The Journal of

ALLERGY
and
CLINICAL IMMUNOLOGY
VOLUME 48 NUMBER 5

Autoimmune progesterone urticaria

Fuad S. Farah, M.D., and Zuhayr Shbaklu, M.D.
Beirut, Leba?ton

Two patients with urticaria occurring at the mid- and premenstrual part of the
cycle are reported. Evidence incriminating progesterone as the cause of urticaria
includes production of lesions udh the administration of exogencvus progesterone,
Gnhibition of urticaria wi,th inhibition of ovdation, positive skin tests with pro-
gesterone, passive cutaneous tramfer, and the demonstration by immunofluorescenre
of nntibodies reactive to the luteinizing cells of the corpus luteum.

Sensitivity reactions to hormones are rare. They are, however, interest-

ing because the sensitivity is directed against a sulxtance secreted by the indi-
vidual as a normal component of one’s homeostatic mechanisms.
Few case reports were found in the literature describing allergic reactions
to progesterone. Guy and associates1 reported one case of urticaria related to
the menstrual cycle; Shelley and associat.es? described an erythema multiforme-
like reaction to progesterone in one patient; Tromovitch and Heggli3 reported
one patient with a reaction of “typical hive-like wheals” caused by progesterone;
and dories and Gordon4 and Hoischrn and Steigledt+ noted pruritic eczematow
eruptions related to this hormone.
The purpose of this communication is to report 2 patients who suffered
from premenstrual urticaria, and to detail the investigations performed to
tletect antiprogestcronc antibodies.

CASE REPORTS
Case 1
r,. iv., a 227year-old single woman, at the age of 20 had consulted her gynecologist
because of absence of menstruation. Following intramuscular injections of an unknown
(lrug 4 to 5 (lay monstrnal periods began, with moderately heavy flow, once every 20 + 5

From the Department of Medicine, Division of Dermatology, American IJniversity Medical

Center.
Received for publication March lS, 1971.
Reprint requests to: Dr. Farah, Department of Medicine, Division of Dermatology,
Americaan TJniverxity hlcdical Center, ReinIt, T,ebanon.

Vd. 48, No. A, pp. k6’i-P6l

258 Farah and Shbaklu J. ALLERGY CLIN. IMMUNOL.
NOVEMBER 1971

TABLE I. Wheal and erythema skin responses to progesterone

Wheal Erythema
Skin site Challenged with (mm.1 (mm.) Figure

Patient 1
Forearm 0.05 mg. Crystalline 18 x 14 (ii x 2.5
progesterone in
alcohol/water
Alcohol/water 14 x 14

Passive transfer,
0.15 ml. serum 0.05 mg. progester- 20 x 14 50 x 35
one in alcohol/water

0.15 ml. serum Alcohol/water - 20 x 25

Normal skin 0.05 mg. progester- 1S x 18

one in alcohol/water
Normal skin Alcohol/water - 25 x 18

Patient 2 0.05 mg. progester- 14x 13 38 x 30

one in alcohol/water
Alcohol/water 12 x 15

2 cm.
Positive reactions are those with a wheal size greater than 10 mm. in diameter and correspond-
ing erythema. Erythema alone was considered negative. The figures represent actual tracings
of responses transferred with transparent tape to the record.7 Multiple controls of pro-
gesterone in the solvent were performed in the skin of 5 normal subjects (2 men and 3 women
ages 22 to 25 years) and were nonreactive.

days. Since that time she complained of an intermittent pruritic eruption of the extremities
and of variable areas of the trunk. The eruption appeared 7 to 10 days prior to the onset
of each of her menses and persisted until 1 to 2 days postmenstrually.
The family history, systemic inquiry, and personal history were not contributory.
Physical examination revealed a healthy appearing young woman in no distress.
Her vital signs were normal. The positive findings were related to the skin, where small
erythematous and edematous lesions were seen over the trunk and extremities. There were
occasions when large patches of wheals and erythema were seen on various locations on the
body. At times swelling of the hands and feet was noted, and at other times pufiness
of the face and periorbital edema were seen.
The laboratory data included a normal complete blood count except for 18 per cent
eosinophilia, the sedimentation rate was 17 mm. in the first hour, fasting blood sugar
86 mg. per cent, blood urea nitrogen 8 mg. per cent, alkaline phosphatase 2 Bodansky
units, total serum proteins were ‘7.1 Gm. per cent (albumin 3.6 and globulin 3.5 Gm. per
cent), VDRL was nonreactive, and the urinalysis and stool examinations were normal.
The patient was given antihistamines (hydroxyzine, 10 mg. three times daily, and
dextro-chlorpheniramine, 6 mg. twice daily) with partial relief.
Fifty milligrams of progesterone in castor oil were given intramuscularly 7 days
prior to the period, at which time an urticarial eruption began to appear. The eruption
increased and became widespread within 24 hours. On another occasion she was given
250 mg. of 17 a-hydroxyprogesterone caproate in castor oil at the beginning of the menstrual
cycle. Ten days later an extensive uticarial eruption appeared associated with menstrual
flow.
Anovlar (containing 4 mg. norethisterone and 0.05 mg. ethinylestradiol) was given,
one t.ablet daily for 20 days of each of two consecutive cycles. The menses appeared normally
VOLUME 48 Autoimmune progesterone urticaria 259
NUMBER 5

but were not associated with a rash. Similar response was obtained with Estinyl (0.02
mg. ethinylestracliol) tablets once daily for 20 days of each cycle.
Skin tests were performed by the injection of 0.1 ml. of 25 mg. per milliliter of
progesterone in oil intradermally in the skin of the patient and in that of a normal control
subject. Both subjects showed a similar reaction, which was thought to be caused by
irritation from the oil.
Synthetic crystalline progesterone (obtained from Roussel Yaclaf, Boulevard des
Invalides, Paris, France) was dissolved in alcohol/water (1.5/1.0 v/v) solvent and used
for skin testing. The progesterone solution, 0.05 ml., containing 1 mg. of progesterone
per milliliter was injected intradermally in the forearm of the patient and in that of a
normal subject. An equal volume of the solvent alone was similarly injected into the
opposite forearms. A definite wheal and erythema reaction was noted at the site tested with
progesterone (Table I).
Passive transfer was performed with 0.15 ml. of the patient’s serum injected into
the forearm of normal subjects. Positive wheal and erythema responses were elicited at
the prepared sites tested with progesterone (Table I).

Case 2
K. B., a 22.year-old married woman, had her menarche at the age of 13. Since that
time she complained of an urticarial, pruritic eruption that began midway between her
periods and persisted until the onset of her menses. The association of this eruption
with the menstrual cycle was regular and constant since menarche. It was interrupted
only during her one pregnancy, when she was completely free from symptoms. HOW-
ever, the urticaria returned with the same regularity after the birth of her child. Family
history, personal history, and systemic inquiry were not contributory.
Physical examination revealed a healthy-appearing young woman with normal vital
signs. The positive findings were confined to the skin, where typical urticarial lesions
were found all over the body.
The laboratory data included a normal hemogram, urinalysis, and stool examination;
the VDRL was not reactive.
An intradermal test with 0.05 ml. of the aqueous progesterone solution (containing
0.05 mg. progesterone) elicited a positive reaction in 15 to 30 minutes (Fig. 1).
She was advised to continue to take Ovral (containing 0.5 mg. norestrel and 0.05 mg.
estradiol) which had been known to prevent the urticarial rash.

IMMUNOFLUORESCENT STUDIES
Serum was collected from the two patients and incubated with 5 p thick sections of
fresh rabbit ovary for 30 minutes at room temperature; they were then thoroughly
washed with saline and incubated with fluorescein-laheled rabbit anti-normal human serum.
The sections were examined for fluorescence with a Reichert Setopan microscope. The
light source was a mercury lamp (Hb 200) with a BG 12 primary filter and 1.5 GG 1 + GG
9 secondary filters. Fluorescence was observed in the corpus luteum and localized to the
periphery of the luteinized cells (Fig. 1). Both patients demonstrated this finding in serum
dilutions of l/256 and l/512, respectively.
The immunofluorescence was judged to be specific because the controls were negative.
These included incubation of the tissue without the patient’s serum and with serum from
4 normal individuals. Furthermore, immunofluorescence was blocked when free progesterone
in concentrations of 1 x 10-h and 1 x lo-6 mM. per milliliter was added to the patient’s
serum before incubation with the ovarian tissue.

DISCUSSION
Urticaria caused by endogenous progesterone is extremely rare, havirlg
been described in the literature’? 3l 6 available to us in only 3 patients.‘, 3 In
the 2 patients described in this report, progesterone has been incriminated by
260 Farah and Shbaklu J. ALLERGY CLIN. IMMUNOL.
NOVEMBER 1971

FIG. 1. lmmunofluorescence localized to the periphery of the luteinized cells of rabbit ovary
after treatment with patient’s serum and later with fluorescein-labeled rabbit antinormal
human serum.

demonstrating exacerbation of the lesions with progesterone injection, positive

skin reactions to progesterone, positive passive transfer with one patient,‘s
serum, and immunofluorescence.
The cutaneous tests with progesterone presented some difficulties in view
of t,he insolubility of the material in water. We observed the same problem with
t,hc rise of a solution in oil as did Zondek and Bromherg,” and interpretation
of the intracutaneous responses was not possible. .Jones and Gordon” used a
one per cent aqueous solution of progesterone, and positive reactions appeared
24 hours later. In the present study, progesterone was solubilized in an slco-
holic solvent containing 1.5/1.0 v/v of alcohol/water. The solvent was some-
what irritating, producing a transient infiammation at t,he site of injection
which was most prominent after 21 hours and subsided gradually. IJowever,
the reaction did not interfere with the interpretation of the immediate wheal
and erythema produced at the site of progesterone injection. Emphasis is
placed on the development of the wheal and not the erythema. The figures drawn
in Table I clearly demonstrate the unequivocal results of the intracutaneous
tests ant1 of the passive transfer reactions.
Furthermore, progesterone produced a definite exacerbation of the urticaria.
Tromovitch and Heggli” considered this findin, u as proof of the causative role
of progcstcronc in their patient.
The tlcmonstration of serum antibodies to progcsteronc by immunofluores-
cence is shown for the first time. It was of interest to note that fluorescence was
confined to the cells in the corpus lutrum that are involved with the production
of progesterone, the lutenized ~11s. The fluorescence was located around the
cell membranes in the probable location of progesterone prior to secretion.
It is interesting in this connection to recall the patient of Guy and amociat,esl
VOLUME 48 Autoimmune progesterone urticaria 261
NUMBER 5

who was treated with injections of corpus luteum in increasing doses with relief
of urticaria.
The evidence for the incriminating progesterone as the cause of urticaria
in these patients is substantial. It is further supported by relief of the patients
from urticaria after they were given antiovulatory agents. However, WC are
not. able to offer an explanation for the relief of urticaria during pregnanq-
in the second patient, since pregnancy is associated with high levels of progest,er-
one. On the other ha.nd, pregnancy is known to ameliorate or improve many
allergic states. This effect of pregnancy may be related to increased steroids due
to hypcrfunction of the adrenal-pituitary axis.
The mechanism hp which endogenous progesterone or other hormones be-
come antigenic is not, known. It is possibly related to the production of some
altered form of the hormone in these individuals. Such an alteration is thought
not to be of functional significance bul could be of immunologic importance, so
that the hormone is no longer recognized as “self” and antibodies form against
it. In this connection it is noteworthy that the urticaria appeared in both indi-
viduals with t,he onset of menstruation, i.e., at the time when ovarian pro-
gesterone production commences. The available data, however, does not exclude
the possibility that the antibodies are directed against a metabolic product of
progesterone. It would be of immunologic interest if one could purify this
antiprogesterone antibody and test its reacbivity against various steroids.
REFERENCES
1 Guy, XV. H., Jacob, I?. N., and Guy, W. Ii.: Sex hormone sensitization (corpus luteulu ),
Arrh. Dermatol. 63: 377, 1951.
2 Shelley, W. B., Preucel, R. W., anal Spoont, 8. F.: Autoimmune progesterone tlermatitisz
-1. A. N. A. 120: 147, 1964.
3 Tromovitch, ‘I’. A., and Heggli, TV. F.: Autoimmune progesterone urticaria, Calif. >Iell.
106: 211, 1967.
4 *Tones, IV’. N., and Gordon, V. H.: Autoimmune progesterone eczema. An en(logenorrs
progesterone hypersensitivity, Arch. Dermatol. 99: 57, 1969.
5 Hoischen, W., and Steigleder, G. IL: Uberemptindlichkiet gegen progesteron bei prurigo
mit prameustrueller exazerbation, Dtsch. Med. Wochenschr. 91: 398, 1966.
6 Zondek, B., and Bromberg, Y. MI.: Endocrine allergy. I. Allergic sensitivity to endog-
enous hormones, J. ALLERGY 16: 1, 1945.
7 Farah, F. S., Kern, M., and Eisen, H. N.: Specific inhibition of wheal an{1 erythema
responses with univalent haptens ant1 univalent antibody fragments, .T. Exp. Melt.
112: 1’711, 1960.