Superovulation with urinary human follicle-stimulating hormone: Correlations with body mass index and body fat distribution

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Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

Superovulation with urinary human

follicle-stimulating hormone: correlations with body mass

index and body fat distribution

F. Zullo, C. Di Carlo, M. Pellicano, C. Catizone, P. Mastrantonio & C. Nappi

To cite this article: F. Zullo, C. Di Carlo, M. Pellicano, C. Catizone, P. Mastrantonio & C. Nappi

(1996) Superovulation with urinary human follicle-stimulating hormone: correlations with body mass index and body fat distribution, Gynecological Endocrinology, 10:1, 17-21, DOI: 10.3109/09513599609041265

To link to this article: http://dx.doi.org/10.3109/09513599609041265

Published online: 07 Jul 2009.

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Gyirecol. Eizdocrinol. 10 (1996) 17-21

Superovulation with urinary

human follicle-stimulating

hormone: correlations with

body

mass index and

body

fat

distribution

F . Zuflo,

C .

Di

Caylo*, M . Pellicano", C . Catixone, P.

Mastrantonio

and

C . Nappi*

Department of Gynecologic and Pediatric Sciences, Medical School of Catanzaro, University of

R e g g o Calabria Ospedale 'A. Pugliese', Catanzaro; and *Department of Gynecology and

Obstetrics, University 'Federico 11' of Napoli, Naples, Italy

Key words: BODY FAT DISTRIBUTION, CONTROLLED OVARIAN HYPEKSTIMULATION, POLYCYSTIC OVARIAN SYNDROME, FOLLICLE-STIMULATING HORMONE, OBESITY

ABSTRACT

Our objective was to investigate the relationship between body mass index (BMI), waist/hip ratio (WHR),

for-

Iicle-stimulating hormone (FSH) dose, length ofstimula- tion and clinical outcome in infrtile women with and without polycystic ovary syndrorne ( P C O S ) undergoing corztrolled ovarian hyperstimulation.

Controlled ovarian hyperstimulation was induced in

60 women for a total of 1 1 1 cycles (48% in P C O S patients) with urinary huinan FSH (u-hFSH).

A s<qn$cant correlation between BMI, u - h F S H dose and duration

of

stimulation was found in PCOS and non-PCOS patients with WHR < 0.8. These correla- tions were not present in P C O S patients with WHR

> 0 . 8 . Pregnant patients received signijcantly Iess am- From o w data we sii'gest a controlled ovarian hyper- s t i r d a t i o n protocol, for obese non-PCOS patients and obese PCOS patients with WHR 0.8, starting with

a double dose ofir-FSH.

yules c$lr-hFSH.

INTRODUCTION

The use of carefully controlled ovarian hyper- stimulation, either in combination with artificial insemination with the partner's semen or not, has been employed with good results in infertile couples with anovulatory , mild endometriosis and unexplained infertility'-'.

T h e production of two to four follicles by gonadotropin stimulation plays a key role in in-

creasing the rate of single or twin pregnancies

without dangerously raising the rate of multiple

pregnancies (more than twins) and ovarian hyper-

stimulation syndrome (OHSS)'. Therefore, to this

aim, it would be extremely useful to assess which

are the factors influencing the ovarian response to

induction of multiple follicular development in terms of gonadotropin requirement, starting dose and length of stimulation. Among these variables, body weight and body-fat distribution represent two important and easily assessed pararneters for consideration.

~ ~~ ~

Corrrcpondence: Dr F. Zullo, via Michetti 10, 80127 Napoli, Italy

17

% l l l l U c't nl.

I r i t i c w i . i t hn,i becii shown that obese w o m e n

i-c~iuirc higher doses of gonadotropin o r

c.Ioinip1iciic citratc t o achieve an optimal ovarian rcipotise t o stiniulntion4-" and, recently, increasing

i . v , t i d l i i p i - n t i o has been s h o w n t o be relatively

,iswc-i.itc:ii with the probability o f conception per

;!;cIc ' . Morcovcr, a direct correlation was found

lict\vec.ii gonadotropin requirement and body \\.tight ti11 the induction o f niultiple follicular d t ~ c'lopiiicritY~''. Ho\vever, other authors have L i i I t d t o o i l t i r i n thcsc data"'.

I !ici.c:i~d body Lveiglit and hypcrandrogenisni

( ~ o i i i i i i o i i feature\ ainong anovulatory wonien \t it11 y o l ~ ~ c y ~ t i ~ ~ o w r y syndrome (PCOS), and

Ii~,~pi.r,iiidrcigc~iiisiii is k n o w n t o be associated with

, i l [ L ~ c : d o \ ' c i r i a > rcsponsivencss to gonadotropin , t i i i i t i L i t i o i i " .

i$oti). E i t distribution provides a reliable estimate

c i f . i i i t i i . o ~ i . i i i ~ a t i ( i i i i n w o i i i c ~ i ' : ' ~ ~ ~ . Therefore, con- \ i i i c v - i i i S t j i c ' 6 - c q w n t association between obesity

; i ~ i t l .iiitirct~ciii~ation i i i PCOS patients, w e under-

t o o k , I \ t i d y to investigate whether there is a

c c ~ r - i x ~ l a t i o n lwt\vccii body mass index (BMI) and

T ~ < i r ! o i i \ p.ir,inictcrs of controlled ovarian hyper-

~ : i i i i ~ i I , m ~ ~ i ~ :is '1 fiinction o f body fat distribution.

MATERIALS AND METHODS

'sixty liifcrtilc p t i e n t s , aged 25-37 years

( i i i i * < i i i zk SI), 30.4 rt

5.3)

wcre included in the

\[tidy J'lic. niean duration o f infertility was 4.1

C

2.4 y c m . 7'~llxtl infertility arid iiiale factor

7 , ~ crc' c.sc-liictcd

I':iiii'iity ic'crc divided into t w o groups: normo- o ~ ~ i i I t i t ( i i - ~ ~ : i i i d I'COS. Patients wcre defined as

, i t i C c - t c d b y I'(:OS when presenting an ultrasono-

g i ~ ' i p l i i c . pittcrii ofpolycystic ovaries (niore than ten ! d l ~ ~ ~ k ~ \ i~,iiigiiig from 2 t o 8 n i n i in diameter i n the

\u ix~ bip \til: ir rcgion of the ovarian cortex; the ovar-

1.111 ~ t r o i ~ t ; ~ i s expandcd and cchogenic; the whole

~ . o l ~ i r i i c I \ grc.itcr tlinn 9 nil) together with one o r i i i ( > i . c ' (it' die syiiiptoins characteristic o f the syn- c i n l i i i c ( o l i ~ o - n ~ ~ i ~ i i ~ ~ r r l i c ~ i , anovulation, hirsutisni, J < . I I C . c>hcsity) ''.I5.

All p.iticiit< uiidcrwcnt controlled ovarian hy-

~ " i . ' f i i i i 1 i l ; i t i o i i hllowed either by timed inter-

i o u i - x . o r b y intraiitcrine and/or intrapcritoneal i l t \ c v i i i i i , i t i o i i nfter scnicn pwparatioii'". The con-

i7-c)llc%if ov:iri~i> liypcrsttiniulatiori protocol started

\ \ i t 1 1 tlic- ~idniinistration of 75 IU ofurinary huinan

ti i I I i t. I c- \ t i 1 I 1 II 1 ;it I 11 g h oriii on e ( LI -hFSH ; M e t r o di n,

Serono, Italy) daily for 7 day\. T h e d o w w a s

doubled after 7 day5 in the absence of ovarim

response and then every 3 days in \tcp-up fashion

Monitoring was performed by t r m s v a g d ul-

trasonography using a 5-mHz transducer attac hcd

to an Aloka sector scanner, and by serum cstr'idio'

evaluation. Both ultrasound ex~iiiinations and

estradiol determinations were performed after thc first 7 days o f treatment and then every 3 day\. Estradiol levels were measured by radloinimunoav-

(ay (KIA) using a commercial kit (Iladiin, R o m e .

Italy)

H u m a n chorionic gonadotropin (hCC;, Profav,

Serono, Italy) 10 000 units w a s ~ciiiiini\tere~i

when o n e to four (2nd n o inore than four) fol- licles reached a minimum diameter of 1 X ~ i i i i i

in the presence ofserum estradiol level5 of between

200 and 1500 pg/inl per follicle > 1 5 i i i i i i Ovula-

tion was assessed by ultrasonographlc nionitoring

and serum progesterone evaluation

I n all cycles, the following paraiiicters we1 i

evaluated: patient BMI, calculated by the r ~ t i o of body weight (kg) divided by the height' (in'), patient w a i d h i p ratio (WHII), cAculatcd 13) tl:c

ratio ofwaist circunifcrence inca\ured 'it tlic unibil -

icus divided by hip circu~iiferciicc (ciii) iiieasurc ti

at the largest measurement of tlic hips, number [if ampules o f u-hFSH adniinistered, ovu1,ition rntc, and pregnancy rate

Statistical analysis was performed

tn

l ' e ~ i r ~ o n ' \

test,

X'

and Student's test w h c n dppropriatc

R E S U L T S

An overall s u n i m a r y of the c l i n i ~ a l o ~ i t c o i ~ i c I\

presented in Table 1. T h e t o t a l iiuiiibc~r of 5 t i i i i t i -

lated cycles w a s 11 1 T h e o\~erall o v ~ i l ~ i t i o n ratc .I\

90 l ( j / ( l O O / 1 1 1 ) a n d t h ~ p r ~ g i i ~ i i c ~ rcitema\ 17 1 %

(19/111) A m o n g the 39 prcgn,uiciec, thrcc

(15.8%) wcre twin T h e r e wcrc i i o liigher riiulti-

ples (triplets o r above) o r any C Jof-m ~ ere O H j \

T h e niean BMI was 25

4

F

3 6 (rcingc 18

7-

34 6), the ~ n e ~ i i nunibcr of L I - ~ F S H .iiiipulcs \\'I)

12 6

t-

4.1 (range 0 5-42 0), m d the liieclli durCition of stimulation wa\ 12 4 d + \ +_ 2 5 (range X-3i)

BMI was found to be significantly correlnted \\ i t h

both the number o f LI-hFSH ,iiiipulcs .idmini\t

and the length o f stiiiiulatioii ( I = 0 380.3, p < 0.001 and Y = 0 4561.11 < 0 001 , r e y m t i \ ci\)

Fifty-eight cycles (52 3'X) w e r e induccd i n 1 1 0 1 1 -

PCOS patients A m o n g tlicw piticiits the i i i c in

Table 1 Clinical outcome of 60 patients with induced controlled ovarian hyperstimulation PCOS

All patients Non-PCOS WHR < 0.8 WHR > 0.8

Cycles 111 58 19 34

Ovulatory cycles 100 (90.2%) 58 (100%) 17 (89.4%) 25 (73.5%)

Peak estradiol (pg/ml) (mean f SD) 512 f 194 419 f 162 512 k 172 632 f 214

Follicles > 18 nim at hCG administration

(mean f SD) 1.6 f 0.4 1 . 4 f 0 . 3 2.0 f 0.6 1 . 8 f 0 . 5

Pregnancies 19 (17.1%) 9 (15.5%) 4 (21.1%) 6 (17.6%)

13.9 f 5.9

u-hFSH ampules administered

Duration of stimulation (days) 1 2 . 4 f 2 . 5 1 2 . 4 f 2 . 0

* 1

1 0 . 8 f 2 . 0 1 3 . 2 f 3 . 2

Body mass index (kg/ni') 2 5 . 4 k 3 . 6 1 : 24.1k3.1 J f 2 4 . 7 5 4 . 2 1 : 28.1k2. 5

PCOS, polycystic ovarian syndrome; WHR, waist/hip ratio; hCG, human chorionic gonadotropin; u-hFSH, uri-

nary human follicle-stimulating hormone;

* variables

significantly correlated (p < 0.001)

1

10.9 k 2.7

1

12.7 f 2.8

1

12.6 f 4.1

BMI was 24.1

f

3.1 (range 18.7-30.0), the mean

number of u-hFSH ampules was 12.7

f

2.8 (range

9-21) and the mean duration of stimulation was 12.4

f

2.0 (range 9.0-18.0). T h e ovulation rate

was 100% (58/58) and the pregnancy rate was

15.5% (9/58). BMI was again found to be signifi- cantly correlated with both the number ofu-hFSH ampules administered and the length ofstimulation ( Y = 0.5788,

p

< 0.001 and r

=

0.5766, p < 0.001,

respectively).

Fifty-three cycles (47.7%) were induced in patients with PCOS. Among these, 19 cycles were

induced in patients with a WHR

<

0.8 and 34

cycles were inducedin patients with a WHR

>

0.8.

In the P C O S patients with W H K < 0.8, the ovulation rate was 89.4% (17/19) and the preg-

nancy rate was 21.1% (4/19). The mean BMI was

24.7

f

4.2 (range 19-32.8), the mean number of

u-hFSH ampules administered was 10.9

f

2.7

(range 6.5-16) and the mean duration of stimula-

tion was 20.8

f

2.0 days (range 8.0-14.0). In this

restricted group of patients, BMI was found to

be significantly correlated with both number

of u-hFSH ampules administered (r = 0.8467,

p < 0.001) and length of Stimulation (r

=

0.8668,

In the PCOS patients with WHK > 0.8 the

ovulation rate was 73.5% (25/34) and the preg-

nancy rate was 17.6% (6/34). No significant differ-

ence was detected in the ovulation rate and

pregnancy rate between P C O S patients with

W H R < 0.8 and P C O S patients with WHR

> 0.8. T h e mean BMI was 28.1

f

2.5 (range 25-

34.6), the mean number of u-hFSH ampules was

13.9

k

5.9 (range 7-42) and thc mean duration of

p < 0.001).

stimulation was 13.2

f

3.2 days (range 8-25). In

this group ofpatients it was not possible to demon- strate any significant correlation ofBMI either with

the number of u-hFSH ampules administered

(r = 0.1343), or with the length of stimulation

(r = 0.0913).

No statistically significant difference was de-

tected among non-PCOS women, P C O S women

with WHR > 0.8 and P C O S patients with W H R

< 0.8, in the number of u-hFSH ampules, in the

length of stimulation, in the number of mature follicles at h C G administration and in the peak estradiol serum levels. However, we observed a mean number of u-hFSH ampules and days of stimulation significantly lower (p < 0.05) in cycles leading to pregnancy than in unsuccessfiil cycles.

DISCUSSION

Weight and body mass are known to be important

parameters in determining the potential of a

woman's reproductive system" but their influence on ovarian response to exogenous gonadotropins is still c o n t r ~ v e r s i a l " ~ ~ ~ ~ ' " .

O u r data confirm a significant inverse correla- tion between BMI and ovarian response to gonadotropin (expressed as u-hFSH ampules and

length of stimulation) at least in normo-ovulatory

patients and in women with P C O S and WHR

< 0.8. This correlation was not found in P C O S

patients with a central-type body fat distribution. Previous papers on this subject seem to show that reduced ovarian sensitivity to exogenous

gonadotropins in obese patients is not related to

different absorption and distribution of the drug18,

Gynecological Endocrinology 19

l w t iould be better explained by altered hy- p o t l i A a i i i c ncuromodul'itioii and/or peripheral ?[crc)id iiietabohsni' T h e lack of correlation in piticiit\ with I'COS a i d W H R > 0 8 is probably c \pI,uiicd by the intraovarian interferences of the i i i ~ r e ~ ~ c c i fi i-c mdrogeii levels and insulin rc-

\ I > t . i n c c Indeed, it h,n been h o w n that both these

c o i i d i t i o i i \ arc pregcnt i i i this subpopulation of

i n I T ( >S ~ ~ o n i e n , hyperaitdrogenisni has bcen

c 1,iiiiicd to be caused by a primitive insulin-re- k i m i i c c' with wcoiic1a-y hyperinsulinism. T h e in-

4 I C J ~ I i n d n level\, together with a reduction in

t l i L . hiriding pi oteinj for insulin-like growth factor

I BP-I), inight x t on the ovarian theca IGF-I

s i n g the rcsponuveness of the fol-

l i t le t o luteinitiiig hormoiic (LH)".

t

rcliii thew Lonsiderdtions, we hypothesize that 111 o i i i 1)COS patient? with WHR > 0.8, the nie-

1 ~ h 0 1 i ~ di?turbdnce charactcriG,tic of the syndrome, c . I L I \ C \ ~ ~ iinLi i c'asc 111 the follicular response to FSH

~ t l i i i h I \ m,i\kcd, up to an '1s yet undetermined point b\ the negative effect on folliculogencsis

< \ i rted b y t h c iiicrcdwd androgen levels". W h e n

~ ~ ~ ~ l ~ c i ~ l . ~ ~ ckw~lopnicnt 1 5 \ct in motion by exo-

< C l l < l L i ? FSH, the incre'iscd sensitivity IS then un-

I'C 0 5 p'ltlcntP 2 ' .

REFERENCES

Aboulghar, A. M., Mansour, R. T., Scrour, G. I., Aiiiin. Y . , Abbas, A. M. and Salah, I. M. (1993). c h ~ i - 1 ~ 1 1 1 s~rpcrstiiiiulatioii and intrauterine insenii- t ~ i t i o i i fi)r thc trcatnient of unexplained infertility.

I.'cr.iii. Src>ri/., 60, 303-6

C : i ) r u n . (;. H. and Keniniann, E. (1991). The role of \iipci-ot'ulation with inenotropins in ovulatory

i!!Ccrtilitv. Fcartil. Steril., 55, 468-77

hl'i\Lnrcmhas, L.. Khastgir, G., Ilavics, W. A. K.

, i d LLC, 5. (1994). Supcrovulation and timed in-

t m . < ) i i r w s . can i t provide a reasonable alternative

!;)I- tliusc unable t o afford assistcd conception? Hunr.

('haiig, A . I]., I i a h e l , R. W. and Forte, C . C .

( I ' M i ) . Influcnct. of weight i n the induction of

I i ~ ~ d ~ i t i o i i with Iiunian nienopausal gonadotropin , i i i d I i u i i i n n chorionic gomdotropin. Fertil. Steril.,

46. .?~P--602

hlcCliirc. N . , McQuinn, B., McDonald, J., K c ) ~ , ~ . i k . ~ ~ [;. T., Healy, 1). I>. and Burger, H. G. 0 2 ) " l h d y weight, body mass index and age:

~ ~ i - t . ~ I i < ~ t o v o f nici!otropin dose and cycle outcome IZ"/""'i., 9. 67-70

masked causing an exaggerated response. Further- more, we found in o u r scries that a significantiy lower number of u-hFSH ampules and a shorter duration of stimulation werc needed in concep- tional cycles than in non-conceptional cycles. This fact m a y b e explained either by an increased chance

of pregnancy in better responders or by a lowcr threshold level for follicular dcvelopnicnt in thew patients. This point needs further obscrvLitions in

order to be clarified.

T h e correlation between BMI and ovarian rc- sponse to u-hFSH, although needing confirmation

on a larger scale, allows us to suggest a controlled ovarian hyperstimulation protocol with a higher starting dose of u-hFSH in obese norrnal o r obese PCOS patients with W H R < 0.8 obese patients in order to achieve an optimal number of mature follicles (two to four)3. In obese PCOS

patients with WHK > 0.8, because of the unpw- dictability of ovarian response, it is probably more appropriate to employ a low-dose, slow-increace protocoP4.

In conclusion, w e can say that simple clinical data, such as BMI and body fat distribution, should be taken into account for a correct personalization

of controlled ovarian hyperstimulation.

in polycystic ovarian syndronic. Fcrti/. Stcril.. 58,

Shepard, M. K., Balniaccda, J. 1'. and Lei.1, C . G .

(1 979). Relationship ofweight t o s~~ccessful induc- tion of ovulation with clomiphenc citrate. Z + d .

Steril., 32, 641-4

Zaadstra, B. M., Seidell, J. C., Van Noord, I-'.

A,,

Veldc, E. R., Habbenia, J. I)., Vricswijk, B. and Karbaat, J. (1993). Fat and feiiiale fecundity: pro- spective study of effect of body fat distribution on

conception rates. Hr. ibfed. j . , 306, 484-7

Halme, J . , Hammond, M. G . , l'albert, L. bl., O'Rand, M., Bailcy, L. and Sloxi, C . (1986). Positive correlation between body weight, Icngth of human menopausal gonadotropin stimulation, and oocytc fertilization rate. Fcrtil. Steril., 45, 372-6

Halme, J., Hammond, M. G , , Uailey, L. and Tal- bert, L. M. (1988). Lower doses of h u i i i a i i menopausal gonadotropin are associated with ini- proved succcss with iri vitm fertihzatioi~ in wonien with low body weight. Airr.]. 0 h s t c . r . Cyirc'c-ol., 158,

64-8 622-4

G y necological EndoLrinology

Superovulntion inducfion Zullo et al.

10. Lewis, C. G., Warnes, G. M., Wang, X. and Mat- thews, C . D. (1990). Failure ofbody mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertil. Steril., 53, 1097-9

1 1 . McClamrock, H. D., Bass, K. M. and Adashi, E. Y. (1 991). Ovarian hyperandrogenism: the role ofand sensitivity to gonadotropins. Fertil. Steril., 55, 73-9 12. Nestler, J. E., Barlascini, C . O., Matt, D. W.,

Stcingold, K. A., Plymate, S. R . and Clore, J. N. (1 989). Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J . Clin. Endocrinol.

M e t n b . , 68, 1027-30

13. Pasquali, K., Casimirri, F. and Plate, L. (1990). Characterization of obese wonien with reduced sex-hormone-binding globulin concentrations. Horni. Metab. Res., 22, 303-6

14. Adanis, J., Polson, D. W. and Franks, S. (1986). Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br. Med. J . , 15. Franks, S. (1989). Polycystic ovary syndrome: a

change in perspective. Clin. Endocrinol., 31,87-120 15. Shcr, G., Knutzen, V. K., Stratton, C . J., Montak-

hab, M. M. and Allenson, S. G. (1984). i n vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infer- tility: phase I. Fertil. Steril., 41, 260-4

17. Rich-Edwards, J. W., Goldnian, M. B., Willet,

W. C., Hunter, D. J., Stanipfer, M. J., Colditz,

C,. A. and Manson, J. E. (1994). Adolescent body mass index and infcrtility caused by ovulatory dis- order. Am.]. Obstct. Gynecol., 171, 171-7

293,355-9

18. Remorgida, V., Giordano, M., Lancra, P., Costan- tini, S. and de Cecco, L. (1993). The relationship between body composition and plasma concentra- tions of exogenously administered urinary follicle stimulating hormone. Hum. Reprod., 8, 1001-4 19. Reid, R. L. and Van Vugt, D. A. (1987). Weight-

related changes in reproductive func,tion. Fertil.

Steril., 48, 905-13

20. Dale, P. O., Tanbo, T., Vaaler, S. and Abyholni,

T. (1992). Body weight, hyperinsulineniia, and gonadotropin levels in the polycystic ovarian syn- drome: evidence of two distinct populations. Fertil.

Steril., 58, 487-91

21. Anttila, L., Ding, Y. Q., Kuutiainen, K., Erkkola, P., Irjala, K. and Huhtaniemi, I. (1991). Clinical features and circulating gonadotropin insulin and androgen interactions in women with polycystic ovarian disease. Fertil. Steril., 55, 1057-61

22. Nobels, F. and Dewailly, D. (1992). Puberty and polycystic ovarian syndrome: the insulin/insulin like growth factor I hypothesis. Fertil. Steril., 58, 23. Polson, D. W., Reed, M. J., Scanlon, M. J., Quiney, N. and Franks, S. (1988). Androstene- dione concentrations following dexaniethasone suppression: correlation with cloniiphene respon- siveness in women with polycystic ovary syndrome. Gynecol. Endocrinol., 2 , 257-64

24. Shohani, Z . , Patel, A. and Jacobs, H. S. (1992). Polycystic ovarian syndromc: safety and effcctive- ness of stcpwise and low-dose administration of purified follicle-stimulating hormone. Fertil. Steril., 655-66

55, 1051-6

Gynecological Endocrinology 21