Clinical Science (1982) 62,183-191
183
Alterations in haem biosynthesis during the human menstrual
cycle: studies in normal subjects and patients with latent and
active acute intermittent porphyria
K . E. L . M c C O L L , A . M . W A L L A C E , M . R . M O O R E , G . G . T H O M P S O N
AND A. GOLDBERG
university Departmenl of Medicine, Gardiner Institute, Western Znjrrnary, Glasgow, and Department of SIeroid
Biochemistry, Royal Iqfirmary, Glasgow, Scotland. U.K.
(Received 6 April 1981; accepted 9 September 1981)
Summary
1. The timing of onset of attacks of acute
intermittent porphyria (AIP) in relation to the
menstrual cycle has been studied in three patients
experiencing frequent attacks. Nineteen of their
27 admissions in attack for which no exogenous
precipitating causes could be identified were
during the 7 days before the onset of menstruation.
2. Haem biosynthesis has been monitored
throughout a complete menstrual cycle in six
normal females and compared with that in male
control subjects. In the females, there was
marked fluctuation in the activity of the ratecontrolling enzyme of haem biosynthesis, 6aminolaevulinate (ALA) synthase, which was
monitored in peripheral leucocytes. The fluctuation did not show any clear association with
menstruation and no association was found
between the enzyme activity and ovarian or
adrenal steroid production as monitored by
measurement of plasma concentrations of androstenedione, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), testosterone, oestradiol and progesterone. The activity
of uroporphyrinogen I (URO) synthase, the
enzyme which is deficient in AIP, was monitored
in peripheral erythrocytes of four of the normal
female subjects and was similar to that found
in four male control subjects. The urinary
Correspondence: Dr Kenneth E. L. McColl, University DepartmeG of Medicine, Gardiner Institute,
Western Infirmary, Glasgow G 1 1 6NT, Scotland,
U.K.
excretion of ALA and porphobilinogen (PBG)
was also similar in the male and female subjects
and there was no association with the phase of
the menstrual cycle or activity of the enzymes
studied.
3. Studies of haem biosynthesis have been
made throughout a complete menstrual cycle in a
26 year old female with latent AIP. The activity
of leucocyte ALA synthase showed more marked
fluctuation than in the normal female subjects
and was highest at the time of menstruation. No
association was apparent between the activity of
ALA synthase and plasma concentrations of
androstenedione, DHA and DHAS. The fluctuation in activity of erthrocyte URO synthase was
similar to that of the normal subjects. The urinary
excretion of ALA and PBG was normal throughout and showed no correlation with fluctuations
in enzyme activity.
4. The human menstrual cycle modifies haem
biosynthesis in normal subjects as well as in
subjects with latent and manifested AIP.
5. The human female menstrual cycle modifies
haem biosynthesis in peripheral blood cells as
well as in the liver.
Key words: haem biosynthesis, hormones,
leucocyte 6-aminolaevulinic acid synthase, menstrual cycle, porphyria.
Abbreviations:
AIP,
acute
intermittent
porphyria; ALA, &aminolaevulinate; DHA,
dehydroepiandrosterone; DHAS, dehydroepiandrosterone sulphate; PBG, porphobilinogen;
URO, uroporphyrinogen I.
0143-5221/82/020183-09$01.50/1@ 1982 The Biochemical Society and the Medical Research Society
184
K.E. L. McColl et al.
Introduction
Haem biosynthesis occurs in all metabolically
active cells in the human body. It is most active in
the bone marrow, where haem is required for
haemoglobin synthesis, and in the liver, where it
is required for the formation of essential haemoprotein enzyme systems such as cytochrome
P-450, cytochrome b,, catalase and tryptophan
pyrrolase [ 11. A diagrammatic representation of
the pathway of haem biosynthesis is shown in
Fig. 1.
Inherited partial deficiencies of certain of the
enzymes of haem biosynthesis present clinically
as the porphyrias [2]. In acute intermittent
porphyria (AIP) there is a partial deficiency
of uroporphyrinogen I (URO) synthase (EC
4.3.1.8) and a compensatory increase in activity
of the initial and rate-controlling enzyme of the
pathway, Gaminolaevulinate (ALA) synthase
(EC 2.3.1.37). Patients with AIP may develop
attacks of systemic illness characterized by
abdominal pain, neuropathy and mental dysfunction and during such attacks there is a marked
increase in the urinary excretion of ALA and
PBG, which are porphyrin precursors formed
before URO synthase. Various factors may
precipitate attacks of porphyria and most have
been shown to induce the activity of ALA
synthase in animal hepatic tissue [31. There is
considerable evidence that certain steroid hormones play an important role in precipitating
attacks of porphyria. Attacks are more common
in females than males and rarely occur before
puberty, being most common in the third decade
[41. Pregnancy may precipitate attacks and some
women experience regular attacks occurring in
the week before menstruation [51. The contraceptive pill and other forms of exogenous
oestrogens may precipitate attacks of acute
porphyria and are also important in the aetiology
of porphyria cutanea tarda (61. There is some
evidence that hormonal influences alter haem
biosynthesis in normal subjects, increased urinary
excretion of porphyrins and precursors being
reported during pregnancy [7-91 and increased
urinary excretion of ALA in women on the contraceptive pill [ 101.
Animal studies have shown that the activity of
ALA synthase in rat hepatic tissue varies
throughout the female sexual cycle, being highest
in oestrus and lowest in dioestrus [ l l l , and a
similar pattern is observed in the Harderian gland
of the female hamster [121. Certain steroid
hormones have been noted to induce the activity
of ALA synthase in rat hepatic tissue. Among the
most potent tested to date are androstenedione,
androstenediol, dehydroepiandrosterone,
1 7hydroxypregnenolone and aetiocholanolone 1131.
In patients with AIP there is an increased ratio of
5-/3/5-a steroids in the urine and increased
urinary excretion of dehydroepiandrosterone and
aetiocholanolone and increased plasma concentrations of dehydroepiandrosterone [ 14, 151. This
overproduction of porphyrinogenic steroids is
most pronounced during attacks and may be of
importance in the aetiology of attacks of
porphyria.
We have studied the timing of the onset of
attacks in relation to the menstrual cycle in three
patients with acute intermittent porphyria. We
have also studied alterations in haem biosynthesis throughout the menstrual cycle in one
female with latent AIP and in six normal females
and in control male subjects.
Subjects and methods
The timing of hospital admission in clinical
attack, relative to the menstrual cycle, was
studied in three patients (ages 23, 24 and 30
years) with AIP. The diagnosis of AIP was based
on decreased activity of erythrocyte URO synthase, increased activity of leucocyte ALA
synthase and increased urinary excretion of
ALA, PBG and uroporphyrin. The patients had
experienced between them a total of 26 attacks
requiring hospital admission, without apparent exogenous precipitating factors over the 3
year period studied. Over this same time they had
in addition suffered a total of eight attacks related
to the ingestion of porphyrinogenic drugs or
alcohol. All had regular menstrual cycles. As a
result of our self-referral hospital admission
system, their admissions were usually within 1 or
2 days of the onset of symptoms of attack.
Studies of haem biosynthesis were made over a
complete menstrual cycle in six healthy female
volunteers (mean age 30 years, range 26-45
years) and, over a similar time period, in six
healthy male volunteers (mean age 30 years,
range 24-44 years). The males and females were
also matched with respect to body weight. They
had normal blood lead and haemoglobin concentrations and none was taking any form of drug
therapy. All abstained from alcohol throughout
the study. Activity of leucocyte ALA synthase
was measured each Monday, Wednesday and
Friday between 09.00 and 10.00 hours. In four
of the males and four of the females the activity
of URO synthase in peripheral erythrocytes was
also monitored. Blood for the enzyme studies was
withdrawn simultaneously from the male and
female subjects and assayed in the same batch.
I
m
COPROPORPHVRINOGEN1
(8-COOH)
UROPORPHVRINOGENI-
UROPORPHVRINOGEN
..........................................................
................................................................................
(~-COOH)
COPROPORPHYRINOGEN
\
COPROPORPHVRINOGEN
OXIDASE
PORPHVRINOGEN (2 - C O O H i ~ / / ~
PROTOPORPHVRINOGEN
OXIDASE
J
.................
*
+ALA
FIG.1. Diagrammatic representation of the pathway of haem biosynthesis. The rate of the pathway is regulated by the activity of the initial
enzyme Gaminolaevulinate (ALA) synthase, which is under negative feedback control by haem.
.
I
i @2zz?iqw
-
I/J
im
PORPHOBILINOGEN
\r
ALA DEHVDRATASE
....................................
CYTOPLASM
Excretion
Products
t
s
186
K . E . L . McColl et al.
The urinary excretion of ALA and PBG was
monitored in four males and three females. In two
of the females the plasma concentrations of
androstenedione, dehydroepiandrosterone (DHA)
and dehydroepiandrosterone sulphate (DHAS)
and in one female the plasma concentrations
of oestradiol, progesterone and testosterone,
were also monitored.
Similar studies were performed throughout one
complete menstrual cycle in a 26 year old female
with latent AIP. The diagnosis was based on
marked depression of the activity of erythrocyte
URO synthase and increased activity of leucocyte ALA synthase in the presence of normal
urinary porphyrin and precursor excretion. The
condition had been inherited from the patient's
mother, who showed the same biochemical
disorder. The patient had never developed a
symptomatic attack of porphyria. Throughout
one complete menstrual cycle the activity of
leucocyte ALA synthase, erythrocyte URO
synthase and urinary ALA and PBG excretion
were monitored as described for the normal
females. Plasma concentrations of androstenedione, DHA and DHAS were also
monitored.
Thirty millilitres of whole blood were required
for the enzyme estimations. The sample was
placed immediately into melting ice and delivered
to the laboratory within 15 min. The leucocytes
and erythrocytes were separated and the activity
of ALA synthase in the former and URO
synthase in the latter measured as described by
Moore et al. [161. Urinary coproporphyrin and
uroporphyrin were measured by the method of
Rimington [171 and urinary ALA and PBG by
the method of Mauzerall & Granick [18]. Spot
urine samples (50 ml) were used when monitoring
ALA and PBG excretion over a complete month
and results expressed in relation to creatinine
excretion.
Androstenedione, DHA, DHAS, oestradiol,
progesterone and testosterone concentrations in
human serum were measured by radioimmunoassay. Antisera for oestradiol, progesterone and
testosterone were raised in sheep as described by
Cook et al. [191. Antiserum against androstenedione was obtained from Guildhay Antisera,
University of Surrey (Reference no. HP/s/6731A). DHA antiserum was purchased from Dr B.
Rudd, Department of Clinical Endocrinology, the
Birmingham and Midland Hospital for Women.
DHAS was measured by a non-extraction
method similar to that described by Smith et al.
[201. Other steroids were measured after extraction into ether or, for progesterone, into n-hexane.
In all radioimmunoassays, incubation with label-
led steroid and antiserum was for a period of at
least 2 h, and antibody-bound and free steroid
were then separated with dextran-coated
charcoal.
Results
Patients with recurrent attacks of AIP
In the three patients with AIP, admissions in
attacks unrelated to exogenous precipitating
factors were most common premenstrually, 19 of
the 27 occurring during the 7 days before
menstruation (Fig. 2).
Normal subjects
Leucocyte ALA synthase. The mean ALA
synthase activity was slightly higher in the
females (150 nmol of ALA h-I g-' of protein)
than in the males (122 nmol of ALA h-' g-I of
protein) but this difference was not statistically
significant. The female subjects showed significantly more fluctuation of activity of leucocyte
ALA synthase than the males (Table 1). In the
six females studied, it was not possible to discern
any association between the fluctuation in enzyme activity and phase of menstruation (Fig. 3).
There was no association of degree of fluctuation
and subject age or body weight.
Erythrocyte URO synthase. The mean activity
of erythrocyte URO synthase was similar in the
male (48.5 nmol of URO h-' 1-I of erythrocytes)
401
14
12
10
0
6
4
Days premenstrual
2
2
D a) I of
menstruation
4
6
8
10
12
14
Days postmenstrual
FIG.2. Frequency of acute attacks of porphyria in
relation to the menstrual cycle. Twenty-seven attacks
without exogenous precipitating factors were studied
in three female patients with acute intermittent
porphyria.
-
Haem biosynthesis and the menstrual cycle
300-I
I::: 6
F1 145yrl
I
0
100
M1 I44 yrl
M2 134 yrl
0
2001
d
v
r
l
0 1
TABLE
1. Leucocyte ALA synthase activity throughout the
month in normal males and females and in female with
latent acute intermittent porphyria (AIP)
The coefficients of variation for the normal females are
significantly higher than those for the males ( P < 0.05
with the Wilcoxon rank test).
Subjects
M 3 130 vrl
0'
Normal males
MI
M2
M3
M4
M5
M6
'
Normal females
FI
F2
200
F3
F4
14 10 6
20
1
4
8 12 1
5
I I I I I I I I I
9 13 17 21 25
Premenstrual
Postmenstrual
Day I of
menstruation
Time (days)
FIG. 3. Activity of leucocyte ALA synthase in six
normal females and six normal males monitored over
4 weeks. The broken line indicates the timing of onset
of menstruation in female patients.
Females
Males
i i ~ + ~ l i i l i > ' i i l i 5
1 1 15 19 23
Day I of
menstruation
Time (days)
FIG.4. Activity of erythrocyte URO synthase in four
normal females and four normal males monitored over
4 weeks.
187
F5
F6
Patient with latent AIP
Mean activity
(nmol of ALA
h-' g-' of protein)
Coefficients
of variation
215
68
175
98
75
11.6
9.2
17.3
20.1
8.8
27.2
I15
192
77
152
218
149
315
22.9
33.1
38.3
60.1
33.8
18.7
43.6
103
(%)
and female (41 nmol of URO h-I 1-' of
erythrocytes) subjects. The degree of fluctuation
of activity was also similar in male and female
subjects (Fig. 4). No association was noted
between alteration of leucocyte ALA synthase
and erythrocyte URO synthase activities.
Urinary ALA and PBG. The mean urinary
excretion and degree of fluctuation of excretion of
ALA and PBG were similar in the male and
female subjects. There was no association
between the urinary porphyrin precursor excretion and leucocyte ALA synthase activity,
erythrocyte URO synthase activity or phase of
the menstrual cycle.
Hormonal studies. No association was found
between leucocyte ALA synthase activity in the
six normal females and the well-characterized
fluctuations of oestradiol and progesterone in the
normal female cycle. This was confirmed by
measurement of oestradiol and progesterone
throughout one complete cycle (Fig. 5). Testosterone was also measured in this cycle, again
with no association with ALA synthase activity.
Androstenedione, DHA and DHAS were
measured throughout the cycle in two normal
females (F5 and F6); these steroids showed little
fluctuation and again no association with alterations in ALA synthase activity was observed
(Fig. 6).
Patient with latent acute intermittent porphyria
The mean activity of leucocyte ALA synthase
in the patient with latent AIP (3 15 nmol of ALA
K . E . L . McColl et al.
188
'1.5
d
Premenstrual
I
Postmenstrual
Day I of
menstruation
Time (days)
FIG.5. Activity of leucocyte ALA synthase and
plasma concentrations of oestradiol, testosterone and
progesterone throughout the complete menstrual cycle
in a normal female (F2).
h-' g-I of protein) was higher than in any of the
normal subjects studied and also above our upper
limit for normal subjects, which is 250 nmol of
ALA h-* g-' protein [211. The degree of
fluctuation in the leucocyte ALA synthase
activity was more than occurred in any of the
normal females when expressed in absolute
values and was exceeded by only one of the
normal females when expressed as coefficients of
variation (Fig. 7). The mean erythrocyte URO
synthase activity (21 nmol of URO h-I 1-I of
erythrocytes) was lower than that of any of the
normal subjects and below our lower limit of
normal, which is 25 nmol of URO h-l 1-' of
erythrocytes [21]. The degree of fluctuation of
erythrocyte URO synthase activity was similar to
that noted in the normal females and males.
Urinary excretion of ALA and PBG was similar
to that in the normal males and females and
showed no association with phase of menstruation or activity of the enzyme studied (Fig. 7).
No association was found between leucocyte
ALA synthase activity and plasma concentrations of androstenedione, DHA or DHAS (Fig.
6). The plasma DHA concentration in this patient
was above the normal female range (0-8-11
nmol/l) on five of the 14 occasions measured.
Discussion
The studies in the three patients with recurrent
attacks of AIP confirm that attacks are most
common premenstrually and this suggests that
the hormonal fluctuations associated with the
female menstrual cycle are modifying hepatic
haem biosynthesis in these patients. The studies
of leucocyte ALA synthase in the normal
subjects, and in the patient with latent AIP,
indicate that haem biosynthesis is being affected
by the menstrual cycle in normal females as well
as in females with latent or manifest porphyria.
The fact that ALA synthase activity varied in
leucocytes indicates that the hormonal fluctuations are altering haem biosynthesis in haematogenous as well as hepatic tissue. We have recently
noted that alcohol and diphenylhydantoin, which
are known to alter hepatic haem biosynthesis and
precipitate attacks of porphyria, also induce
ALA synthase in peripheral leucocytes of normal
subjects [22, 231. The marked fluctuation in
activity of leucocyte ALA synthase in the healthy
females, which was absent in the males, is most
likely to be due to the fluctuating hormonal levels
associated with the female menstrual cycle.
(Further substantiative evidence might have been
obtained by studying a group of postmenopausal
females, but we were unable to obtain any
suitable volunteers).
A number of explanations are possible for the
lack of correlation between the fluctuations in the
activity of leucocyte ALA synthase and phase of
the menstrual cycle or the plasma levels of
certain ovarian hormones. Firstly, the hormonal
fluctuations associated with the menstrual cycle
are complex and ALA synthase is probably
influenced by several of these hormones as well as
by their metabolites. Clear association between
the alteration in one hormone and ALA synthase
activity may be obscured by the influence of
other hormones on the enzyme. Secondly, delay
in the enzyme response to changing concentrations of an inducing steroid would be expected,
which might further complicate the association.
Animal studies have shown that a single injection
of oestradiol results in oscillations in the activity
of ALA synthase lasting for up to 90 h [241.
In the patient with latent AIP, the magnitude
of the fluctuation of the activity of leucocyte
ALA synthase, in absolute values, was more than
that seen in the normal females. This is consistent
with the partial block in the haem pathway at the
level of URO synthase which exists in haematogenous as well as hepatic tissue of such patients.
Animal studies have demonstrated that induction
of ALA synthase by porphyrinogenic agents is
considerably enhanced by the presence of a
partial enzymatic block in the pathway [25,261.
The mechanism by which certain hormones
induce ALA synthase activity is not clearly
Haem biosynthesis and the menstrual cycle
189
q
1.)
.a
Y
200
g
150
c
100
0
I
Premenstrual
Postmenstrual
Day I of
menstruation
Time (days)
Ibl
5a
9 5
14 1 2 1 0 8
6
4
Premenstrual
2
+
I
2
4
8
8 1012
Postmenstrual
Day I of
Menstruation
Tims (days)
14 1 2 1 0
8
6
4
Premenstrual
2
t
I
2
4
6
8 1012
Postmenstrual
Day I of
menstruation
Timc (days)
FIG.6. Activity of leucocyte ALA synthase and plasma concentrations of dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS) and androstenedione during a
complete menstrual cycle in normal females F5 (a) and F6 (b), and in a female with latent acute
intermittent porphyria (c). Different scales have been used for the three subjects.
understood. ALA synthase is under negative
feedback control by haem and any lowering of
the free haem concentration results in its induction. Certain synthetic acetylenic substituted
steroids, including norethindrone and ethynyloestradiol, have been shown to destroy microsomal haem and cytochrome P-450 in rats 1271.
The haem degrades to abnormal green deri-
K . E . L. McColl et a/.
190
500 -
300 -
400
200100-
0-
OJ
to.7
/r
'V"
2
161412108 6
2
x
m
4
Premenstrual
1
E
k06
r
Postmenstrual
o
-E
Day I of
menstruation
Time (days)
FIG.7. Activity of leucocyte ALA synthase and
erythrocyte URO synthase and urinary excretion of
ALA and PBG throughout the complete menstrual
cycle in a 26 year old female with latent acute
intermittent porphyria.
vatives similar to, though not identical with, the
green pigments formed by allylisopropylacetamide, a chemical used to produce experimental
porphyria in animals. These animal studies,
however, may be of little relevance to the human
as the hormones studied were synthetic rather
than endogenous and the concentrations many
times greater than occur physiologically. Animal
studies have shown that the steroid hormones
which induce ALA synthase all have a similar
structure 1281. It is therefore possible that these
hormones are able to competively inhibit the
feedback of haem by occupying its receptor site.
The observation that both haem 1291 and
oestradiol [241 cause similar oscillatory changes
in hepatic ALA synthase would be in favour of
them both acting in a similar way, such as
occupying a common receptor.
Our observations may be relevant to the
interpretation of enzyme studies for the detection
of patients with latent porphyria. It is now widely
recognized that many patients with the genetic
trait for AIP have normal porphyrin and precursor excretion and can be identified only by
measuring the activity of the enzymes of haem
biosynthesis in their peripheral blood cells 12 11. It
is important that these patients are identified and
counselled concerning the avoidance of factors
which may induce acute attacks. The marked
fluctuation noted in the activity of leucocyte ALA
synthase in the normal females and particularly
in the patient with latent AIP should be borne in
mind when interpreting single enzyme estimations. Erythrocyte URO synthase does not
seem to be affected to any significant extent by
the hormonal fluctuations.
The observation that the human menstrual
cycle is modifying haem biosynthesis in haematogenous as well as hepatic tissue may be of
relevance to the understanding of sex hormonerelated alterations in haematopoiesis. Healthy
women are known to have a lower haemoglobin,
erythrocyte count and packed cell volume than
male counterparts [301. Castration of the male
rat results in a fall in the erythrocyte count, which
is reversed with testosterone administration,
whereas spaying of female rats causes a rise in
the erythrocyte count, which is reversed by
oestrogens [ 3 1I. The stimulatory effect of androgens on haematopoiesis has been utilized with
various degrees of success in the treatment of
certain forms of aplastic anaemia in man 1321.
Our studies indicate that sex hormones may
modify haematopoiesis as a result of their effect
on the rate-controlling enzyme of haem biosynthesis, ALA synthase. Haem synthesis is
known to control globin synthesis 1331. Granick
(341 showed that steroids which induce ALA
synthase in embryonic liver cells also accelerate
haem and haemoglobin synthesis in chick blastoderm cultures. Like these steroids, the hormone
erythropoietin, which plays a major role in
stimulating erythropoiesis, increases ALA synthase activity in rabbit bone marrow cultures
1351. Thus ALA synthase may be an important
control point for the hormonal regulation of
haematopoiesis.
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