Клиника Генезис Днепр IVF

Sex Hormones
Alek Itsekson, M.D., Ph.D., Aneta Lazarov, M.D., Mario Cordoba, M.D., Moshe Zeitune, M.D., David Abraham, M.D., and Daniel S. Seidman, M.D.
OBJECTIVE: To study skin diseases and hypersensitivity to female sex hormones in patients with the premenstrual syndrome (PMS).
STUDY DESIGN: Thirty women answered a questionnaire related to PMS and underwent gynecologic, dermatologic and laboratory examinations. Intradermal testing was performed with estradiol valerate, progesterone and placebo. Desensitization treatment was instituted in 15 patients.
RESULTS: Ten patients were diagnosed with PMS and concomitant skin disease, including pruritus vulvae, hyperpigmentation, papular eruption and acne vulgaris (group A). Ten patients diagnosed with PMS but without skin disease served as the first control group (group B). The second control group consisted of 10 healthy women (group C). Immediate and delayed hypersensitivity reactions to sex hormones were observed in all patients with PMS and PMS-related skin diseases (groups A and B) but not in healthy women (group C). Desensitization produced a decrease in PMS symptoms and improvement in the skin disease related to PMS.
CONCLUSION: Skin diseases may be a part of PMS. Demonstration of a delayed allergic reaction to female sex hormones may uncover a signfi cant pathogenetic mechanism in patients with recurrent skin disease and PMS.
(1 Reprod Med 2004;49: 195—199)
Keywords: premenstrual syndrome, skin diseases, sex hormones.
It is possible to define the premenstrual syndrome (PMS) as the cyclic occurrence of psychological and somatic symptoms in the luteal phase of the menstrual cycle that disappear at, or soon after, the onset of menstruation.1-3 Common somatic symptoms include bloating, breast swelling, pelvic pain, headache, weight increase, skin disorders and changes in bowel habits.4 Some skin diseases, such as estrogen dermatitis5 and autoimmune progesterone dermatitis,6 have been related to a premenstrual flare. In those series, no data were provided as to whether the patients also suffered from PMS. Our purpose was to study skin diseases observed in women with PMS and to test the presence of hypersensitivity to female sex hormones.
From the Department of Obstetrics and Gynecology, Dermatology Clinic and Institute of Pathology, Meir Hospital, Sapir Medical Center, Kfar Saba, and Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Israel.
Address reprint requests to: Aneta Lazarov, M.D., Dermatology Clinic, Meir Hospital, Sapir Medical Center, 44281, Kfar Saba, Israel ( Этот e-mail адрес защищен от спам-ботов, для его просмотра у Вас должен быть включен Javascript ).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
0024-7758/04/4903-0195/$15.OO/O © Journal of Reproductive Medicine®, Inc.
The Journal of Reproductive Medicine®

Immediate and delayed hypersensitivity to estradiol and/or progesterone may play a pathogenic role in patients with PMS and skin diseases related to it.
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Materials and Methods
Thirty women were enrolled in the study. PMS was defined as recurrent episodes of 4 symptoms from a list of 17 (Figure 1) that appear in the premenstru

Estrogen and progesterone autoimmune dermatitis may be a derma tologic expression of PMS.
al period (luteal phase) and completely disappear in the intermenstrual phase.7’8 A group of 10 patients had PMS and recurring skin disease with premenstrual exacerbation (group A). Ten patients with PMS only constituted the first control group (group B), and 10 healthy women constituted the second control group (group C).
The patients were requested to answer a questionnaire on the presence, frequency and severity of their symptoms related to PMS. The different symptoms were evaluated according to the Visual Analogue Score using a scale from 0 to 10 (0 = absent symptoms, 1—3 = mild symptoms, 4—6 = moderate symptoms, 7—9 severe, and 10 extremely severe symptoms). The symptoms’ evolution was assessed and described by each patient using a calendar of premenstrual experiences, which is a validated self- assessment daily diary.9 Subject selection of the patients with PMS met National Institute of Mental Health Premenstrual Syndrome Workshop criteria.7
Mood swings
Depression, sadness
Tension, irritability
Anxiety, nervousness
Anger, short temper
Crying spells
Swelling of extremities
Breast tenderness. fullness
Abdominal bloating
Abdominal cramping
Aches and pains
Low backache
Headaches
Fatigue
Appetite increased or decreased
Craving for sweets or salt
Insomnia

Each patient underwent a clinical examination by a gynecologist and a dermatologist. A vaginal or abdominal ultrasound evaluation was performed. Laboratory tests, including blood count, blood chemistry, electrolytes, calcium, magnesium, zinc, levels of progesterone, estrogen, thyroid- stimulating hormone, prolactin and cortisol, were carried out on day 21 of the menstrual cycle. Bacteriologic and mycologic tests were performed on the vaginal area.
Intradermal testing with estradiol valerate 10 mg/mL, progesterone BP 50 mg/mL and a placebo containing ethyl oleate BP in 10% benzyl alcohol was performed. Of these substances, 0.02 mL was injected intradermally in the forearm of each patient immediately after the estimated time of ovulation. The tests were read at 20 minutes and after 1 and 5 days. Intradermal testing was considered positive when erythema and infiltration >5 mm were observed at the site of the test after 20 minutes, according to standard definitions.’° Persistence of a papule for >24 hours at the site of the test was required in order to consider the test positive.5 This delayed hypersensitivity reaction was confirmed by persistence of the papule after 5 days. Standard positive (histamine) and standard negative (normal saline) controls were performed as well. Each patient reported daily changes at the test sites for one month following the procedure. Intradermal testing with the same substances was performed on the 2 control groups.
All patients with PMS and skin disease were patch tested with a standard series for epicutaneous testing, TRUE Tests, with the medicament and corticosteroids series (Chemotechnique Diagnostics, Malmo, Sweden), as well as with cosmetics. The patch tests were applied on unaffected skin on the upper back, removed at 2 days, read on days 2 and 3 and graded according to standard patch test definitions. 1’
On the fifth day, biopsies from positive intradermal test sites were obtained from 2 patients with PMS and skin disease. The biopsies were evaluated after staining with hematoxylin and eosin and with estrogen and progesterone monoclonal antibodies.
Desensitization treatment was instituted in 5 patients from group A and in all patients from group B. Therapy consisted of separate monthly estrogen and/or progesterone interdermal injections according to the positive immediate and delayed skin test reactions. Each month the volume of intradermal

Figure 1 Symptoms related to PMS.

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Table I Group A: Skin Disease and Hypersensitivity Reactions to Estradiol and Progesterone, 24-Hour Reading

injection was doubled, with 0.04 mL in the first month, 0.08 mL in the second and 0.16 mL in the third.
All clinical and laboratory tests and other diagnostic procedures were in accordance with the ethical standards of the institutional and national committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 1983.

Results

Thirty women aged 15—47 years were studied. Ten patients had PMS and recurrent skin disease with premenstrual flares at the time of enrollment (group A). The most frequent symptoms of PMS were mood swings, tension, irritability, breast fullness, headaches and craving for sweets or salt.
Pelvic examination, ultrasound evaluation and blood tests were unremarkable. Bacteriologic tests revealed normal vaginal flora. Mycologic cultures were negative for Candida and dermatophytes. All 10 women in group A had also experienced recurrent skin disease with a premenstrual flare. Five patients had pruritus vulvae with a duration of 1 years and that flared premenstrually. Patient 3, aged 44, with pruritus vulvae, also had primary hyperaldosteronism and chronic hypertension. Patient 2 had severe exacerbation of the pruritus vulvae during treatment for infertility with medroxyprogesterone acetate. One patient had round, macular hyperpigmentation, 1 cm in diameter, on the lower lip. This lesion became very dark during the premenstrual period. Two patients had acne vulgaris, which increased markedly in the second half of the menstrual period. Another 2 patients had pruritic papules that appeared on the face, hands and trunk in the premenstrual period and spontaneously involuted after menses, resembling those seen in autoimmune progesterone and estrogen dermatitis. All 10 patients experienced exacerbation of their skin lesions and pruritus in the premenstrual period.
Patch tests were negative at the 48- and 72-hour readings. Thus, contact allergy on the vulvar area with relevant allergens was excluded.
Table I summarizes the patients from group A according to their skin disease and hypersensitivity to the female sex hormones tested. Immediate or delayed allergic reactions to estradiol and/or progesterone are shown in Table II. Delayed allergic reaction to estradiol was observed in 1 patient, to progesterone in 4 and to both in the remaining 5 patients. Five patients reported a decrease in pruritus at the site of the positive test after the day-5 reading and a new increase in pruritus 1—2 weeks later. The placebo was negative in all patients in group A.
Group B consisted of 10 patients with PMS and no skin disease. Those 10 demonstrated delayed allergic reaction to some of the sex hormones tested, as read at 24 hours (Table III). The placebo was negative in all cases.
Group C included 10 healthy women, without PMS or skin disease, aged 23—44 years. No positive reactions to estradiol, progesterone or placebo were seen in the early or late readings.
The biopsies revealed focal spongiosis of the epidermis and a mild perivascular lymphocytic infiltrate in the superficial dermis. There was no positive reaction with monoclonal antibodies in the sections studied.
Desensitization treatment resulted in a marked decrease in PMS symptoms. Complete relief from pruritus vulvae was achieved in patient 3. The hyperpigmentation in patient 6 disappeared completely. Neither patient experienced any recur-

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Table II Group A: Immediate and Delayed Allergic Reactions to Estradiol and/or Progesterone

rences after 1 year. The clinical symptoms in 1 patient with a papular eruption and 2 with acne improved as well after desensitization treatment.

Discussion

According to most studies, PMS occurs in 30—40% of the female population.2 Severe PMS is reported in <10% of women.12 Although some skin diseases, such as estrogen dermatitis,5 autoimmune progesterone dermatitis6 and erythema annulare centrifugum, 13 are related to premenstrual exacerbation, there are no reports of dermatologic findings in patients with PMS in the dermatologic literature. Skin diseases, such as atopic eczema, urticaria4 and vulvitis,14 have been mentioned as symptoms of PMS by some authors in the gynecologic literature.
We found that in some patients with PMS, some skin diseases were exacerbated premenstrually:
pruritus vulvae, hyperpigmentation, pruritic papular lesions and acne vulgaris. These diseases we consider to be skin symptoms of PMS. Clinical evidence that the skin symptoms were part of PMS was provided by several facts:

1. Exacerbation of the skin disease premenstrually and clinical improvement after menses.
2. Improvement in clinical signs and symptoms of PMS in patients with PMS only and with PMS and skin diseases who were treated with desensitization.
3. Involution or improvement in skin disease after desensitization in patients with PMS and premenstually exacerbated skin diseases.
4. Common findings of allergic hypersensitivity reaction to some of the sex hormones tested in patients with PMS only and with PMS and skin diseases.

The results observed in the control group with PMS only (group B) demonstrate the presence of immediate and delayed hypersensitivity to estradiol, progesterone or both. The delayed hypersensitivity to female sex hormones was confirmed by histopathologic findings of perivascular lymphocytic infiltrates in the biopsies from the positive intradermal test sites. The presence of delayed hypersensitivity reaction to female sex hormones may be a significant pathogenetic mechanism of PMS itself, suggesting a possible role of delayed hypersensitivity to one’s own female sex hormones as an autoimmune phenomenon in PMS. These findings may also be related to changes in the balance of the autonomic nerve system response (Figure 1). Thus, the delayed hypersensitivity to female sex hormones in PMS and related skin disease, followed by a cascade of immunologic and neuroendocrine events, shows a relationship between endocrine, immune and neural responses.
The negative results from the control group of healthy women (group C) further validates the posTable II! Group B: Hypersensitivity Reactions to Estradiol and Progesterone in Patients with PMS and No Skin Disease

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itive results in patients with PMS and PMS plus related skin disease.
In our experience, intradermal testing with estradiol and progesterone may be a valuable diagnostic method for patients with suspected PMS and in those with PMS and related dermatologic conditions. It is of utmost importance to perform the intradermal testing in the luteal phase of the menstrual cycle since the test could produce false negative results if done in the follicular phase. Early and late readings of the test sites are mandatory.
There are many hypotheses on the etiology of PMS; they include biologic, psychological and social bases. Although the precise etiology of PMS has not yet been established, we concur with a concept by Schmidt et al,15 who suggested that PMS may represent an abnormal response to normal hormonal changes.
The high incidence of delayed hypersensitivity reactions in patients with PMS and with PMS and related skin disease in our series may also be the resuit of the high exposure to xenoestrogens in the environment. Such xenoestrogens include some pesticides, such as DDT; plastics; spermicides; detergent breakdown products; and high levels of estrogen in commercially raised meat animals. Recently the role of xenoestrogens and xenohormones as possible etiologic agents in breast cancer was discussed in the literature.16
Although our patients with PMS and recurrent premenstrual skin diseases were heterogeneous in clinical presentation as well as in their response to the female sex hormones tested, our study provides evidence that skin diseases may be part of the premenstrual syndrome. Immediate and delayed hypersensitivity to estradiol and/or progesterone may play a pathogenic role in patients with PMS and skin diseases related to it. The success of desensitization therapy also suggests links in the pathogenetic mechanisms of PMS and skin disease related to PMS. We recommend that these results be confirmed by studying a larger group of patients. The results obtained from these studies may help to delineate the dermatologic symptoms related to PMS. Estrogen and progesterone autoimmune dermatitis may be a dermatologic expression of PMS.

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