The fluctuations in estrogen and progesterone that define menstruation are associated with numerous physiological and psychosocial changes. There is limited understanding of the effect of these hormonal changes on the skin, however it is clear that several skin diseases are influenced by them (Table 1).
This article explores the clinical manifestations and mechanisms of the menstrual cycle and its effects on the skin. A better understanding of these mechanisms may improve the management of perimenstrual dermatoses in the future.
Physiology of the menstrual cycle and its effect on the skin:
Many of the effects of estrogen on the skin are based on observations of estrogen at reduced levels in postmenopausal women and from in vitro and animal studies. Estrogens are important for the normal functioning of several structures in the epidermis and dermis, including the vasculature, hair follicles, sebaceous/apocrine glands, eccrine glands, and melanocytes.
In cultured human cells, estrogen receptors (ER) B, progesterone receptors, and androgen receptors are expressed in keratinocytes, fibroblasts, and skin macrophages. ER alpha receptors are found on skin fibroblasts and macrophages, but not on keratinocytes. ER alpha and beta receptors are also found in melanocytes.
Estrogens are associated with collagen synthesis, increased skin thickness and dermal water content (due to production of hyaluronic acid), and improves skin barrier and wound healing function. In postmenopausal women, low levels of estrogen cause collagen atrophy and reduce water content. Estrogen stimulates melanogenesis, along with thyroxine and melanocyte-stimulating hormone which can result in premenstrual hyperpigmentation.
The effects of estrogen on pigmentation were related to changes in pigmentation observed during pregnancy, including patches of increased pigmentation on the face, and darkening of the skin on the areola, perineum, and skin of the linea alba, which diminished later. of childbirth. Hyperpigmentation is seen in some women taking oral contraceptives. Estrogens induce water and salt retention, causing edema of the hands and feet, which is a characteristic of premenstrual syndrome.
The effects of progesterone are less clear. During the second phase of menstruation, there is an increase in the vasculature and an increase in sebum production, which has been attributed to the effect of progesterone.
Studies show that high levels of estrogen and progesterone in the periovulatory period inhibit delayed hypersensitivity reactions, while low levels of these hormones (perimenstruation) are associated with greater reactivity to the patch test, which represent exacerbations in atopic patients. This suggests that estrogens and progesterone may inhibit cellular immunity.
Autoimmune progesterone dermatitis (APD) is a rare mucocutaneous disease characterized by cyclical skin changes, as a result of progesterone produced during the luteal phase of the menstrual cycle, therefore it does not occur in post-menopausal women. Skin manifestations can vary from eczema, erythema multiforme (EM), purpura and petechiae, dermatitis herpetiformis, fixed drug eruption and stomatitis to urticaria, angioedema and anaphylaxis.
Symptoms generally begin 3-10 days before the start of menstruation and subside 5-10 days after the start. In women with irregular periods, the correlation may not be obvious, so the patient may have symptoms for several years prior to diagnosis. A similar entity related to estrogen sensitivity in the premenstrual period, known as estrogen dermatitis (OD), has been described.
The pathogenesis of APD is not entirely clear. The results of the intradermal progesterone test produce type 1 and 4 hypersensitivity reactions.
Estrogens are processed by the skin as a foreign antigen and presented to immunocompetent cells, causing an autoimmune response to endogenous estrogens. Similar mechanisms have been proposed for progesterone autoimmunity. Previous exposure to progesterone in oral contraceptives or during pregnancy in predisposed individuals causing hypersensitivity to endogenous hormones and APD subsequently.
However, APD resolves during pregnancy. It is suggested that the gradual increase in progesterone during pregnancy acts as a desensitizing agent, reducing symptoms.
Due to the increased production of glucocorticoids during pregnancy, the decreased maternal immune response also plays a role in improving symptoms.
The diagnosis of APD is based on the appearance of recurrent skin lesions in relation to the menstrual cycle and demonstrating progesterone sensitivity through the administration of intradermal, intramuscular, or vaginal progesterone.
There are no specific histological findings of the disease, although perivascular lymphocytic inflammation with eosinophils can be observed. Direct immunofluorescence is negative.
The main goal of treatment in APD is to suppress the peak of progesterone during the luteal phase of the menstrual cycle. Patients are successfully treated with conjugated estrogens, gonadotropin releasing analogues, tamoxifen, danazol and bilateral oophorectomy.
OD responds to the antiestrogen agent tamoxifen. Hormonal desensitization has been attempted as a potential agent, although it is not routinely used in clinical practice.
Other dermatoses exacerbated by menstruation
Dermatoses such as atopic dermatitis, contact dermatitis, psoriasis, acne and even EM and fibrous tumor can be exacerbated premenstrually or perimenstrually.
Almost half of all patients with atopic eczema experienced deterioration of their condition in the week before menstruation, resolving rapidly after the onset of menstruation. The permeability of the skin barrier is greatest just before menstruation.
This increases the skin’s susceptibility to the effects of environmental allergens and irritants, which partially explains premenopausal flare-ups of eczema in some women.
Psoriasis has several factors that aggravate it and others that relieve it, hormonal influences being some of them. Worsening of psoriasis symptoms in perimenopause has been shown to be blocked by concurrent therapy with long-term antiestrogens, such as tamoxifen, supporting the influence of estrogen on psoriasis symptoms. The influence of estrogen on immunity is complex. Helper T cells show a dose-dependent effect on estrogen, and estrogen also stimulates the production of regulatory T cells through ER alpha. The B cell response to estrogen is via ER B, increasing the production of antibodies.
As psoriasis is considered an immunological disease, this complex influence of estrogen on the immune system explains the menstrual variation of psoriasis.
Premenstrual acne exacerbation is multifactorial. High levels of androgens and estrogens during the follicular phase and periovulation cause increased sebum production, resulting in a higher level of skin lipids and a subsequent increase in skin microflora.
The combined use of combined estrogen/progesterone contraceptives causes improvement of acne by suppressing androgens secreted from the ovary, and by increasing the levels of sex hormone binding globulin, decreasing the amount of free, biologically active androgens. Additionally, progesterone blocks androgen receptors, inhibiting the action of circulating androgens.
Therefore, premenstrual exacerbation of acne may be explained by low levels of progesterone in the late stage of the menstrual cycle.
An EM-like rash has recently been reported, with prostaglandins being implicated in its etiology.
The dynamic effects of cyclical changes in estrogen and progesterone in women of reproductive age affect the severity of several inflammatory dermatoses, including some of the most common conditions seen in clinical dermatology and general practice. In addition, there are a number of rare premenstrual diseases, of which APD is the best characterized.
Table 1: Dermatoses exacerbated during the menstrual cycle
- acne vulgaris
- Aphthous ulceration
- Atopic eczema
- Autoimmune progesterone dermatitis
- Autoimmune estrogen dermatitis
- Dermatitis herpetiformis
- Erythema multiforme
- Herpes simplex
- Hyperpigmentation
- lichen planus
- Lupus erythematosus
- Vulvar itching
- Psoriasis
- Rosacea
- Solitary fibrous tumor
- Urticaria
Table 2: Clinical characteristics of autoimmune dermatitis due to progesterone
- Angioedema
- Anaphylaxis
- Aphthous ulceration/stomatitis
- Dermatitis
- Eczema
- Erythema multiforme
- Fixed drug rash
- Spots
- Palmoplantar dyshidrosis
- Papules
- Pruritus
- Stomatitis
- Urticaria
- Vesicles
What does this article contribute to dermatological practice?
Perimenstrual exacerbations of dermatoses are common and generally overlooked. Hormonal variations and their action on the skin during various phases of the menstrual cycle explain the causes of perimenstrual exacerbations of dermatoses. APD and OD, although rare, are underdiagnosed, and treatment can improve symptom management and control. This article highlights the importance of recognizing perimenstrual dermatoses to provide appropriate treatment.
