcytotoxic drugs on the testis have been studied by testicular biopsy, semen analysis and endocrine assessment of the hypothalamic-pituitary-testicular axis. T h e r e is no doubt that the cytotoxic drugs which damage the testis, predominantly affect the germinal epithelium. Indeed it has been suggested that the aikylating agents and vinblastine do not interfere with Leydig cell fimction (68, 78). Light microscopy of testicular biopsies obtained from patients treated with cyclophosphamide (18) and chlorambucil (56) revealed normal-looking Leydig cells despite germinal aplasia; furthermore tile plasma testosterone levels of patients with cytotoxic-induced azoospermia or germinal aplasia were nearly always within the normal range (31, 77). More recently, however, the concept that the Leydig cell is resistant to cytotoxic-indueed d a m a g e has been challenged. C h a p m a n et al. (13) studied 74 men who had received cyclical combination chemotherapy with M V P P (mustine, vinblastine, procarbazine and prednisolone) for advanced or recurrent Hodgkin's disease. All patients received 6 or more cycles of M V P P and 11 men received additional combination chemotherapy. These men had finished their chemotherapy between 1 and 62 months (median 27 months) earlier. Follicle stimulating hormone (FSH) levels were consistently raised after therapy at all periods of study. Median luteinising h o r m o n e (LH) levels were at, or just above, the upper limit of normal, and median testosterone levels were no,'mal. C h a p m a n et al. (I3) suggested that tile persistent increase in FSH concentrations reflected the d a m a g e d germinal epithelium and the high normal LH concentrations in tile presence of normal testosterone concentrations indicated a degree of Leydig cell damage due to the cytotoxic therapy. Using similar criteria De Kretser et al. (17) have suggested that isolated germinal epithelial damag,, is rare and that Leydig cell function is nearly always impaired as well, irrespective of the testicular pathogenesis. An alternative interpretation of the data of C h a p m a n et al. (13) is that the high normal LH levels reflect damage to the tubular system rather than the Leydig ceil. Thus although it is believed that the elevation in serum FSH level associated with various disorders ofspermatogenesis (7, 17, 25, 34, 59) is due to a decreased negative feedback, at the hypothalamic-pituitary level of inhibin, the postulated FSH-suppressing h o r m o n e produced by the Sertoli cells (73) ; it has been shown that in higher concentrations than those required for FSH-suppression, inhibinlike preparations may affect L H secretion (26). This would mean that the lowered inhibin concentrations associated with tubular damage would result in a marked rise in FSH levels and a much more modest rise in the LH levels. Decreased libido and sexual performance during cflemotherapy was reported by 74% of the males studied by C h a p m a n et al. (13). Impotence only occurred in 8 % although it may be that this symptom was not reported reliably. Impotence associated with a low plasma testosterone level was even less common~ and only occurred in 2 out of 74 men. There is no known method of correcting cytotoxic-induced tubular damage once it has occurred, however the effects of androgen deficiency due to Leydig cell damage may be ameliorated by androgen replacement therapy. Unfortunately it would seem that in the men studied by C h a p m a n et al. (13) the sexual dysfunction was rarely due to androgen deficiency. Therefore, irrespective of whether or not subtle changes in Leydig cell function have occurred, treatment with a n d r o g e n s i s ~ery seldom indicated in these patients. Gynaecomastia has been described as a complication of chemotherapy since it has been associated with the use of busulphan (29), vincristine (71), bischloronitrosourea
CHI-;MOTHERAPY AND GONADAL FUNCTION
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(61) as well as combination c h e m o t h e r a p y (65) with mustine, vincristine, procarbazine a nd prednisone ( M O P P ) . It has been interpreted as a clinical manifestation of Leydig cell dysfunction although tile exact mechanism is unclear. In the study o f S h e r i n s et al. (65) 9 out of 13 pubertal boys developed gynaecomastia after their combination chemotherapy but no prepubertal boy showed this complication after the same treatment. T h e y suggested that the gynaecomastia was an accentuation of the transient breast enlargement observed normally in early puberty but e n h a n c e d by a relative decrease in serum testosterone. T h e r e was no indication that these boys failed to progress normally through puberty a nd therefore hormonal treatment was unnecessary. Most of the d a t a pertaining to single cytotoxic agents have been concerned with the variable effects on fertility of cyclophosphamide an d chlorambucil. Studies (31, 56) have shown t h a t the degree of d a m a g e to the germinal epithelium of adult, p r e p u b e r t a l and pubertal, males is related to the dose of chlorambucil received: the min imal total dose necessary for azoospermia was 400 mg (56). Chlorambucil and presumably other alkylating agents m a y cause qualitative changes in the biochemical nature of h u m a n semen as well as a reduction of the sperm count. C a l a m e r a et al. (9) studied 6 patients treated for i y m p h o m a s with chlorambucii. During treatment, severe oligospermia or azoospermia developed but, in addition, the seminal fructose and citric acid concentrations increased. After w i t h d r a w a l of the drug recovery of the germinal epithelium preceded the return to normal of the seminal fructose an d citric acid concentrations. Tile practical relevance of these observations is u n k n o w n , but w h e n the seminal fruc'tose a nd citric acid concentrations were restored to normal, by treatment with androgens or H C G , this }lad no effect on the azoospermia. Cyclophosphamide-induced testicular d a m a g e is also dose-dependent (43, 54), but it is less cleat" w h e t h e r the degree of d a m a g e is related to the duration of the treatment. Buchanan et al. (8) in a follow-up of 96 male patients, who developed azoospermia within 6 months of starting cyclophosphamide therapy, showed that, in 12 patients, spermatogenesis r e t u r n e d within 15-49 months after stopping the drug. T h e r e t u r n of spermatogenesis was not significantly related to the d u r a t i o n of therapy, total dose or length of follow-up after stopping treatment. H o w e v e r the n u m b e r of patients studied was small. Lendon et al. (43) did find a significant i m p r o v e m e n t in testicular tubular morphology with increasing time after complet!on of c o m b i n a t i o n c h e m o t h e r a p y for acute lymphatic leukaemia in childhood. However, there were obvious differences in the cytotoxic d r u g t r e a t m e nt and the ages of tile patients studied by these 9 groups. Thus difficulty in separating tile contribution of t}ie duration of treatment from the total dose of the d r u g receivdd, studies performed with small numbers, follow-up of patients invariably less than 4-5 years after therapy ceased an d the advent of c o m b i n a t i o n c h e m o t h e r a p y have all obscured the definition of the precise factors which d eterm i n e w h e t h e r d a m a g e d germinal epithelium is capable o f r e c o v e r y or not. It might be th o u g h t that such data could be more easily derived from animal experiments using single cytotoxic drugs r a t h e r than a combination but species variation m a y be. an i m p o r t a n t variable (15). In a small study of 16 patients who had completed their combination c h e m o t h e r a p y for d i s s e m i n a t e d / l y m p h o m a , Roeser a al. (57) suggested that serial measurements of the serum F S H level were useful in predicting likely recovery of spermatogenesis. However, they provided no evidence to suggest that tile previously elevated F S H level declined before the sperm count returned to normal, therefore there would a p p e a r to be no a d v a n t a g e in m e a s ur i ng the serum F S H level r a t h e r than the sperm count after
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s t o p p i n g c h e n m t h e r a p y . C h a p m a n et al. (13"., stated that t h e y c o u l d not s u b s t a n t i a t e this f i n d i n g o f a decline in the s e r u m F S H level, w h i c h is har.dl.v very surprising as so few of their patients r e g a i n e d s p e r m a t o g e n e s i s (4 out o f 64~. T h e r e p o r t s of recover)' 0f" s p e r m a t o g e n e s i s in m a n y ot" the p a t i e n t s p r e v i o u s l y t r e a t e d w i t h single cvtotoxie a g e n t s (8', or a c o m b i n a t i c m of 2 or 3 d r u g s (57~ is e n c o u r a g i n g b u t the o u t l o o k for thc H o d g k i n ' s p a t i e n t s t r e a t e d w i t h M V P P (13~ or M O P P (57) a p p e a r s poor. C e r t a i n l y tbr u p to 4 years after t h e cessaxion of such t h e r a p y tot H o d g k i n ' s disease a z o o s p e r m i a is a n e x t r e m e l y c o m m o n c o n s e q u e n c e . It is not k n o w n i!" the a z o o s p e r m i a is irreversible; Sherins a n d l)e Vita (64:, described 2 p a t i e n t s w h o received M O P P t h e r a p y for H o d g k i n ' s disease a n d wire s h o w e d n o r m a l s p e r m a t o g e n e s i s 4 a n d 7 years af~er the e n d of t r e a t m e n t , h o w e v e r , the m a j o r i t y o f such p a t i e n t s have not been followed for longer t h a n 5 years p o s t - t r e a t m e n t . L o n g - t e r m studies are badly n e e d e d a n d as t h e n u m b e r a n d f r e q u e n c y o f a d m i n i s t r a t i o n of'courses of M V P P or M O t ' P m a y v a r y b e t w e e n R e g i o n a l O n e o l o g i c a l centres, i n d i v i d u a l centres will need. l,'J o b t a i n their o w n d a t a o n testicular f u n c t i o n after such t r e a t m e n t . I n t h e m e a n t i m e , it iew of the g u a r a n t e e d inli:rtility, d u r i n g t r e a t m e n t (13, 57~. the tow f r e q u e n c y a n d u n p r e d i c t a b i l i t y of recover), of s p e r m a t o g e n e s i s after t r e a t m e n t , s p e r m s t o r a g e s h o u l d be available for m a l e p a t i e n t s u n d e r g o i n g MX,'PP or M ( ) P t ' t h e r a p y , since m a n y of" these p a t i e n t s m a y enjoy p r o l o n g e d survival, U n t i l 1979 there h a d been no r e p o r t in the l i t e r a t u r e o f s e r u m p r o l a c t i n e s t i m a t i o n s in p a t i e n t s with c y t o t o x i e - i n d u c e d g o n a d a l failure. C h a p m a n et al. (13) then m a d e the interesting o b s e r v a t i o n that 18 o f tht:ir 74 m e n treated w i t h M V P P t h e r a p y tbr H o d g k i n ' s disease h a d u n e x p l a i n e d h y p e r p r o l a c t i n a e m i a . H y p e r p r o l a c t i n a e m i a is a recognised cause of m a l e h y p o g o n a d i s m b u t this is usually m a n i f e s t e d by i m p o t e n c e arid d e c r e a s e d libido; s p e r m a t o g e n e s i s m a y be i n f l u e n c e d bv raised p r o l a c t i n levels, but a z o o s p e r m i a is a most u n l i k e l y c o n s e q u e n c e ( t 1, 21 ). T h u s the consistent a z o o s p e r m i a d u r i n g M V P P t h e r a p y in the m e n s t u d i e d by C h a p m a n el al. ( 1 3 ) must be d u e to the direct effect o f t h e cytotoxic d r u g s on the g e r m i n a l e p i t h e l i u m . It is also u n l i k e l y t h a t the u n e x p l a i n e d h y p e r p r o l a c t i n a e m i a was significantly a l t e r i n g sexual activity as only 6 m e n were imp o t e n t f o l l o w i n g cessation o f c h e m o t h e r a p y a n d in 3 o f these the s y m p t o m a n t e d a t e d their illness. T h e cause o f t h e m o d e r a t e l y raised p r o l a e t i n levels in these m e n is u n k n o w n a n d f u r t h e r studies ark n e e d e d to c o n f i r m this g'roup's findings.
Cytotoxic-induced t e s t i c u l a r d a m a g e in the pre-pubertal and pubertal m a l e Despite i n c r e a s i n g e v i d e n c e of c y t o t o x i c - i n d u c e d g o n a d a l d a m a g e in the a d u l t , r e p o r t s c o n c e r n i n g the effects o f ey~moxic d r u g s on t h e g o n a d a l f u n c t i o n o f c h i l d r e n a r e s c a n t y a n d controversial. I n 1972 Berry et al. (4) r e p o r t e d n o r m a l testicular histologs, in a 6year-old boy vcho h a d received a total o f 7790 m g o f c y c l o p h o s p h a m i d e i n t e r m i t t e n t l y over 180 days. A little later Arneil (1) o b s e r v e d n o r m a l testicular histology in 7 prep u b e r t a l boys w h o r e c e i v e d c y c l o p h o s p h a m i d e for m a l i g n a n t disease. T h e d o s a g e level varied from 3 to 24 rng/d a n d d u r a t i o n o f t h e r a p y from less t h a n 50 to 400 d. R a p o l a et al. (55) s t u d i e d 4 m a l e s w h o h a d r e c e i v e d c y c l o p h o s p h a m i d e d u r i n g p u b e r t y / o r k i d n e y disease. T h e 2 p a t i e n t s w h o w e r e m o r e a d v a n c e d in p u b e r t a l m a t u r a t i o n w h e n they received c y c l o p h o s p h a m i d e s u b s e q u e n t l y s h o w e d n o r m a l tcsticular histology whilst t h e 2 patients, r e p o r t e d to be " b i o l o g i c a l l y y o u n g e r " w h e n t r e a t e d , s h o w e d c o m p l e t e a b s e n c e of s p e r m a t o g e n e s i s on biopsy. T h e s e a u t h o r s (55) w e n t o n to s p e c u l a t e t h a t t h e v u l n e r a b i l i t y of t h e g e r m i n a l e p i t h e l i u m to c y t o t o x i c - i n d u c e d d a m a g e v a r i e d w i t h t h e d e g r e e o f p u b e r t a l m a t u r a t i o n . H o w e v e r , the total dose o f c y c l o p h o s p h a m i d e r e c e i v e d
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was h i g h e r in the a s p e r m a t o g e n i c patients t h a n in the 2 with n o r m a l s p e r m a t o g e n e s i s a n d the n u m b e r of patients studied was very small. T h e c o n c e p t of v a r i a b i l i t y o f sensitivity of the testis to cytotoxic d a m a g e was g r a d u a l l y e x t e n d e d to i n c o r p o r a t e the view that the p r e - p u b e r t a l testis was relatively insensitive to such an insult. T h e earlier histological reports ( 1 . 4 ) were reinforced by h o r m o n a l studies (16, 39. 50.51 ) w h i c h s h o w e d no a b n o r m a l i t i e s in s e r u m FSH, L H a n d testosterone c o n c e n t r a t i o n s in p r e p u b e r t a l boys who, h a d received c y c l o p h o s p h a m i d e s o m e years earlier. Similarly Sherins et aZ. (65j found g e r m i n a l aplasia a n d very high s e r u m F S H levels ill boys w h o h a d received M O P P t h e r a p y for H o d g k i n ' s disease w h e n p u b e r t a l : they also - t u d i e d 6 boys w h o received the s a m e t r e a t m e n t but w h o w e r e p r e - p u b e r t a l w h e n the 5- received their c h e m o t h e r a p y a n d at the time of study. S e r u m F S H , L H a n d testosterone c o n c e n t r a t i o n s were a p p r o p r i a t e for their age in these 6. A m o r e recent r e p o r t by L e n d o n et aL (43) has m a d e it quite clear that the p r e - p u b e r t a l testis m a y be d a m a g e d by cytotoxic d r u g s . T h e y studied t e s t i c u l a r histology in 44 boys treated with c o m b i n a t i o n c h e m o t h e r a p y for a c u t e l y m p h a t i c leukaemia. Nearly all o f their patients h a d received their c h e m o t h e r a p y w h e n p r e - p u b e r t a l a n d the m e a n t u b u l a r fertility index ( p e r c e n t a g c o f seminiferous tubules c o n t a i n i n g identifiable s p e r m a t o g o n i a ) was 50°/i~ o f that in a g e - m a t c h e d controls. E i g h t e e n o f the testicular biopsies h a d a severely depressed t u b u l a r fertility index of 4 0 % or less. T h e c o n c l u s i o n from this histological s t u d y (43) has been reinforced by t h e studies o f p o s t - p u b e r t a l patients with a b n o r m a l i t i e s o f g o n a d o t r o p h i n secretion a n d a m a r k e d r e d u c t i o n in their s p e r m counts tbllowing the a d m i n i s t r a t i o n of c y c l o p h o s p h a m i d e (44, 52) a n d c h l o r a m b u c i l (31) d u r i n g p r e - p u b e r t a l life. S o m e o f the confusion in t h e l i t e r a t u r e c o n c e r n i n g the v u l n e r a b i l i t y o f the p r e - p u b e r t a l testis to cytotoxic d a m a g e has arisen because of the reliance on h o r m o n a l tests of testicular f u n c t i o n to define w h e t h e r such d a m a g e has occurred. Shalet et al. (63) have n o w s h o w n in an e n d o c r i n e s t u d y of t h e 44 boys whose testicular histologies w e r e earlier r e p o r t e d by L e n d o n et al. (43), that m o d e r a t e l y severe d a m a g e to t h e t u b u l a r system o f the testis unassociated with L e y d i g cell i m p a i r m e n t m a y not be d e t e c t e d in the p r e - p u b e r t a l boy using c u r r e n t tests ot" testieular function. It is this co-existence of a b n o r m a l m o r p h o l o g y a n d n o r m a l testicular tianction test-s, w h i c h has c o n t r i b u t e d to the c o n c e p t t h a t the p r e - p u b e r t a l testis m a y be less susceptible to eytotoxic d a m a g e t h a n the p u b e r t a l testis; this c o n c e p t r e m a i n s to be p r o v e n . A t t e m p t s have been m a d e to define the dose o f c h l o r a m b u c i l (31) or c y c l o p h o s p h a m i d e (44) r e q u i r e d in a boy to cause testicular d a m a g e b u t these h a v e been t h w a r t e d by the lack of an a d e q u a t e dosage range, small n u m b e r s a n d the v a r i a t i o n in the p u b e r t a l status of the patients studied. T h e i m p r o v e d prognosis o f c h i l d r e n t r e a t e d for a c u t e l y m p h a t i c l e u k a e m i a a n d H o d g k i n ' s disease has m e a n t that i n c r e a s i n g a t t e n t i o n m u s t be paid to the q u a l i t y o f life a t t a i n e d by t h e survivors. L o n g t e r m follow-up o f s u c h patients is m a n d a t o r y so that it can bc established w h e t h e r or not the c y t o t o x i c - i n d u c e d d a m a g e to the g e r m i n a l e p i t h e l i u m sustained by such a high p r o p o r t i o n of these patients, proves reversible or not. At t h e present time only single-case reports (33, 45) exist a n d t h e r e f o r e firm advice c o n c e r n i n g f u t u r e fertility c a n n o t be given to these y o u n g males or their parents. P
Cytotoxic-induced gonadal d a m a g e in the adult feznale T h e clinical m a n i f e s t a t i o n s o f c y t o t o x i c - i n d u c e d g o n a d a l d a m a g e in t h e female i n c l u d e a m e n o r r h o e a or o l i g o m e n o r r h o e a a n d m e n o p a u s a l s y m p t o m s such as flushing a n d d y s p a r e u n i a . As in the male, the early studies r e p o r t e d g o n a d a l failure after single
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cytotoxic d r u g t h e r a p y with one o f the fi)llowi~lg 3 a l k y l a l i n g a g c n t s - - c h l o r a m b u c i l (19, 27), b u s u l p h a n (2, 2(.), 4(3) a n d c y c l o p h o s p h a m i d c (10, 22., 24, 21~, 41, 48, 76, 79, 20). Most i n t o r m a t i o n is a v a i l a b l e oil t h e effects o f c y c l o p h o s p h a m i d e on female r e p r o d u c t i v c f u n c t i o n . Uldall e t a / . (76) s t u d i e d 34 w o m e n with g i o m c r u l o n e p h r i t i s t r e a t e d with d a i l y c y c l o p h o s p h a n f i d e lor an a v e r a g e of 18 n l o n t h s . E i g h t e e n w()mcn d e v e l o p e d a m e n o r r h o e a a n d on a v e r a g e this c o m p l i c a t i o n o c c u r r e d w i t h i n 7 m o n t h s o f s t a r t i n g cycle)p h o s p h a m i d e . T h e periods olfly r e t u r n e d in 1 o u t o f the 9 p a t i e n t s w h o d i s c o n t i n u e d the d r u g an average, o f 12 m o n t h s previously. U r i n a r y ocstrogcns were low a n d u r i n a r y g o n a d o t r o p h i n s elevated suggesting t h a t the a m e n o r r h o e a was d u e to c y c l o p h o s p h a m i d e i n d u c e d d a m a g e at a n o v a r i a n r a t h e r t h a n h y p o t h a l a n f i c - p i t u i t a r y level. W a r n e e/ al. (79) s t u d i e d the o v a r i a n m o r p h o l o g y in 6 w o m e n w h o h a d received c y c l o p h o s p h a r n i d e for g l o m e r u l o n c p h r i t i s o r r h e u m a t o i d arthritis. N o n e s h o w e d e v i d e n c e o f follicular m a t u r a t i o n a n d ova were only seen in 2. T h e s e ova were a b n o r m a l in a p p e a r a n c e a n d n o n e gave. e v i d e n c e o f d e v e l o p m e n t into p r i m o r d i a l follicles. T h e s e a u t h o r s (79) s u g g e s t e d tha~ c y c l o p h o s p h a n f i d e p r e v e n t e d the swelling or prolili:ration of thecal cells to form tbllicle:~ a n d in g r e a t e r c u m u l a t i v e doses or over l o n g e r periods, c y c i o p h o s p h a m i d e m a y also acl directly on the ovary to d e p l e t e the n u m b e r of ova. F r e c k m a n et al. (27) d e s c r i b e d similar histological c h a n g e s in the ovaries o f w o m e n w h o h a d received e h l o r a m b u c i l tbr breast c a r c i n o m a . In the studies o f U l d a l l et al. (76) a n d W a r n e et al. (79) r e c o v e r y o f o v a r i a n f u n c t i o n after cessation o f c y c l o p h o s p h a m i d e was rare, h o w e v e r , K u m a r et al. (41) r e p o r t e d 6 o u t o f 8 w o m e n to h a v e h a d a r e t u r n o f m e n s t r u a l f u n c t i o n after cyclop h o s p h a m i d e - i n d u c e d o v a r i a n ' f a i l u r e . T h e w o m e n h a d been t r e a t e d |or less t h a n 9 m o n t h s w h i c h m a y explain the l a r g e r n u m b e r o f reversible cases. H o w e v e r a h h o u g h wc c a n bc c e r t a i n t h a t the m e a n d u r a t i o n o f c h e m o t h e r a p y was less in the s t u d y o f K u m a r et al. (41) thz'.n t h e o t h e r 2 studies (76, 79), it is m o r e difficult to k n o w if the total dose o f c y c l o p h o s p h a m i d c received by t h e p a t i e n t s was significantly diflerent in the 3 studies, as is likely; n e i t h e r K u m a r et al. (41) n o r U l d a l l et al. (76) m e n t i o n the total dose o f the d r u g received by their patients. N o n e t h e l e s s it is very likely that the total dose of cyclop h o s p h a m i d e received is an i m p o r t a n t d e t e r m i n a n t o f the reversibility of this c o m p l i c a t i o n : Belohorsky et al. (2) ~nacle t h e a d d i t i o n a l o b s e r v a t i o n t h a t the dose Of the d r u g , i.e. b u s u l p h a n , received by their l e u k a e m i c p a t i e n ts, d e t e r m i n e d h o w soon after initiation o f t r e a t m e n t the a m e n o r r h o e a d e v e l o p e d . T h e difficulties in establishing w h e t h e r the d u r a t i o n o f c h e m o t h e r a p y is a n i m p o r t a n t factor in the reversibility of g o n a d a l d a m a g e in the malt- exist just as s t r o n g l y in the t~male. O n t h r o t h e r h a n d a g e - r e l a t e d susceptibility to such d a m a g e in the a d u h female is an established v a r i a b l e . T h u s a h h o u g h t h e d u r a t i o n of t r e a t m e n t is likely to be i m p o r t a n t , proof" is lacking. J a c o x (37) in a stud), of" the efl~cCs o f e x t e r n a l i r r a d i a t i o n on o v a r m n f u n c t i o n , stated that after a single dose of 500 r a d s to t h e ovaries, 6 to 8 m o n t h s o f a m e n o r r h o e a c o u l d be e x p e c t e d in y o u n g w o m e n , a n d p e r m a n e n t sterility in the m a j o r i t y o f w o m e n o v e r the age o f 40. I n c o n t r a s t W a r n e et al. (79) f o u n d n o a g e - r e l a t e d susceptibility in their p a t i e n t s with c y c l o p h o s p h a m i d e - i n d u c e d o v a r i a n failure. T h i s is c u r i o u s in ~,iew o f t h e studies (40, 58, 66), t h a t w e r e s u b s e q u e n t l y to a p p e a r , r e p o r t i n g t h a t there was a n a g e - r e l a t e d susceptibility to c y t o t o x i c - i n d u c e d o v a r i a n failure. W a r n e et at. (79) o n l y s t u d i e d a small n u m b e r o f w o m e n over t h e age o f 35 years a n d t h e y c o m m e n t e d in their article that a m c n o r r h o e a d e v e l o p e d in the first 4 m o n t h s o f t r e a t m e n t in 4 patients, 35 years o f age or older. T h e latter is a p o i n t f u r t h e r e x a m i n e d by K o y a m a et al. (4.0) w h o s t u d i e d w o m e n w i t h breast c a r c i n o m a t r e a t e d w i t h d i f f e r e n t c y t o t o x i c d r u g s i n c l u d i n g cyclo-
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p h o s p h a m i d e . T h e a v e r a g e dose' o f e y c l o p h o s p h a m i d e given betbre the onset o f a m e n o r r h o e a in p a t i e n t s in their 40s, 30s a n d 20s was 5.2 g, 9.3 a n d 20.4 g respectively. S h e r m a n et al. (66) r e i n | b r e e d this v i e w in their s t u d y o f breast c a n c e r p a t i e n t s in an a d j u v a n t trial w h o received m c l p h a l a n a n d 5-fluorouracil, Sixty-four p e r cent of" w o m e n , 40 years o r over, d e v e l o p e d i r r e g u l a r m e n s e s or a m e n o r r h o c a . By c o n t r a s t only 12 °A~o f those w o m e n 39 years a n d y o u n g e r r e p o r t e d a c h a n g e in m e n s t r u a l p a t t e r n . It c o u l d h a v e b e e n pred i c t e d that a g e - r e l a t e d susceptibility was likely to be an i m p o r t a n t v a r i a b l e as it has b e e n well k n o w n lor m a n y years that the n u m b e r o f o o c y t e s decreases steadily with i n c r e a s i n g age (5), t h e r e l o r e o v a r i a n f i m c t i o n in o l d e r w o m e n , w h o h a v e fewer r e m a i n i n g oocytes, is mort: v u l n e r a b l e to the efl~.cts o f b o t h e x t e r n a l i r r a d i a t i o n a n d c h e m o t h e r a p y . I nitial studies o f l b m a l e p a t i e n t s , w h o h a d d e v e l o p e d a m e n o r r h o e a or o l i g o m e n o r r h o e a d u r i n g t r e a t m e n t w i t h a l k y l a t i n g a g e n t s , were based on c h a n g e s in t h e u r i n a r y o e s t r o g e n a n d total g o n a d o t r o p h i n levels (76, 79) a n d histological e x a m i n a t i o n o f o v a r i a n biopsies (27. 79). T h e typical h o r m o n a l findings in p a t i e n t s w i t n c y t o t o x i c - i n ~ u c e d o v a r i a n d a m a g e were e l e v a t e d u r i n a r y g o n a d o t r o p h i n levels a n d low u r i n a r y o e s t r o g e n levels. Not surprisingly, in m o r e r e c e n t p u b l i c a t i o n s (58, 60) e l e v a t e d s e r u m F S H a n d L H levels a n d low s e r u m oestradiol levels h a v e been t b u n d in f e m a l e breast c a n c e r p a t i e n t s w h o d e v e l o p e d o v a r i a n failure following e i t h e r c y c l o p h o s p h a m i d c or m e l p h a l a n as p a r t o f their a d j u v a n t c h e m o t h e r a p y . If p r i m a r y o v a r i a n d a m a g e is s u s p e c t e d then tile single most i m p o r t a n t h o r m o n e e s t i m a t i o n is the s e r u m F S H c o n c e n t r a t i o n (3, 30). T h e o b s e r v a t i o n t h a t a m c n o r r h o e a o c c u r r e d in s o m e w o m e n w h o h a d n o r m a l m e n s e s at t h e start o f t h e t h e r a p y (40, 58), has led to a suggestion t h a t the p r o l o n g e d disease-free interval observed in breast c a n c e r p a t i e n t s giver, a d j u v a n t t h e r a p y m i g h t be a t t r i b u t a b l e to t r e a t m e n t - i n d u c e d a l t e r a t i o n in e n d o c r i n e f u n c t i o n . T o test this hypothesis F i s h e r el at. (23) s t u d i e d the r e l a t i o n s h i p b e t w e e n disease-free survival a n d d e p r e s s i o n o f o v a r i a n f u n c t i o n in p r o - m e n o p a u s a l p a t i e n t s with p r i m a r y breast c a n c e r w h o received a d j u v a n t c h e m o t h e r a p y w i t h m e l p h a l a n a l o n e o r in a d d i t i o n to 5 - f l u o r o u r a c i l . T h e result i n d i c a t e d t h a t Iooth the y o u n g e r p a t i e n t s (~< 39 years) a n d the o l d e r p a t i e n t s ( 4 0 - 4 9 years) w i t h positive axillary n o d e s w h o r e c e i v e d p r o l o n g e d m e l p h a l a n t r e a t m e n t as a n a d j u v a n t to m a s t e c t o m y c o n t i n u e d to d e m o n s t r a t e a significantly g r e a t e r disease-free survival t h a n d i d p a t i e n t s w h o received p l a c e b o . T h o s e in the y o u n g e r a g e g r o u p s h o w e d a g r e a t e r i m p r o v e m e n t ill disease-fi'ee survival at 4 years relative to their c o n t r o l s t h a n d i d those in t h e o l d e r a g e g r o u p . In c o n t r a s t to t h e findings relative to disease-free survival, o v a r i a n f u n c t i o n was m o s t affected in t h e o l d e r a g e g r o u p . T h e r e f o r e it w o u l d a p p e a r t h a t w h i l e suppression o f o v a r i a n f u n c t i o n m a y a c c o u n t for s o m e o f t h e a d j u v a n t c h e m o t h e r a p e u t i c effect in p r e - m e n o p a u s a l w o m e n , o t h e r factors w e r e also responsible. S h e r m a n et al. (67) looked m o r e closely at the h o r m o n a l features o f the m e n s t r u a l cycle in t h e prem ~ n o p a u s a l breast c a n c e r p a t i e n t s , w h o m a ; . n t a i n e d r e g u l a r menses, h a v i n g r e c e i v e d t h e s a m e a d j u v a n t c h e m o t h e r a p y as in the s t u d y o f F i s h e r et al. (23). I n this w a y t h e y h o p e d to d e t e c t subtle h o r m o n a l c h a n g e s w h i c h m i g h t reflect failure to o v u l a t e or a defect in t h e follicular or luteal p h a s e o f t h e cycle. T h e h o r m o n a l c h a r a c t e r i s t i c s w e r e c o m p l e t e l y n o r m a l after 3 to 14- courses o f c h e m o t h e r a p y so t h a t n o t o n l y w e r e t h e m e n s t r u a l cycles r e g u l a r , t h e y were also o v u l a t o r y . A p u z z l i n g o b s e r v a t i o n , w h i c h h a s n o t yet b e e n e x p l a i n e d , c o n c e r n s t h e re-establishm e n t o f m e n s e s in 2 4 % o f t h e p r e - m e n o p a u s a l p a t i e n t s w h o d e v e l o p e d a m e n o r r J a o e a d u e to their c y t o t o x i c t h e r a p y (6). T h e s e w e r e p a t i e n t s t r e a t e d for b r e a s t c a n c e r w i t h cyclop h o s p h a m i d e , m e t h o t r e x a t e a n d 5-fluorouracil a n d t h e p e r i o d s in this g r o u p o f p a t i e n t s returned despite continued chemotherapy.
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Apart from breast cancer, the other majo r malignancy in which the abnormalities of reproductive function following c h e m o t h e r a p y have been studied, is Hodgkin's disease. Sobrinho et at. (72) studied l0 t-Iodgkin's disease patients'who developed amenorrhoe'a or oligomenorrhoea shortly after c h e m o t h e r a p y was started. A variety of d r u g combinations were used and every patie,:t received at least one alkylating agent but no more than 4 patients received the same d r u g combination. Menstruation returned in only 1 patient 2 months after the end of a 14 m o n t h course of vinblastine an d another patient b e c a m e pregnant d u r i n g treatment with m e c h l o r e t h a m i n e and chlorambucil a n d underwent a therapeutic abortion. A not h er small group of 13 patients with Hodgkin's disease were studie8 by Morgenfield et al. (49). These patients were treated with ch lo ramb uci l , vinblastine and a m e t h y l h y d r a z i n e derivative, some also received cyclophosphamide. T h e women were divided into 2 groups; those who developed a m e n o r r h o e a and those who did not. T h e latter group received markedly lower doses of the drugs. T h e first large study was reported by C h a p m a n et al. (12) w h o studied'~'epr~.luctive function in 41 w o m e n with a d v a n c e d Hodgkin's disease. All except 1 had received standard M V P P c h e m o t h e r a p y (74) an d 21 had additional M V P P as m a i n t e n a n c e therapy or other drugs if the disease relapsed after M V P P . At the beginning of the study, 7 w o m e n were still receiving c h e m o t h e r a p y and 34 had finished their treatment. T h e patients were observed over a 16-month period, at the end of which, the age rarrge was 20-51 years (median 30 years), and the group had been off c h e m o t h e r a p y from 10-78 m o n t h s (median 36 months). At the end of the study 12t~ had regular ovulatory menstrual cycles, 2 6 % ha d oligomenorrhoea and 62 g~, had complete a m e n o r r h o e a with biochemical evidence of p r i m a r y ovarian failure. It was interesting to note that over the 16 months of the study ovarian function deteriorated rather than improved. D u r i n g this time the menstrual pattern in 6 w o m e n ch an g ed from oligomenorrhoea to a m e n o r r h o e a . This deterioration in ovarian function, after c h e m o t h e r a p y has been completed, contrasts sharply with the earlier observation of B o n n a d o n n a et al. (6) that the menstrual cycle was re-established in 2 4 % of pre-menopausal breast cancer patients despite continued c he mot he ra py. O v a r i a n biopsies were obtained from 6 patients of C h a p m a n et al- ( 1 2 ) and there was a reduction in the primordial follicles in all cases. Where such a gross depletion of primordial follicles occurs, recovery ofovarian function would be unexpected but if the major manifestation of the cytotoxic-induced ovarian d a m a g e is impaired follicular m a t u r a t i o n then restoration of ovarian function is more likely. I n sharp contrast to the 24% incidence of unexplained hyperprolactinaemia in m e n with Hodgkin's disease, C h a p m a n et al. (12) only tbund 1 such case in the female study. This group (12, 13) further suggested that 3 of the 74 males and 3 of the 41 females had a prolactin-secreting pituitary m i c r o a d e n o m a . This view is based on a radiological rather than a tissue diagnosis; such radiology is notoriously difficult to interpret (75) and, if true, would suggest a relationship between Hodgkin's disease or its treatmen t an d prolactin-secreting pituitary tumours. M a n y of the females treated for Hodgkin's disease (12) lost interest in sexual interco~rse; libido diminished progressively d u r i n g therapy a n d this appeared to correlate well with the progressive loss of ovarian function. At the end of the study 4 6 % of the wome n reported no sexual activity an d menopausal symptoms such as flushing and dyspareunia were common. Separation a n d divorce were m u c h more frequent in these women than in the general population a n d C h a p m a n et al. (12) suggested that the u n d e r lying cause for this disruption in their personal relationships was the cytotoxic-induced ovarian failure, however, proof was lacking. T h erap eu tically there can be no d o u b t that
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patients distressed by the menopausal symptoms associated with ovarian failure w~Ii benefit from cyclical oestrogen and progesterone therapy. It is not yet clear how long such patients S'hould be treated or whether all patients with biochemical evidence of ovarian failure should receive steroid replacement therapy. Occasional pregnancies have been described in women (12, 38) with previous evidence of impaired ovarian function following chemotherapy for Hodgkin's disease. T h e suggestion (38) that hormonal therapy may help such women to conceive is unsubstantiated, similarly there is no evidence to indicate that hormone manipulation during chemotherapy may protect ovarian function.
C y t o t o x i c - i n d u e e d ovarian failure in the p r e - p u b e r t a l a n d pubertal female There have been relatively few studies on the effects o f cytotoxic drugs on gonadal function in the pre-pubertal and pubertal female. Tile reports of Pcnnisi et al. (51), Etteldorf et al. (18) and Lentz et al. (44) found no evidence of menstrual dysfunction in women, who had received cyclophosphamide for renal disease during childhood. Each of these 3 reports described successful pregnancies amongst their patients. Less encouraging was the morphological study of Miller et al. (48) in which the autopsy findings in a 13-year-old girl, who had received cyclosphosphamide for 29 months, revealed ovaries totally lacking in follicles. Siris et al. (70) examined the'effects of childhood leukaemia and chemotherapy on puberty and reproductive function in 35 girls and women. Twenty-eight patients had normal pubertal maturation during a median time of 74 months after diagnosis of Ieukaemia and 49 months of chemotherapy. Seven patients were abnormal, 4 exhibited hypothalamic-pituitary dysfunction and 3 had evidence of primary ovarian dysfunction. None of these 3 latter patients had received cyclophosphamide and intereslingly only 9 out of the 35 females had received this drug. T h e main drugs used were vincristine, methotrexate, 6-mercaptopurine and steroids although 1 of the 3 girls with primary ovarian dysfunction had also received busulphan. Shalet et al. (62) found definite biochemical evidence of ovarian failure in 2 out of 7 pre-pubertal girls who had received combination chemotherapy for acute lymphatic leukaemia. A further 5 pre-pubertal girls were studied by Shalet (unpublished data) and 1 had a very high FSH concentration consistent with primary ovarian damage. These 3 girls with biochemical evidence of ovarian failure had all received cyclophosphamide and some 3 Years after that study still show abnormalities of FSH secretion. O n e girl is still pre-pubertal, one has completed her pubertal maturation quite normally but still has oligomenorrhoea some 2 years after menarche and the third is now aged 14½, has progressed through puberty but has not yet had a period. Clearly longer follow-up is necessary to assess the clinical significance of the impaired ovarian function. In the pre-pubertal and pubertal female there are insufficient data to c o m m e n t on the relationship between cytotoxic-induced ovarian d a m a g e and the total drug dosage, duration of treatment and potential reversibility of such d a m a g e after treatment has finished. T h e morphological evidence that such gonadal damage occurs is, however, just as convincing in the female as in the male. HimelsteinBraw et al. (32) studied the ovaries of 31 leukaemic girls obtained at autopsy. Follicle development was inhibited in nearly all. In the ovaries in which follicle development
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occurred, the n u m b e r and size of antral follicles was reduced compared to the controls. All girls had been treated with cytotoxic drugs. T h e ovaries of those girls treated for less than 1 week were normal, whereas all ovaries from girls treated for more than 2 months showed inhibition oftbllicle growth. This suggested that it was the treatment and not the disease that had inhibited follicle development. Prolonged treatment (1-2 years) caused a reduction in the n u m b e r ofsmall non-growing follicles in 2 cases. T h e impaired follicular m a t u r a t i o n in such patients may prove reversible but ira serious depletion of primordial follicles has occurred tbllowing exposure to cytotoxic drugs in.childhood then a prcmature menopause may be a long-term sequel. It is quite likely that the age-related susceptil3illty to cytotoxic-induced ovarian thilure in the a du l t female may bc extended to the pre-pubertal female, however, other irnportant variables such as drug metabolism and clearance may also depend on the age and pubertal status of the subject.
Conclusions 1. Tile ma j or group of drugs responsible tbr cytotoxm-induced gonadal d a m a g e are the alkylating agents such as cyclophosphamide, busulphan, chiorambucil and melphalan. O t h e r drugs such as vinblastine an d cytosine arabinoside have also been incriminated. 2. With the advent of combination c h e m o t h e r a p y it has become increasingly difficult to estimate the precise thctors w h ich determine the degree of cytotoxic-induced gonadal d a m a g e or the capability of recovery from such damage. Gonadal damage is certainly dependent on the total dose of the d r u g received but there is no conclusive evidence that the duration of c h e m o t h e r a p y is an important variable. Age-related susceptibility is another d e t e r m i n a n t of cytotoxic-induced gonadal d a m a g e in the a dul t female but not in the adult male. 3. T h e pre-pubertal and pubertal gonad may be d amag ed by cytotoxie c h e m o t h e r a p y but the concept that the pre-pubertal testis is less susceptible to such d a m a g e than the pubertal testis remains unproven. 4. In the male the cytotoxic drugs capable of d a m a g i n g the testis, primarily affect the germinal epithelium. However, there is increasing evidence that Leydig cell function ma y not be as resistant to cytotoxic-induced d a m a g e as previously believed. 5. Recovery of gonadal function after cytotoxic-induced d a m a g e is well recognised following treatment with single alkylating agents. It is likely that the duration of time after cessation of c h e m o t h e r a p y is an important d e t e r m i n a n t of such recovery. However, the outlook for patients treated with combination c h e m o t h e r a p y such as M V P P or M O P P appears poor, although there are no large studies which have assessed gonadal function in such patients more than 5 years after the che]notherapy finished. 6. In the male undergoing M V P P or M O P P therapy, sperm storage should bc available before such treatment is initiated. I n the symptomatic female with cytotoxic-indueed ovarian failure, treatment with an oestrogen an d a progesterone preparation should b e offered if there is no specific contra-indication. 7. Long-term follow-up studies are badly needed and as the n u m b e r of courses and frequency of administration of these cytotoxic drug combinations m a y vary between different centres, individual centres will need to obtain their own data on the incidence Of this complication a n d the possibility of recovery in their o w n patients.
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R e c e n t studies h a v e c o n c e n t r a t e d on a d u l t patients t r e a t e d for breast c a n c e r or H o d g k i n ' s disease. S i m i l a r stvdics are r e q u i r e d in patients t r e a t e d fi)r o t h e r m a l i g n a n t a n d n o n - m a l i g n a n t conditions.
References 1. 2. 3. 4. 5. 6.
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