Gender is an important variable in many diseases [
Physicians taking care of women with allergic, autoimmune, and skin diseases need to recognize gender influenced systemwide inflammation. The following is a case series of women with skin diseases that improved with ovarian suppression. We review the stage-specific molecular changes in the ovary. The behavior of estrogen receptors in immune cells varies under inflammatory conditions and can dysregulate T-cell function, leading to B-cell hyperreactivity and an increase in autoantibody production per B cell. Immunomodulation is possible with progestins and metformin. The morphologic features shown below illustrate how annular lesions that favored one side directed our differential diagnosis, laboratory testing, and treatment plan (see Figures
(a) 40-year-old female with abrupt onset of palmoplantar pustulosis. (b) Significant improvement occurred after three months of therapy with norethindrone-based oral contraceptive pills.
(a) A 23-year-old Indian female presented with a single patch of alopecia areata. (b) Hair regrowth is evident after 3 months of therapy with norethindrone and metformin.
(a) A 19-year-old Caucasian female presented with a large temporal patch of alopecia areata. (b) Significant hair regrowth is evident after three months of therapy with norethindrone and metformin.
(a) A 25-year-old female with type I DM and onset of necrobiosis lipoidica at puberty. (b) A reduction in peripheral erythema and active border ensued after one year of therapy with norethindrone-based oral contraceptive pills.
(a) A 20-year-old Caucasian female presented with vitiligo on the knees, with the right knee involved more than the left knee. (b) Repigmentation occurred after one year of norethindrone-based oral contraceptive therapy.
Sexual differences in the immune system have long been observed, with females generally demonstrating a more vigorous immune response than males [
Sex hormones, including estrogen, progesterone, and prolactin, affect immune cells via intracellular receptors. Intracellular estrogen receptors are found in B and T lymphocytes, neutrophils, macrophages, NK cells, bone marrow, and thymic stromal cells [
Ultimately, estrogen tends to favor Th2 cell line development by affecting the maturation and development of B and T lymphocytes [
The X chromosome contains many genes that affect immune function [
Physiologically, during each menstrual cycle, several follicles simultaneously mature in an attempt to reach ovulation. This cluster of maturation has been proposed to be secondary to rising levels of follicular-stimulating hormone (FSH). This follicular wave, stimulated by FSH, reciprocally causes a proportional decline depending on the number in the cohort stimulated and the amount of their released secretions. From there, only the dominant follicle (DF) escapes atresia when the FSH surge equally declines [
The oocyte, itself, governs follicular activation, and within it, the PTEN pathway (phosphatase and tensin homolog deleted on chromosome 10) determines the actual initiation of growth, or the preservation of the dormant follicular pool. PTEN is part of a larger pathway and is a negative regulator of PI3K (phosphoinositide 3-kinase) signaling pathway. P13k, through the action of many downstream substrates (i.e., FOXO3), positively activates the primordial follicle. Thus, PTEN can altogether prevent this and maintain dormancy (Figure
McLaughlin and McIver [
Several different causes of premature ovarian failure (POF) are implicated, ranging from iatrogenic (chemotherapy, radiation, and surgery) to autoimmune and genetic conditions. It is estimated that 10–20% of POF is caused by autoimmunity, yet this remains controversial as the exact correlation is still unclear [
Once the dominant follicle has emerged and bypassed all the negative-regulating factors, multiple preparatory events, including vesiculation, mucification, and cumulus rupture, line up to take place. Prior to ovulation, as the secondary follicle matures, a fluid-filled cavity, or antrum, forms adjacent to the oocyte. This separates the granulosa cells surrounding the oocyte into two populations: cumulus cells that encapsulate the oocyte and the mural granulosa cells that form the follicular wall. Differentiation of this cell population and the formation of the antrum mark the transition of the secondary follicle to the antral (Graafian) or tertiary follicle [
In the absence of fertilization and resultant trophoblastic human chorionic gonadotropin (HCG) secretion, the corpus luteum undergoes luteolysis, a dynamic process resulting in structural and functional regression. And as a result, progesterone production ceases just prior to the collapse of the corpus luteum organ [
Women are considered to be genetic mosaics due to lyonization, or random X-chromosome inactivation in somatic cells [
X-chromosome-associated mosaicism also plays a significant role in the distribution of cutaneous diseases. Perhaps the most famous example of genetically influenced skin patterning is Blaschko’s lines. First described by Alfred Blaschko in 1901, alternating bands of diseased and normal skin occur and are pathognomonically associated with over a dozen of X-linked skin disorders such as incontinentia pigmenti, anhidrotic ectodermal dysplasia, and hypomelanosis of Ito [
Another form of patterning that occurs in cutaneous lesions is lateralization. This pattern is exclusively seen in X-linked congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome). This syndrome presents as scaly erythematous plaques on one-half of the body with abnormalities in ipsilateral internal organs and bones. This unique distribution is attributed to lyonization and a gene defect in the sonic hedgehog pathway that controls left-right patterning [
The influence of hormones on immunity has been the subject of recent reviews. Our goal was to align certain morphologic and distributive features in the skin with the variable physiology of the menstrual cycle. The ovary is pivotal in maintaining the hormonal equilibrium required for follicular development, preservation of the reproductive tract, development of secondary sexual characteristics, and general metabolic finesse [
Progestins and androgens have immunomodulatory effects [
Other medications that impact hormone driven immunity include gonadotropin hormone releasing agonists and metformin. Metformin inhibits PTEN and preserves the dormancy of the follicular pool. This effect decreases the follicular mass, correcting the androgen and insulin discord seen in polycystic ovary syndrome [