SllO Journal of Obstetricsand Gynaecology(l986)6, (Suppl. 2) S1104115 frintedin GreatBritain Return of fertility in women discontinuing injectable contraceptives K. Fotherby Royal Postgraduate Medical School, London Gera Idine Howard Charing Cross Hospital Medical School, London CONCERN has been expressed about the return of fertility in women who have discontinued the use of injectable contraceptives. This concern, has applied mainly to women who have been using depot med- roxyprogesterone acetate (Depo-Provera) in spite of preliminary results (Schwallie and Assenzo, 1974; Pardthaisong et al., 1980; Pardthaisong and Gray, 1981) which suggested that although there was a delay in the return of fertility, the cumulative preg- nancy rates at 1 and 2 years after discontinuation (approximately 78 and 92 per 100 women respec- tively) were similar to those observed in women who had used an intra-uterine contraceptive device. It has been shown (Fotherby, 1982) that ovulation may return before the end of the injection interval in women using norethisterone oenanthate (Noris- terat), but these studies have been performed main- ly in short term users. Since in long term users the incidence of amenorrhoea may reach 45 per cent (Howard et al., 1982), a figure not much different from that reported for women using medroxy- progesterone, questions regarding fertility after dis- continuation of norethisterone oenanthate are also raised. Two reports within the past 2 years (Fother- by et al., 1984; Pardthaisong, 1984) largely dispel this concern. FERTILITY AFTER INJECTABLE CONTRACEPTIVES Pardthaisong (1984) followed up a group of 796 Thai women for 4 years after discontinuation of depot medroxyprogesterone acetate injections in order to become pregnant. For comparison, groups of women stopping use of oral contraceptives or an intra-uterine device were also studied. It was assumed that the contraceptive effect of the oral contraceptive ended after taking the last pill, that of the device ended on removal and that of the injec- tion continued for 15 weeks after the last dose. The proportion of women in each group who did not become pregnant is shown in Table I. Women stop- ping oral contraceptives achieved pregnancy more quickly than the former depot medroxyprogest- erone users but there was less difference between the latter and the intra-uterine device users. The median delay to conception was 3 months for the oral contraceptive group, 4.5 months for the device group and 5.5 months (that is, 37 weeks after the last injection) for the depot medroxyprogesterone group. Age did not appear to affect the return of fertility until 5 months after discontinuation but thereafter return of fertility tended to be quicker in women under 25 than in those aged 30-40. The Table I. Proportion of women who did not conceive (Pardthaisong, 1984) Depot Intra-uterine Months after rnedroxyprogesterone Oral contraceptive discontinuation acetate contraception device 6 12 18 24 36 46.5 24.7 40.1 23.8 15.1 24.2 12.6 8.2 12.6 8.5 5.1 6.7 6.4 4.1 3.2 J Obstet Gynaecol Downloaded from informahealthcare.com by Nyu Medical Center on 05/01/13 For personal use only.
Transcript
SllO Journal of Obstetricsand Gynaecology(l986)6, (Suppl. 2) S1104115 frintedin GreatBritain
Return of fertility in women discontinuing injectable contraceptives
K. Fotherby Royal Postgraduate Medical School, London
Gera Id i ne Howard Charing Cross Hospital Medical School, London
CONCERN has been expressed about the return of fertility in women who have discontinued the use of injectable contraceptives. This concern, has applied mainly to women who have been using depot med- roxyprogesterone acetate (Depo-Provera) in spite of preliminary results (Schwallie and Assenzo, 1974; Pardthaisong et al . , 1980; Pardthaisong and Gray, 1981) which suggested that although there was a delay in the return of fertility, the cumulative preg- nancy rates at 1 and 2 years after discontinuation (approximately 78 and 92 per 100 women respec- tively) were similar to those observed in women who had used an intra-uterine contraceptive device. It has been shown (Fotherby, 1982) that ovulation may return before the end of the injection interval in women using norethisterone oenanthate (Noris- terat), but these studies have been performed main- ly in short term users. Since in long term users the incidence of amenorrhoea may reach 45 per cent (Howard et al. , 1982), a figure not much different from that reported for women using medroxy- progesterone, questions regarding fertility after dis- continuation of norethisterone oenanthate are also raised. Two reports within the past 2 years (Fother- by et al . , 1984; Pardthaisong, 1984) largely dispel this concern.
FERTILITY AFTER INJECTABLE CONTRACEPTIVES Pardthaisong (1984) followed up a group of 796 Thai women for 4 years after discontinuation of depot medroxyprogesterone acetate injections in order to become pregnant. For comparison, groups of women stopping use of oral contraceptives or an intra-uterine device were also studied. It was assumed that the contraceptive effect of the oral contraceptive ended after taking the last pill, that of the device ended on removal and that of the injec- tion continued for 15 weeks after the last dose. The proportion of women in each group who did not become pregnant is shown in Table I. Women stop- ping oral contraceptives achieved pregnancy more quickly than the former depot medroxyprogest- erone users but there was less difference between the latter and the intra-uterine device users. The median delay to conception was 3 months for the oral contraceptive group, 4.5 months for the device group and 5.5 months (that is, 37 weeks after the last injection) for the depot medroxyprogesterone group. Age did not appear to affect the return of fertility until 5 months after discontinuation but thereafter return of fertility tended to be quicker in women under 25 than in those aged 30-40. The
Table I. Proportion of women who did not conceive (Pardthaisong, 1984)
Depot Intra-uterine Months after rnedroxyprogesterone Oral contraceptive
Fotherby and Howard: Fertility after injectable contraceptives S l l l
Weeks
Figure 1. Time of conception (weeks after last injection) in women discontinuing norethisterone oenanthate.
duration of use of the injection appeared not to affect the return of fertility, there being no differ- ence between those women receiving one to four injections and those receiving more than nine.
Similar data are not available for women who have discontinued norethisterone oenanthate in order to become pregnant but findings from our own trials (Fotherby et al., 1984) with this injectable contraceptive suggest that it also does not lead to any impairment of fertility. Information was avail- able for 40 women who had been enrolled in our clinical trial of norethisterone oenanthate injections and who became pregnant after discontinuation (see Figure 1). At least 17 of these women discontinued injections in order to become pregnant. Assuming a duration of 8 weeks for the anti-fertility effect of norethisterone oenanthate injections, 14 preg- nancies (35 per cent) occurred within 12 weeks of discontinuation (that is, 20 weeks after the last injection), 21 (52 per cent) within 6 months and 31 (77 per cent) within 12 months. Some of the women had received more than 25 injections of norethister- one oenanthate, mainly with an interval of 8 weeks; there was no correlation between the number of injections received and the time taken for concep- tion to occur. Spontaneous abortion occurred in 5 pregnancies, 13 women had legal abortions and in the remaining 22 the pregnancy went to term with delivery of a normal baby. The 40 women for whom information was available may well be a minimum number since it is possible that some women who discontinued injections and subsequently became pregnant were lost to follow up either due to their moving away from our area or because they re- ceived antenatal care at another hospital. The findings therefore are encouraging; almost 80 per cent of the women who became pregnant did so
within 1 year and all 17 women who discontinued with the intention of becoming pregnant conceived within 3 months. Allowing an 8 week period for the clearance of norethisterone from the body, the con- ception rate obtained in our study was not different from that observed in women using either no con- traceptive method or discontinuing non-steroidal methods of contraception.
Of the group of women studied by Pardthaisong (1984) 35 were subsequently found to be nulligravi- dae; there appeared to be no significant difference between nulligravid and parous women in the return of fertility. In our own study, 12 of the 40 women were nulliparous and the time after discontinuation at which they became pregnant (33.6f17-1 weeks; s.d.) after the last injection did not differ signifi- cantly from that (36.0f23.0 weeks) of the 28 parous women. These preliminary results therefore do not support the suggestion that the injectable con- traceptives should be used only in parous women.
SERUM PROGESTAGEN CONCENTRATIONS AND OVULATION IN WOMEN AFTER DISCONTINUATION QF INJECTABLE CONTRACEPTIVES Differences between the two injectable contracep- tives in the rate of return of fertility after discon- tinuation are explicable in terms of the uptake and metabolism of the progestagen and its effect on ovarian function. Figure 2 shows the time taken for serum concentrations of medroxyprogesterone ace- tate to become undetectable after injection of 150mg of the depot preparation. Of the 56 women studied, in only 7 (12 per cent) had the concentra- tion become undetectable by the end of the 90 day injection interval and in 13 (23 per cent) medroxy- progesterone acetate was detectable for more than
J O
bste
t Gyn
aeco
l Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Nyu
Med
ical
Cen
ter
on 0
5/01
/13
For
pers
onal
use
onl
y.
s112 Journal of Obstetrics and Gynaecology.(l986) Vol. WSuppl. 2
. _
Progesterone 10-
6-
4-
6 2
3 0 k
, , , , I , , ,I, , , , I I L 0
Figure 2. Time (days after last injection) at which ovulation occurred (Progesterone), as indicated by a significant increase in serum progesterone concentration, and at which medroxyprogesterone acetate levels became undetectable (Medroxyprogesterone), in women discontinuing depot medroxyprogesterone acetate.
210 days; this latter value is a minimum since in a further 8 women blood sampling was not continued for a long enough period to determine the exact time that medroxyprogesterone acetate was cleared from the circulation. The time when changes occurred in the serum progesterone concentrations indicative of luteal function and signifying that ovulation had occurred are also shown in Figure 2. Only 1 of 31 women (3 per cent) ovulated before the end of the 90 day injection interval and in 11 (35 per cent) ovulation was delayed for more than 240 days after injection; in a further 7 women sampling was not continued for a sufficiently long period to deter- mine the time of ovulation. Ovulation appears not to occur until serum medroxyprogesterone acetate concentrations are very low or undetectable.
Similar data in respect of women discontinuing norethisterone oenanthate are shown in Figure 3.
Compared to medroxyprogesterone acetate the up- take and clearance of norethisterone oenanthate are much quicker; in 15 of the 61 women (25 per cent) serum norethisterone concentrations became unde- tectable before the end of the 60 day injection interval and in 40 women (66 per cent) within 90 days. In only 9 women (15 per cent) was norethister- one detectable more than 120 days after injection. Ovulation also occurred much earlier in women discontinuing norethisterone than medroxy- progesterone. Twenty-one of 63 women (33 per cent) ovulated within 60 days of injection and 37 (59 per cent) within 90 days. Ovulation was delayed beyond 120 days in 21 per cent of the women. The data in Figure 3 also indicate another difference between norethisterone and medroxyprogesterone; in most women discontinuing norethisterone oenan- thate injections, ovulation occurs while there is still
J O
bste
t Gyn
aeco
l Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Nyu
Med
ical
Cen
ter
on 0
5/01
/13
For
pers
onal
use
onl
y.
Fotherby and Howard: Fertility aher injectable contraceptives S113
12
10
8
6
4
c 2 E s o
5
c
& 12
10
n
8
6
4
2
0 30 60 90 120
Days after injection Figure 3. Time (days after last injection) at which ovulation (Progesterone) occurred, as indicated by an increase in serum progesterone concentration, and at which serum norethisterone levels became undetectable (Norethisterone), in women discontinuing norethisterone oenanthate
a significant blood norethisterone concentration. The information for the two progestagens is
summarised in Tables I1 and 111. The values in Table 111 must be regarded as minimum values since in some women sampling was not continued for a sufficiently long period to ascertain the exact values. The Table does show the essential differences between the two formulations; the uptake and metabolism of medroxyprogesterone acetate are much slower than those of norethisterone oenan- thate and hence ovulation is inhibited for a much longer period of time. The mean (or median) time to ovulation is similar to the clearance for norethis- terone whereas for rnedroxyprogesterone acetate the mean (or median) time to ovulation is consider- ably longer than that of the clearance. The large variation between women using either formulation,
as shown by the range of values for both clearance and return of ovulation, should also be noted. In women discontinuing depot rnedroxyprogesterone acetate the mean time for the return of ovulation (approximately 210 days) is only slightly less than the median time for the return of fertility (approxi- mately 260 days after the last injection) quoted by Pardthaisong (1984).
The median time to conception in women discon- tinuing norethisterone oenanthate was about 170 days compared to just over 80 days for the return of ovulation. This finding might suggest that norethis- terone oenanthate continues to exert an antifertility action after the return of ovulation. Although it may do so for a short time the long value of 170 days is probably an artifact; not all the women in our study discontinued injections in order to become pregnant
J O
bste
t Gyn
aeco
l Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Nyu
Med
ical
Cen
ter
on 0
5/01
/13
For
pers
onal
use
onl
y.
S114 Journal of Obstetrics and Gynaecology (1986) Vol. 6/Suppl. 2
Table I I . Time required for serum progestagen concentrations to become undetectable and for ovulation to occur (rise in serum progesterone concentrations) in women discontinuing depot medroxyprogesterone acetate (M.P.A.) or norethisterone oenanthate (N.O.). Figures refer to number of women with percentage ofthe number studied in parentheses
Time after Progestagen undetectable Ovulation injection
Table II and Figures 2 and 3 are based on information published by Kirton and Cornette, 1974; Howard era/., 1975; Weiner and Johansson, 1975; Ortiz era/., 1977; Fotherby era/., 1978; Goebelsmann era/., 1979; Benagiano era/., 1980; Fotherby er a/., 1980a.b; Werawatgoompa er a/., 1980; Sang et a/., 1981; Koetsawang et a/., 1982; Fotherby and Koetsawang, 1982; Bassol et a/., 1984; Lan et a/., 1984; and Garza-Flores era/., 1985.
Table 111. Summary of pharmacokinetic data for depot medroxyprogesterone acetate (M.P.A.) and norethisterone oenanthate (N.O.). Values are days after injection for serum progestagen values to become undetectable (clearance) and for serum progesterone concentrations to reach luteal phase levels (ovulation). Values are mean fs .d . with median in parentheses
M.P.A. N. 0.
CI ea ra nce 160,9572.3 88.9f32.2 (161) (83)
range 5-0 range 38-210 Ovulation 21 1.1 k66.9 85.1 f35.3
The pharmacokinetic data indicate that norethister- one oenanthate exerts less inhibitory effect on the hypothalamic-pituitary-ovarian system so that ovu- lation, and hence probably fertility, return earlier after discontinuation of this drug than after depot medroxyprogesterone acetate. The preliminary findings indicating no difference between nullipar- ous and parous women in the rate of return of fertility after discontinuation suggest that the inject- able contraceptives need not be restricted to women who have completed their family.
G. (1984) Ovarian function following a single admi- nistration of depornedroxyprogesterone acetate at different doses. Fertility and Sterility 42, 2,16222.
Benagiano G. , Fotherby K., Coutinho E., De Souza J.
and this would have led t' a lengthening Of the median time to conception. the effect Of age has to be considered; Pardthaisong (1984) found the median time to conception to be longer in women C.,- Hingordni V., Takker D., Koetsawang S. and over 30 years of age than in younger women. In his Srisupandit S. (1980) Return of ovarian function and sample only 9 per cent were over 30 compared to 36 endornetrial morphology in wornen treated with per cent in our small sample. norethisterone oenanthate. Fertility and Sterility 34,
45W60. Fotherby K. (1982) Metabolic effects of injectable con-
traceptives. British Journal of Clinical Practice, Sym- CONCLUSION After discontinuation of depot medroxyprogester- posium Supplement 2630. one acetate or norethisterone oenanthate there is M. G , SOme particuIarb with the former, in the and Bye P. G. T. (1978) Occurrence of ovulation in return Of ovarian function and fertility, but after wornen receiving the injectable contraceptive allowing for the clearance of the progestagen from norethisterone oenanthate. Contraception 18, 535- the body, fertility does not appear to be impaired. 542.
Fotherby K., Howard G, , Shrimanker K,,
J O
bste
t Gyn
aeco
l Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Nyu
Med
ical
Cen
ter
on 0
5/01
/13
For
pers
onal
use
onl
y.
Fotherby and Howard: Fertility after injectable contraceptives S115
Fotherby K. and Koetsawang S. (1982) Metabolism of injectable formulations of contraceptive steroids in obese and thin women. Contraception 26, 51-58.
Fotherby K., Koetsawang S. and Mathrubutham M. (1980a) Pharmacokinetic study of different doses of Depo-Provera. Contraception 22, 527-536.
Fotherby K., Saxena B. N., Shrimanker K., Hingorani V., Takker D., Diczfalusy E. and Landgren B. M. (1980b) A preliminary pharmacokinetic and pharma- codynamic evaluation of depot-medroxyprogesterone acetate and norethisterone oenanthate. Fertility and Sterilify 34, 131-139.
Fotherby K., Yong-En S., Howard G., Elder M. G. and Muggendge J. (1984) Return of ovulation and fertility in women using norethisterone oenanthate. Contraception 29, 447-455.
Garza-Flores J., Cardenas S., Rodriquez V., Cravioto M. C., Diaz-Sanchez V. and Perez-Palacios G. (1985) Return to ovulation following the use of long- acting injectable contraceptives. Contraception 31,
Goebelsmann U., Stanczyk F. Z., Brenner P. F., Goebelsmann A. E., Gentzchein E. K. E. and Mishell D. R. (1979) Serum norethindrone (NET) concentrations following intramuscular NET enan- thate injection. Contraception 19, 28S312.
Howard G., Blair M., Chen J. K., Fotherby K., Mug- geridge J., Elder M. G. and Bye P. G. (1982) A clinical trial of norethisterone oenanthate (Norigest) injected every two months. Contraception 25, 3 3 s 343.
Howard G., Warren R. J . and Fotherby K. (1975) Plasma levels of norethisterone in women receiving norethisterone oenanthate intramuscularly. Con- traception 12, 45-52.
Kirton K. T. and Cornette J. C. (1974) Return of ovulatory cyclicity following an intramuscular injec- tion of medroxyprogesterone acetate (Provera). Contraception 10, 39-45.
Koetsawang S, Nukulkarn P., Fotherby K., Shrimank- er K., Mangalam M. and Towobola K. (1982) Transfer of contraceptive steroids in milk of women using long-acting gestagens. Contraception 25, 321-- 331.
361-365.
Lan P. I., Aedo A. R., Landgren B. M., Johannisson E. and Diczfalusy E. (1984) Return of ovulation following a single injection of depo-medroxy- progesterone acetate. Contraception 29, 1-18.
Ortiz A., Hiroi M., Stanczyk F. Z., Goebelsmann U. and Mishell D. R. (1977) Serum medroxyprogester- one acetate (MPA) concentrations and ovarian function following intramuscular injection of Depo- MPA. Journal of Clinical Endocrinology and Meta- bolism 44, 32-38.
Pardthaisong T. (1984) Return of fertility after use of the injectable contraceptive Depo-Provera. Journal of Biosocial Science 16, 23-34.
Pardthaisong T. and Gray R. H. (1981) The return of fertility following discontinuation of oral contracep- tives in Thailand. Fertility and Sterility 35, 532-534.
Pardthaisong T., Gray R. H. and McDaniel E. B. (1980) Return of fertility after discontinuation of depot medroxyprogesterone acetate and intra- uterine devices in northern Thailand. Lancet i , 509- 512.
Sang G. W., Fotherby K., Howard G., Elder M. G. and Bye P. G. (1981) Pharmacokinetics of norethis- terone oenanthate in humans. Contraception 24, 15-27.
Schwallie P. C. and Assenzo J. R. (1974) The effect of depomedroxyprogesterone acetate on pituitary and ovarian function and the return of fertility following its discontinuation. Contraception 10, 181-202.
Weiner E. and Johansson E. D. B. (1975) Plasma levels of norethindrone after i.m. injection of 200mg norethindrone enanthate. Contraception 11,419425,
Werawatgoompa S. , Vaivanijkul B., Leepipatpaiboon S., Channiyom K., Virutamasen P. and Dusitsin N. (1980) The effect of injectable norethisterone oenan- thate on ovarian hormones in Thai women. Con- traception 21, 299-309.
Correspondence should be addressed lot Dr K . Fotherby. Department of Steroid Biochemistry. Royal Postgraduate Medical School. Hammersmith Hospital. London W12 OHS J
