Studies on ovarian and adrenal steroids at different phases of the menstrual cycle

CONTRACEPTION

STUDIES ON OVARIAN AND ADRENAL

STEROIDS

MENSTRUAL

AT DIFFERENT

PHASES

OF THE

CYCLE

III. Steroid and lutropin levels before and after the administration of a single contraceptive dose of depot-medroxyprogesterone acetate (DMPA). A.-R. Reproductive

Aedo,

B.-M. Landgren

Endocrinology

and Gynecology,

Research

Karolinska

and E. Diczfalusy*

Unit and Department

sjukhuset,

Stockholm,

of Obstetrics Sweden

ABSTRACT Ovarian and adrenal steroids and biologically active lutropin were measured in peripheral plasma samples obtained from 5 normally menstruating women. Plasma samples were collected every 3 h for a period of 39 hours in the periovulatory period of a pretreatment (control) cycle and then 16 and 54 days after a single i-m. injection of 150 mg of depotmedroxyprogesterone acetate (DMPA). Sixteen days after DMPA administration, the levels of estradiol, progesterone, 17-hydroxyprogesterone, and lutropin were reduced to early follicular phase levels. No further decrease was found in 17-hydroxyprogesterone and lutropin levels; however, an additional decrease occurred in the levels of estradiol and in the "morning" levels of progesterone 54 days after the administration of DMPA. Furthermore, the levels of pregnenolone, androstenedione, testosterone and dihydrotestosterone were significantly diminished in all samples collected after the administration of DMPA. Fifty-four days following the administration of DMPA, the levels of cortisol and 17-hydroxypregnenolone were significantly reduced. The administration of DMPA did not interfere with the circadian rhythm of cortisol,pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 17-hydroxyprogesterone, and androstenedione levels. A significant circadian rhythm was also found in testosterone (after 16 days) and lutropin (after 54 days) levels. No circadian variation was found in estradiol, progesterone and dihydrotestosterone levels

* To whom reprint Submitted

requests

for publication

should be directed. June22,

Accepted

for publication

AUGUST

1981 VOL. 24 NO. 2

July

6,

1981 1981

117

CONTRACEPTION

It is concluded tnat a single intramuscular injection of 150 mg of DMPA results in a slight, but significant suppression of adrenocortical activity, without, however, interfering with the circadian rhythm in the secretion of the principal adrenocortical steroids. The administration of DMPA strongly affects ovarian secretory activity, as evidenced by the peripheral estradiol and progesterone levels, which are gradually reduced to levels below those of the follicular phase.

INTRODUCTION

Medroxyprogesterone acetate (MPA) is a potent progestational agent, which has been, and still is extensively used for the treatment of a variety of conditions, such as endometrial cancer (l-5), breast cancer (6-8), renal cancer (9,10), precocious puberty (ll-16), hirsutism (17,18), endometriosis (19), etc. Furthermore, a microcrystalline suspension of this drug is used as a long-acting injectable contraceptive (for review: 20-24). A large number of investigations (25-29) have addressed themselves to the elucidation of the mechanism of action of depot-medroxyprogesterone acetate (DMPA). From these investigations it appears to be clear that ovulation suppression is the principal mode of contraceptive action of DMPA, as evidenced i.a. by the absence of the midcycle surge in estradiol and lutropin levels and of the subsequent rise in progesterone levels. With the exception of the study of Briggs and Briggs (30), who measured testosterone levels in plasma samples of women treated with DMPA, little information appears to be available in the literature as to the peripheral levels of steroids other than estradiol and progesterone in healthy women treated with contraceptive doses of DMPA. When MPA was given in frequent and massive doses to children with precocious puberty (12,13,31) and to patients with advanced forms of cancer (32,33), a more or less complete suppression of adrenocortical function was found. However, the reports concerning the effect of DMPA on adrenal activity when given in contraceptive doses are not consistent. Jones et al. (34) reported slight suppression of plasma cortisol levels with a-htly blunted metyrapone response, but these findings have not been confirmed by other investigators (30,35). In a previous paper of this series, we have studied the short-term changes in plasma levels of a variety of ovarian and adrenal steroids toqether with those of lutrooin in the follicular. oeriovulatorv.and luteal phases of the normal menstrual cycle (45). On the-basis of this"study, it was felt that the experimental design adopted enables the evaluation of even modest changes in the circadian rhythm of the steroid levels. Hence, the present study was designed with the special purpose of critically assessing the changes induced by a single contraceptive dose of DMPA in

118

AUGUST 1981VOL. 24 NO. 2

CONTRACEPTION

the peripheral levels of different at frequent intervals.

MATERIAL

adrenal

and ovarian

steroids

measured

AND METHODS

Clinical material. Five healthy women with a history of regular menses and proven fertility volunteered for this study. They had not used steroidal contraception or intrauterine devices for at least three months before the start of the investigation. Prior to the initiation of the study, a complete gynecological examination was carried out, and the hematological status of the subjects was carefully checked before, during and after the completion of the study. The clinical data of the volunteers are indicated in Table I. The blood sampling adopted in this investigation was similar =@-iY to t e procedure described in a previous paper (45). Ten ml blood was withdrawn every third hour through a catheter inserted in the antecubital vein. The sampling started in all subjects at 18.00 h and conon three different tinued until 09.00 h two days later. It was performed occasions: during the periovulatory period of the pretreatment (control) cycle and 16 and 54 days after a single injection of 150 mg of depotmedroxyprogesterone acetate (DMPA, Upjohn Co., Kalamazoo, Michigan, USA). The DMPA was given as a deep intragluteal injection on the fourth day of the cycle following the control cycle. In addition to this blood sampling, daily samples of 10 ml were also withdrawn in the control cycle for 10 days around the expected time of the LH surge. The exact day of the LH peak of the control cycle was assessed by a retrospective analysis of the lutropin and progesterone levels. Determination of steroids and lutropin. A rapid radioimmunoassay method was used for the cortisol measurements (36) and for the daily progesterone determinations (37). The analysis of all other steroids involved separation and purification on celite columns, using previously described methods (38-40). Lutropin was estimated by an in vitro bioassay (41) as applied to plasma samples (42,43). The results ofli.i?@%n assays are expressed in terms of the First International Reference Preparation of Gonadotrophins (FSH and LH/ICSH) for Bioassay (Code number : 69/104), and those of the steroid analyses in SI units.

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119

CONTRACEPTION

Table

I. Clinical

Subject

data of the 5 subjects

Age

Height

Weight

(yrs)

(cm)

(kg)

who volunteered

Previous pregnancies

Cycle length (days)

for this study

Starting day of periovul$tory sampling

LS

35

153

50

3

25-26

LH-4

AB

28

173

69

2

28-30

LH

BA

37

174

80

2

25-28

LH-1

CL

35

163

51

2

28-30

LH-2

HA

31

165

56

5

28-30

LH

*

120

Day in relation to the LH surge, as established on the basis of daily hormone assays.

in retrospect

AUGUST 1981 VOL. 24 NO. 2

CONTRACEPTION

The results found in the different Calculation of the results. subjects were grouped according to the clock time. A lognormal distribution of individual hormone levels was assumed (44). The data were analyzed for the detection of a circadian rhythm before and after DMPA administration and to assess the changes in hormone levels after the administration of the drug. The significance of the findings was assessed by a two-way analysis of variance, using appropriate contrasts. The design used in the calculations was exactly the same as reported in the previous paper (45). The hormone levels of the samples obtained immediately after the insertion of the catheter (18.00 h) were not included in the calculations, due to clear manifestations of stress in some of the patients, as judged by the strongly elevated levels of cortisol and 17-hydroxypregnenolone in these samples. Hence, all calculations are based on the analysis of 13 samples collected during a period of 36 hours.

RESULTS The geometric mean levels and 95% confidence limits of the hormones analyzed are shown in Figs. l-3, and the statistical assessment of the findings is presented in Tables II and III. Circadian rhythm. The significance of the ratio of variances (Fvalues) obtained in the analysis of variance of the hormone levels measured in the different sampling periods is shown in Table II, under "morning" and "evening" column "A", and the values obtained by contrasting levels in each of the sampling periods are shown under column "5" of the same Table. The analysis of the contrasts between "morning" and "evening" samples revealed that the levels of progesterone, dihydrotestosterone and estradiol did not show any circadian rhythm, neither in the control period nor in the samples taken 16 and 54 days after the administration of DMPA. Cortisol, pregnenolone, dehydroepiandrosterone and androstenedione levels showed a circadian rhythm in all three sampling periods. However, a circadian rhythm in 17-hydroxyprogesterone levels was detected only in the samples taken 16 and 54 days after the injection of DMPA. The circadian rhythm in testosterone levels was significant only during the period 16 days after DMPA and that of lutropin only in the samples obtained 54 days after DMPA administration. Comparison of pretreatment hormone levels with those found 16 and 54 days after the administration of DMPAYthe it can be seen that the administration of DMPA resulted in a siqnificant lowering of progesterone, 17-hydroxyprogesterone, androstenedione, testosterone. estradiol and lutrooin levels both 16 and 54 davs later. Furthermore,. it can also be seen'from the data of Table III ‘that the estradiol levels were lower in all samples 54 days after the administration

AUGUST

1981 VOL. 24 NO. 2

121

CONTRACEPTION

CORTISOL CONTROL 600,

TREATMENT 16 DAYS

mnOl/l

54

DAYS

PREGNENOLONE

17 -HYDROXY PREGNENOLONE

DEHYDROEPIANDROSTERONE

21

Fig. 1.

3

9

15 21

3

9

21

3

9

15 21

3

9

21

3

9

15

21

3

9

CLOCK TIME (HOURS)

Geometric means and 95% confidence limits of

peripheral cortisol, pregnenolone, and dehydroepiandrosterone

17-hydroxypregnenolone

levels in five women before and

16 and 54 days after a single injection of 150 mg of depomedroxyprogesterone

acetate (DMPA). Samples obtained

during a period of 36 h

were analyzed. The control samples

were collected during the periovulatory period.

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AUGUST

1981 VOL. 24 NO. 2

CONTRACEPTION

LH TREATMENT

CONTROL

54 DAVS

16 DAYS

PROGESTERONE

17-HYbROXYPROGESTERONE

ESTRADIOL I400 7 pmol/l

600

1000 2000

1 --

Fig. 2.

21

3

9

1s

21

3

9

.?I

3

9

H

21

3

9

21 3

9

15 21 3

9

CLOCK TIME (HOURS)

Geometric means and 95% confidence limits of the

peripheral plasma levels of biologically active lutropin (LH), progesterone,

17-hydroxyprogesterone

and estradiol in 5 women

before and after the administration of DMPA. For further details see legend to Fig. 1.

AUGUST

1981 VOL. 24 NO. 2

123

CONTRACEPTION

ANDROSTENEDIONE CONTROL

TREATMENT 16 DAYS

54

Luvs

TESTOSTERONE 2000

PrnOl/l

1000 0 !

DIHYDROTESTOSTERONE 2000 Pmol/l 1

0

21

3

9

15

21

3

9

21

3

9

15

n

3

9

21

3

9

15

n

3

9

CLOCK

TIME

(HOURS)

Fig. 3.

Geometric means and 95% confidence limits of

peripheral androstenedione, testosterone

testosterone and dihydro-

levels before and after the administration

of DMPA. For further details see legend to Fig. 1.

124

AUGUST

1981 VOL. 24 NO. 2

(column

error

and the residual

A

0.6gNS

5.62***

3.07**

2.32*

2.81**

0.6gNS

17-Hydroxyprogesterone

Androstenedione

Testosterone

Dihydrotestosterone

Estradiol

Lutropin

were

period

occasions.

calculated

B

because

-

did

and

not reveal

any

B.

2.76**

;::$

2.26*

7.67***

6.32***

0.8ZNS

8.44***

7.32***

8.43***

B

significant

13.7***

_

2.83NS

O.lONS

31.9***

13.8***

-

17.7***

21.9***

7.49***

22.2***

54 DAYS

13.1***

A

difference

samples

and residual

"evening"

occasions

ADMINISTRATION

in column

,104NS

39.7***

42.4***

46.7***

-

49.2***

44.3***

54.2***

52.5***

B

DMPA

"morning"

to sampling

between

due

(1, 48)

of variance

significant.

the analysis

NS: not

A and

l.8gNS

2.57**

l.9BNS

6.05***

7.41***

7.88***

1.61NS

8.32***

7.62***

7.28***

13.7***

A

16 DAYS

FOLLOWING

to contrasts

the variation

: (12, 48) in column

-

O.lONS

2.8gNS

3.93NS

22.6***

-

2.45NS

23.5***

4.45* *** 30.3

: p < 0.01, ***:p < 0.001,

the sampling

a) Periovulatory

between

- = No contrasts

*: p < 0.05,**

the F-values

4.05***

Progesterone

for

8.40***

of freedom

8.04***

Dehydroepiandrosterone

between

attributable

21.0***

(CONTROL)

17-Hydroxypregnenolone

Degrees

ratios

(F-values)

PRETREATMENTa)

B)

18.8***

(column

3.49***

error

Pregnenolone

Cortisol

HORMONE

of variances

A) and the variance

II. The ratios

Table

$

K

;;:

$

compared

**+ NS ***+

*J. *+

***J.

***+

***+

*+

***+

***+

**

levels

obtained

found

e.g.***+

and

C:16

means

in the control

for

hormone

h

those

of another

lower

(lower)

levels

in the

and

one.

***+

**+ **%q,

*+ ***+ 'j. NS ***+ ***+ ***+ ***+

c:54

NS

**+ NS ***J-

NS NS NS **+ NS NS ***+

16:54

samples c)

acetate

period

16 days

after

group DMPA

i.e. 6 sampling

second

the two mornings),

with

significantly

higher

period.

NS

*+ ***+ ***+

*+ **+ ***+ ***+ ***+ ***J,

NS ***+

NS NS *+ NS *+ NS NS ***+

C:16

"Evening"

16:54

administration.

during

the control

***+ ***+

samples b)

significant.

compared

are

09.00

***+

**+ ***+

***.&

****

***+

***+

NS ***j. *+ NS

between

of 150 mg medroxyprogesterone

levels

C:54

DMPA

NS: not

of a group

occasions.

06.00

of the corresponding

to the levels

***+

after

***+

*: p < 0.05;

occasions

(03.00,

at all other

are compared.

values

***+

NS

NS

*J,

***+

***+

***+

NS

***+

***+

***+

***+

***+

***J,

***4

NS

NS

NS NS NS

C:16

"Morning"

*+

and 54 = 54 days

: p < 0.01;

16 = 16 days

in the first,

= the

than

r(s)

c) Values

NS

***+

**+

***J.

NS ***+

***+

16:54l)

**+

Ii:

hormone

administration

C:54

groups a)

the

in mean

C:16

Between

54 days,after

of differences

of 13 sampling

"morning"

occasions

b) Only

a) The means

p < 0.001;

C= control,

***:

1)

Cortisol Pregnenolone 17-Hydroxypregnenolone Dehydroepiandrosterone Progesterone 17-Hydroxyprogesterone Androstenedione Testosterone Dihydrotestosterone Estradiol Lutropin

16 and

Significance

periods,

III.

zampiing

Table

two

CONTRACEPTION

of DMPA compared to those seen after 16 days. Also the progesterone levels were lower 54 days after the injection of DMPA, but only in the "morning" samples. On the other hand, the androstenedione and, in part, the testosterone levels were higher 54 days after the injection of DMPA compared to those found 16 days after DMPA administration. No significant changes were observed in the 17-hydroxyprogesterone and lutropin levels between the 16th and 54th day after DMPA administration. The changes observed in the levels of other steroids were as follows: a) The cortisol levels found 54 days following DMPA administration were lower than those seen 16 days after the injection of the drug, or during b) The pregnenolone, 17-hydroxypregnenolone and the control period. dihydrotestosterone levels 16 and 54 days after DMPA administration were significantly lower compared to the pretreatment values. This was mainly due to a lowering of the "evening" values after 16 days of administration, whereas both "evening" and "morning" levels were suppressed after 54 days- exposure to DMPA. c) Dehydroepiandrosterone levels were lower 16 days after DMPA administration than in the control samples. This was due to a decrease in the "evening" levels of this steroid. A comparison of dehydroepiandrosterone levels obtained 16 and 54 days after DMPA administration revealed higher levels of this steroid in the "evening" samples of the 54th day.

DISCUSSION Adrenal effects. Does medroxyprogesterone acetate (DMPA) affect cortisal?Zztion when given in contraceptive doses? Jones et al. (34) measured cortisol in single samples collected from 10 patientsfore and after one or several injection(s) of DMPA and concluded that the cortisol levels were suppressed by DMPA treatment. On the other hand,Vermeulen and Thiery (35) and Briggs and Briggs (30) found no changes in cortisol levels when the levels of this steroid were measured one month after the second injection and three months after a single injection of DMPA, respectively. The present data demonstrate a very slight, but statistically significant, suppression of cortisol levels following the administration of a single dose of 150 mg of DMPA, suggesting slightly diminished adrenal activity. The fact that the administration of DMPA induces a slight suppression of adrenocortical steroids is further strengthened by the slight, gradual decrease in 17-hydroxypregnenolone levels. We have previously reported (46,47) that the levels of this steroid represent a sensitive indicator of adrenal activity, at least as sensitive as those of cortisol. In experimental animals, MPA is known to induce adrenal atrophy (48,49) and depletion of pituitary ACTH concentration (50). Furthermore, in men, MPA has been successfully used for the treatment of glucocorticoid insufficiency (52). These effects were attributed to a cortisol-like property of the drug, which was confirmed by Briggs and Briggs (51).

AUGUST 1981 VOL. 24 NO. 2

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CONTRACEPTION

Hence DMPA has a cortisol-like effect both in experimental animals and in human beings. Indeed, the fact that patients treated with high doses of MPA (33,53) did not show any signs of adrenal insufficiency when the peripheral plasma levels of cortisol were very low, or even zero, convincingly demonstrates this cortisol-like effect of the drug. Hence, the slightly diminished cortisol levels found in this study are only significant from the statistical, but not from the pharmacological, point of view. Since DMPA diminishes adrenocortical function only very slightly, but exerts per se a glucocorticoid activity, it might also be questioned whether thexl;i?ce of these two is just right, or whether the administration of DMPA might lead to some sort of an excess of glucocorticoid activity. All available metabolic evidence (35,54) suggests that the latter is not the case. Hence, the changing balance in corticoid activity in DMPAtreated women does not seem to result in any hormonal and metabolic alterations of concern. This view is strongly supported also by the present findinq of an intact circadian rhvthm in the levels of a varietv of steroids of predominantly adrenocortical origin, such as cortisol, 17hydroxypregnenolone, dehydroepiandrosterone, androstenedione and pregnenolone. Ovarian effects. Does the administration of DMPA result in a diminished testosterone secretion? There is some evidence indicating that MPA treatment decreases testosterone levels in hirsute women (17,18) and in women with polycystic ovarian syndrome (55). Also, in a study on the effect of MPA on the metabolism and "biological activity" of testosterone, a "tendency" toward diminished levels was reported (56). On the other hand, in a study carried out by Briggs and Briggs (30),no changes were found in testosterone levels in women treated with contraceptive doses of DMPA. The data reported in the present paper indicate a significant decrease in testosterone levels in parallel with significantly diminished levels of dihydrotestosterone and androstenedione. Obviously, some caution is needed in the interpretation of these data, because the pretreatment levels were obtained in the periovulatory period, which is associated with a slight, but significant rise in androgen levels (45). However, a comparison of the testosterone levels found following DMPA administration with those reported by us for the follicular phase (45) also suggests that the administration of DMPA results in partially diminished peripheral testosterone levels. Furthermore, since there was an intact circadian rhythm in androstenedione (and 16 days after DMPA administration also in testosterone)levels, it is reasonable to assume that DMPA mainly suppressed ovarian androgen secretion. Whether the mechanism of action of this DMPA-mediated suppression involves a reduced ovarian testosterone secretion pari passu with that of estradiol, a decrease in sex hormone binding globuliTi-'rev~57), an increase in hepatic steroid A-ring reductase (58), a change in metabolic clearance rate (56) or other factors, perhaps in combination with these, remains to be elucidated.

128

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CONTRACEPTION

Examination of the estradiol levels found in this study reveals a significant and gradual decrease to levels lower than those reported by us for the early follicular phase (45,59). Other investigators, using a longitudinal type of sampling, also reported on relatively low estradiol levels in DMPA-treated women (26,28,30,60,61). These investigators also described occasional day-to-day fluctuations (60) and an increase in estradiol levels at the end of the third post-injection month (28,61). Since our data were obtained by frequent sampling during limited periods of time, it is difficult to compare them with results based on daily, or less frequent sampling during prolonged periods of time. Also the progesterone levels exhibited a decrease with time; hence the estradiol and progesterone levels indicate a gradual suppression of ovarian steroid secretion under the influence of DMPA. On the other hand, the 17-hydroxyprogesterone levels did not show any progressive decline, although the clear-cut circadian rhythm in the peripheral levels of this hormone following the administration of DMPA seems to provide some evidence in favor of the view that DMPA mainly suppressed ovarian, but not adrenal secretion of 17-hydroxyprogesterone (cf. 45). Pituitary effects. Except for the estimation of biologically active LH, n-was made in this study to assess the effect of DMPA on pituitary function. The levels of LH were unchanged between the 16th and 54th day and were of the same order as those found by us during the follicular phase (45). There is agreement in the literature that the administration of DMPA abolishes the midcycle LH surge; whether the residual tonic levels of gonadotrophins measured by others (immunoreactive FSH and LH) are of the order of the follicular phase (26) or of the luteal phase (60), must be answered by other types of investigations.

ACKNOWLEDGMENTS

The expert technical the bioassays of lutropin

assistance of Mrs. Monica Lindberg is gratefully acknowledged.

This investigation received Organization-s Special Programme

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1981 VOL. 24 NO. 2

in performing

financial support from the World in Human Reproduction.

Health

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CONTRACEPTION

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