Hormonal changes during the first year of use of subdermal levonoregestrel implants, NORPLANT®

CONTRACEPTION

HORMONAL CHANGES DURING

THE FIRST

SUBDERMAL LEVONOREGESTREL M.M.

Shaabanl**,

A.A.

I.M.

Gomaa3,

Departments of and Pharmacology3,

M.

El-Nasharl,

Salah’

Obstetrics Faculty P.O.

Box

YEAR OF USE OF

IMPLANTS,

and

NORPLANT*

S.A. A.M.

Ghaneimah*,

Abdel-Aleem’

and Gynecology I, Biochemistry* of Medicine, Assiut University, 30,

Assiut,

Egypt

Abstract inserted during the first eight Sixty-three wcmen had NORPLANT @ implants days of the menstrual cycle. Blood specimens were withdrawn at the time of insertion and every three days during one of the following months of observation; the first, third, sixth, ninth and twelfth month after Ten subjects were sampled at multiple times during implant use. insertion. A total of 83 months of observation was available. The serum concentrations of levonorgestrel (LNG), FSH, LH, prolactin (PRL), estradiol (E2) and progesterone (prog) were measured in each specimen. LNG concentration rapidly declined during the first 15 days of use, the decline became more and an almost steady level was gradual during the subsequent two weeks, reached during the remainder of the year. There were no significant trends of change in the levels of FSH, LH, E2 and prog during the year. Frequent peaks in E2 concentration were observed and were generally associated with PRL concentration showed a slight but or followed by LH surges. significant rise during the second half of the year. Rises in prog concentration suggestive of ovulation occurred in 36 percent of the months in all these instances, there were evidences of observation. However, The bleeding episodes were usually, suggestive of deficient luteal phase. related to decline in E2 and prog concentrations. but not always, Submitted Accepted

* **

for publication for publication

NORPLANT” is contraceptive

5, 26,

1984 1984

the Population Council’s subdermal implants.

To whom correspondence

NOVEMBER

October October

should

1984 VOL. 30 NO. 5

be

registered

trademark

for

addressed

391

CONTRACEPTION

Introduction NORPLANT@ consists containing are

intended

net has

cumulative been reported

acceptability

of

3625

six

polydimethylsiloxane

mg of

levonorgestrel. The five-year use.

for

pregnancy (1).

rate There

(Silastic’@)

capsules,

They are implanted method has a very low

of 0.7 per 100 are indications

women after that it

subdermally failure rate; four will

each and a

years of use enjoy good

(2).

Studies on hormonal changes during NORPLANTQO use (3,4) have involved small numbers of cycles. They have demonstrated a decline in the plasma levonorgestrel level during the first 60 days and fairly constant levels These studies have indicated that the released progestogen thereafter. inhibits ovulation in many but not all the cycles. Studies on changes in use have been few (5) and did not pituitary hormones during NORPLANT” involve simultaneous estimation of the levels of ovarian hormones. The present study aims at throwing more light on the mechanism(s) of action of NORPLANT@ implants by the simultaneous measurement of serum levonorgestrel (LNG), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and progesterone (prog) at three-day prolactin (PRL), intervals during the first, third, sixth, ninth and twelfth months of its use. A previous work from our unit (6,7) has determined the normal levels in blood of the main reproductive hormones for our population in a study that involved 20 young, normal women who were sampled daily during ovulatory It showed that serum progesterone values of 5 ng/ml or menstrual cycles. more in one blood specimen, or of 3 ng/ml or more in two specimens three days apart could be taken as highly suggestive of ovulation in a menstrual cycle. The highest luteal phase value of prog reached in any one cycle varied between 7.8 ng/ml and 23.1 ng/ml. The peak phase (the day of LH peak and the preceding one) values of estradiol were in the average 207*61 (SD) pg/ml, while the average of the values obtained during the follicular phase (the days of the cycle preceding the peak phase) was 72+34 pg/ml and of the luteal phase (days after the peak phase) was 103*19 pg/ml. Serum prolactin values were in the average 11.5+3.8 ng/ml, 15.1t7.5 ng/ml and 14.6k6.0 ng/ml during the follicular, peak and luteal phases, respectively.

Materials

and

Methods

Sixty-three women volunteered for the study. Their ages ranged between 28 and 32 and parity between 3 and 8. They were not breast-feeding and had had regular menstruation before the implant insertion. They had not been taking any hormonal treatment for a minimum of three months. Insertion was made in the left upper arm during the first eight days of the cycle. Each subject gave a venous blood specimen at the time of insertion and every three days during one of the following months of observation: the first, third, sixth, ninth and twelfth months after insertion. Blood was always withdrawn frcxn the right arm. Ten of the subjects gave repeated specimens during the first, third and sixth months, resulting in a total of 83 months

392

NOVEMBER

1984VOL.30NO.S

CONTRACEPTION

of

observation.

the

disruption

use

(2).

Months of

were

menstrual

chosen cyclicity

rather during

than the

menstrual early

cycles phase

of

because

of

NORPLANT

@

The

serum was separated and divided into small aliquots that were kept In each specimen the levels of FSH, LH, PRL, E2 and frozen until assayed. prog were measured using the reagents of the World Health Organization Program for the Distribution of Matched Reagents for the Radioimmunoassay of Hormones in Reproductive Physiology and the methods described in the Method Manual (Sixth Edition) of that program. Levonorgestrel was measured Levonorgestrel-15, (8). antilevonorgestrel-3-CMD-BSA Germany. The significance different months Each of occurred bleeding

of of

by radioimmunoassay as previously described 16-3H (specific activity 50 uci/mmol) and were gifts from Schering A.G., Berlin,

the differences between observation was assessed by

the subjects kept daily records during the months of observation. not requiring a sanitary napkin.

the the

values student’s

obtained t test.

during

of any bleeding or spotting that Spotting was defined as vaginal

Results

Table I shows the mean values of the serum concentrations of LNG, FSH, LH, PRL, E2 and prog in different months of observation during the first year of NORPLANT” use. The third month levels of levonorgestrel were much lower than those of the first month (P<.OOl ) . There was a subsequent significant drop in the ninth month values relative to those of the sixth month The trend of change in levonorgestrel concentration in the ten (P<.Ol). subjects who were longitudinally followed during the first, third and sixth months of use is shown in Figure 1. The drop in LNG levels was steep during the first two weeks and became gradual during the subsequent two weeks. There was marked interindividual variability. There were no significant changes in the mean serum concentrations of LH, FSH, estradiol and progesterone for the successive periods of observation during the first year of NORPLANT@ use. The level of prolactin, however, showed a rising trend during the second half of the year, with the mean twelfth month values significantly higher than those of the sixth (P<.OOl), third (P<.OOl) and first months of use (P<.OOl). In 30 out of 83 months of observation (36 percent), the serum concentration of prog reached the value of 5 ng/ml or more on one occasion or of 3 ng/ml or more on two successive occasions, suggesting the occurrence of ovulation The incidence of such high values did not differ from one in these months. month to the next. Figures 2-7 depict representative examples of the hormonal profile of six of the subjects who were longitudinally followed during the first, third and sixth months of NORPLANT@ use. Estradiol concentrations were in the range obtained in the normal menstrual cycle with occasional spikes and

NOVEMBER

1984 VOL. 30 NO. 5

393

Prog

c2

PRL

LH

FSH

Values

of samples

of NORPLANT

Prolactin

I: Mean

(ng/ml)

0.6

50

10.0

(ng/ml)

(W/ml)

6.9

-t

-+

_t

-t

0.3

30

8.7

4.3

5.6 + 3.2

63

Preplacement

use

161

1.9

85

9.7

23.4

-t

_+

t -

1.4

78

6.5

-421.4

l.Ol+- 0.82 4.5 + 3.1

1.7

105

8.2

24.1

-t

-t

+

0.9

110

4.3

+18.9

0.41+- 0.15 5.2 f 3.2

107

3rd Mon

198

1.5

96

10.6

17.4

+ _

+

+

1.2

87

6.6

+17.1

0.39+- 0.24 4.4 -+ 2.8

FSH,

89

9th Mon

the First

(LNG),

1.5

111

13.7

11.5

-t

+ _

t _

1.3

70

7.6

+17.9 -

0.31+- 0.13 4.7 -f 3.2

During

6th Mon

(Prog)

of Levonorgestrel

Progesterone

Concentrations (E2) and

1st Mon

(+ SD) of Serum

(PRL), Estradiol

(IU,'L)

(IU/L)

LNG ng/ml

Number

Table

LH,

1.1

78

15.0

14.8

+ _

_t

1.0

58

+10.2

+14.1 _

0.34+_ 0.10 4.2 -+ 3.0

112

12th Mon

Year

CONTRACEPTION

Figure

1

The geometric mean (2 2 SD) of serum concentrations of levonorgestrel in 10 subjects who were sampled every 3 third and sixth months of days during the first, NORPLANT@ use.

NOVEMBER 1984VOL.30NO.5

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CONTRACEPTION

PRL LW *olloo -80

FSH 100 90

,--cLH

80

-

FSH

70

b-4

Proloctin no/ml

IU/L

-80

IU/L -20

-70 -60 - 50 -40

-IO- 30 -20 - IO -0 -0 Prolg b LNG 5.5 5.0 4.5

Proocsteronc fig/m

E2 1412

Estradiol pg /ml Levonorgcstrcl ng/ml

1200 - 180

3.5

P: I ‘p

-140

3.0

r

\

-120

2.5

i

!

- 100

\

- 80

4.0

: 1 &

-160

“..q

- 20 d0

oI5

30 ---?&=% 60

Figure Serum concentrations ha1 f) , levonorgestrel, (lower half) during of NORPLANT@ use in

396

- 60 - 40

D ;:’ ‘t.

of

150

165

180

2

FSH, LH, estradiol the first, third one subject.

prolactin (upper and progesterone and sixth months

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1984 VOL. 30 NO. 5

CONTRACEPTION

PRL

FSH 80 70 60

*-+

LH

;L-O

FSH

-.

-

LH

IU/L

- 70 -20

IU/L

Proloctin

b-q/ml

p”

- 60 -50

E2 1266

Prog 8. LNG P roQcrtcronc Estrodiol

ng/ml

220

pg /ml

LewnorgeStret

200 160

q/ml

1 160

1

IS

30

75

60

so

I

I50

1

I65

160

Days

Figure 3 Serum concentrations of FSH, LH, prolactin (upper half), levonorgestrel, estradiol and progesterone (lower half) during the first, third and sixth months of NORPLANT@'use in one subject.

NOVEMBER 1984VOL.30N0.5

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CONTRACEPTION

FSH 130-

*__y, ----,

120R

IIO-

PRL LH 1401'30

II hp

loo-

I, I

so60

LH IU/L FSH IU/L Prolactin ng/ml

1 -60

A?

_f 'O I

\ ,

60-1

:

-70 20-60 -50 -40 -'O-30 -20 - IO 20-o

Prog 8, LNG 6.56.0-

o........0 Progesterone

ng/ml I&_$:

o- -4 Estrodiol pg /ml -

5.5SO-

i!

I

Lcvonorgestrei

ng/ml

\

-160 p

-160

,fii

-I40 -120 - 100

OC-.

”

I5

30

90

60

Figure

Serum

Is0

398

I60

4

concentrations of FSH, LH, levonorgestrel, estradiol (lower half) during the first, third of NORPLANT@ use in one subject.

half),

165

prolactin

(upper

and progesterone and sixth months

NOVEMBER1984 VOL. 30 NO. 5

CONTRACEPTION

FSH

PRL c?--z

LH

-

FSH

-

-

LH ‘150

IU/L

- 140

IU/L

Proloctin

ng/ml

4

Q I

. 110 -30-100

I I I I I

a

I30 - 120

I

Prog

0

. 00 -80

,........oprogcst ng/ml EZ -..dEstrodiol pg /ml 3:: Lewmrgestr;l nwnl_ 240

LNQ

6.5. 6.0.

!

5.5 -

:..:

220

50. 4.5 4.0r

a

I5

1

30

/O

I1

_....I

60

SO

75

150

165-

180

Days Figure

5

Serum concentrations of FSH, LH, prolactin (upper estradiol and progesterone half), levonorgestrel, (lower half) during the first, third and sixth months of NORPLANT@ use in one subject.

NOVEMBER1984 VOL. 30 NO. 5

399

CONTRACEPTION PRL

FSh

LH ,40,‘50

IJO-

I

120 -

w

IIO100 so

-

60

-

70

-

60-

+-4

LH

-

FSH

ti.4

Proloctin

* ,,........ Q

Progesterone

-..9

Estrodiol

-

Levonorgestrel ng/ml

P I\ II ’ I ’ I 1 I ’ I II

IU/L

_I IO

_~‘I00

IU/L ng /ml

- so - 80

J

R

R . .

ng/ml

pg /ml

-

I60

-160 - 140 - 120 100 -

60

- 60

_

01 15

30

so

75

60

40

-

20

wo

165

IS0

-

180

Days

Figure Serum

half),

concentrations

(lower half) during of NORPLANT@ use in 400

of

levonorgestrel, the one

6

FSH,

LH,

estradiol first, subject.

third

prolactin and and

NOVEMBER

(upper

progesterone sixth months

1984VOL.30NO.5

CONTRACEPTION

FSH ioor

so80-

PRL

+----o LH IlJ/L -FSH -,-

130

IU/L Proloctin

ng /ml

LH 100 - 90 - 80

70-

- 70 -20

R /I

60.

- 60 - 50 - 40 -10

-30 - 20 - IO

-0

Prog 8 LNG 7.5 w ......-oProgesterone nghl 7.0 .+.. + E~8tradiol pg/ml 6.5

ao-

-

Levonorgestrei

JO

E2 1486 300 - 280

Q

260

ng/ml

-240

5.5-

- 220

5.0 -

-200

4.5 -

- 180

4.0-

160 - 140 - 120 100 80 -60 - 40

A,

20

.--h&__

15

SO 150

30 60

Figure

JO 165

I80

7

Serum concentrations of FSH, LH, prolactin (upper and progesterone half), levonorgest rel , estradiol (lower half) during the first, third and sixth months of NORPLANT@ use in one subject.

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1984 VOL. 30 NO. 5

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CONTRACEPTION

broad peaks (Figures 2, 3, 4 and 6). Estradiol rises were usually associated or immediately followed by surges in LH concentration. (Examples can be found in all figures.) But these Eg and LH peaks were not always followed by evidences of ovulation. Rises in FSH concentration were rare Serum progesterone values suggestive of ovulation were and modest. occasionally obtained (Figure 4, during the first month; Figure 5, during the sixth month; and Figure 7, during the sixth month). However, the level of progesterone tended to be in the low normal range; in none of the months studied was a level of more than IO ng/ml obtained. The progesterone rises were frequently short-lived (Figure 6 during the first month and Figure 7 not attended by a rise of estradiol (Figure 5, during the third month), sixth month) and/or followed shortly thereafter by menstrual bleeding. A particular hormonal profile obtained in one month did not always repeat a pattern suggestive of ovarian activity may itself in subsequent months; be followed by a pattern suggestive of ovarian quiescence (Figure 4) and vice versa (Figure 7). Bleeding estradiol bleeding spite of

episodes generally followed a drop in the concentration or progesterone or both, but not all the nadirs were (Figures 3, 4 and 6)) and bleeding occasionally a rising concentration of E2 (Figure 6, sixth month).

of either followed by occurred in

Discussion The serum concentration of levonorgestrel during the first year of variability. NORPLANT@use showed wide, interindividual The mean values showed a steep decline during the first two weeks of use; the decline became gradual during the subsequent two weeks. The decrease of the mean ninth month values relative to those of the sixth month may have depended partially on this broad range of interindividual variability. The decline in serum concentration of LNG after the first month of use is undoubtedly related to decline in the release rate of the proqestoqen from the Nash -et al. (9) have found that the --in viva release rate of capsules. levonorqestrel from the Silastic capsules frequently showed an appreciable decrease during the first 100 days of use and a more gentle decrease They also noticed a significant difference in release rate thereafter. among subjects. The hyperemia attending the local inflammatory reaction that follows insertion could be contributing to the initial high level in circulation, and its subsidence together with progressive fibrosis around the capsules may respectively contribute to the rapid, followed by slow, decline in blood level. The extent of this fibrosis may be a determining factor in interindividual variability (10,ll). The blood levels may also reflect other influences such as the depressive effect of the progestogen on the production of the sex hormone binding globulin (12) on which levonorgestrel is carried in the circulation. The method used for determining LNG in the present study measures both the free and the protein-bound moieties of the progestogen. The absence of obtained during is no tendency the contraceptive

402

any significant change in values of FSH, LH, E2 and prog the successive months of observation indicates that there of the pituitary-ovarian axis to escape from the effect of during the first year of use.

NOVEMBER 1984VOL.30NO.5

CONTRACEPTION

The present study confirms, in a larger nunber of subjects, the previous observation (3,4) of occurrence of frequent, irregular estradiol peaks during NORPLANT@ use, indicating unsuppressed Follicular activity. The rises in serum estradiol concentrations were frequently associated with surges in LH concentrations, indicating the operation of the positive feedback mechanism of estradiol. This finding differs from that of Weiner et al. (13) who noted inhibition of the positive feedback of estradiol during treatment with subcutaneous Silastic implants containing levonorgestrel. However, in the latter study, rods delivering higher doses of levonorgestrel were used, and in none of the subjects studied did ovulation occur; while in the present investigation, ovulation was not uncommon. Evidence of ovulation, taken as a serum progesteorne value of 5 ng/ml or more on one occasion or of 3 ng/ml or more in two successive blood specimens three days apart, was observed in 36 percent of the months of The incidence of ovulation observed in the present study observation. during NORPLANT’a use might have been higher than this since we were studying months rather than menstrual cycles; ovulation could have been missed if it occurred shortly before or after the month of observation. In none of the Evidences of deficient luteal function were frequent. instances of presumptive ovulation was a typical luteal phase endocrine profile obtained; the progesterone rises never reached the level of IO unattended by a simultaneous rise ng/ml. Rises were generally short-lived, in estradiol concentration and, in many instances, were followed closely by withdrawal bleeding. Deficient luteal function could, therefore, be a This is contributing factor in the contraceptive effect of NORPLANT@‘. likely to be the effect of levonorgestrel on the ovaries. Mukherjee --et al. (14) have shown that the administration of small doses of norgestrel reduced the ability of the corpus luteum to synthesize progesterone from preqnenolone on incubation --in vitro. The present investigation shows the occurrence of a rise in serum prolactin concentration during the latter part of the first year of NORPLANT” use. However, it must be mentioned that the majority of the high PRL values were within the normal range found in our population (7). The tendency to rise may be related to the effect on prolactin secretion of the frequent spikes This and broad peaks of estradiol secretion observed during NORPLANT” use. observation needs further follow-up. Our study indicates that the effect of NORPLANT@ implants pituitary-ovarian axis of a subject may vary from time to time. be related to time-to-time variability in the amount of the released from the six capsules.

on the This may qestogen

NORPLANT@’ use was frequently associated with disruption of menstrual Bleeding and rhythm, particularly during the early phases of use (2). spotting frequently followed a decline in the concentration of estradiol But not all the nadirs were followed by blood loss and/or progesterone. and blood losses occasionally occurred despite rising levels of these An endometrial factor may he involved in causing such bleeding steroids. episodes.

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CONTRACEPTION

Acknowledgements This study was supported by a grant from the Rockefeller Foundation. Reagents for the assay of hormones were obtained from the WHO Program for the Distribution of Matched Reagents for the RIA of Hormones in Reproductive Physiology. Special thanks are due to the technical staff of the the Reproductive Biology Unit of the Assiut University Faculty of Medicine.

References 1.

Sivin, I., Diaz, S., Holma, P., Alvarez-Sanchez, F. and Robertson, D.N.: A four-year study of NORPLANT@ implant. Studies in Family Planning 14:184-191, 1983.

2.

Shaaban, N.M., Salah, M., Zarzour, A. and Abdullah, implants and TCu 380 Ag IUD prospective study of NORPLANT" Studies in Family Planning 14:163-169, 1983. Egypt.

3.

Plasma levels of d-norgestrel, Weiner, E. and Johansson, E.D.B.: estradiol and progesterone during treatment with Silastic implants containing d-norgestrel. Contraception 14:81-92, 1976.

4.

Moore, D.E., Roy, S., Stanczyk, F.Z. and Mishell, D.R., Jr.: Bleeding and serum d-norgestrel, estradiol and progesterone patterns in women using d-norgestrel subdermal polysiloxane capsules for contraception. Contraception 17:315-328, 1978.

5.

Abdalla, M.I., Shafeek, M.A., Fayad, M.M. and Ibrahim, 1.1.: Subdermal levonorgestrel implants and pituitary function. Contracept. Deliv. Syst. 4:323-325, 1978.

6.

Gomaa, A.A.: Ph.D. Thesis: Treatment of Pathological Hyperprolactinemia. Assiut University, 1980.

7.

Shaaban, N.M., Hammad, W.A., Ghaneimah, S.A., Salem, H.T. and Gomaa, A.A.: Serum prolactin concentration during ovulatory menstrual cycle. J. Egypt. Obstet. and Gynaec. 6:19-27, 1980.

8.

Spona, J., Weiner, E., Nieuweboer, B., Humpel, M., Schneider, W.H.F. Injectable depot contraceptives of and Johansson, E.D.B.: d-norgestrel basis. II. Clinical pharmacokinetic studies with d-norgestrel undecylate in women. Contraception 15:413-428, 1977.

9.

Nash, H.A., Robertson, release from Silastic

D.N.,Young, capsules and

A.J.M.

and

Atkinson,

L.:

S.A.: A in Assiut,

Steroid

rods. Contraception 18:367-394,

1978.

404

NOVEMBER

1984 VOL. 30 NO. 5

CONTRACEPTION

10.

Eenagiano,

G.,

sustained

siloxane implants. Acta Endocrinol. 11.

Ermini,

M.,

sustained siloxane

12.

13.

14.

Ermini,

contraceptive I. 73:335,

Carpino,

M.,

Carenra,

effects

F.,

with

Diffusion 1973. Russo,

M.

Victor, A. and Johansson, E.D.B.: decreases in sex hormone binding levels in plasma. Contraception Weiner, E., feedback of d-norqestrel. Mukherjee, Effect of

Gynaec.

NOVEMBER

of

contraceptive effects with implants. Acta Endocrinol.

Johansson, E.D.B. estradiol during Contraception T.K.,

Wright,

S.W.,

I-.

and

megestrol

G.:

G.:

Studies

on

polydimethyl-

and Wide, I-.: Inhibition treatment with subcutaneous 13:287-298, 1976. hl..J.H.

on

in humans.

acetate

Effects of d-norgestrel globulin capacity on the 16:115, 1977.

Davidson,

Studies

polydimethyl-

and Benagiano, subcutaneous 73:360, 1973.

norgestrel on corpus luteum function. Brit. Comwlth. 79:175-182, 1972.

1984VOL.30N0.5

Roflini,

subcutaneous

and

J.

induced d-norqestrel

of positive implants

Fotherby,

of

K.:

Obstet.

405