Biology of Female Sexual Dysfunction

Content Written By: Irwin Goldstein, MD

The structure and function of women's genitalia are highly dependent on the sex steroid hormonal milieu. As a woman ages or a young woman is exposed to medicines that interfere with the hormonal milieu (eg oral contraceptives, tamoxifene), her supply of sex steroid hormones (estradiol, testosterone and progesterone) diminishes significantly. Of note, not all women have absent estradiol synthesis in the menopause. During menopause, ovarian estradiol production ceases in all women. However, estrogen continues to be synthesized in the periphery (eg, skin, adipose tissue, bone, muscle) in postmenopausal women through conversion of androstenedione to estrone and testosterone to estradiol, but the amount of estradiol synthesized depends, in part, on the enzymatic activity of aromatase.

Estrogens and androgens are required for genital tissue structure and function. These hormones act on estrogen and androgen receptors, respectively, which exist in high numbers in genital tissues, including the epithelial/endothelial cells and smooth muscle cells of the vagina, vulva, vestibule, labia, and urethra. Diminished estrogen production for natural or iatrogenic reasons renders women’s genital tissues highly susceptible to atrophy. Physical examination of the postmenopausal woman’s genitalia shows clitoral atrophy, phimosis, and nearly absent labia minora. The appearance of a woman's labia minora mirrors her level of estradiol, because these labia are exquisitely sensitive to estradiol. The urogenital area termed the vestibule is very important in female sexual function because it contains organs that are sensitive to both estrogen and androgen. For example, the clitoral tissues and prepuce are androgen sensitive. The minor vestibular glands, which are located in the labial-hymenal junction, are embryologically derived from the glands of Littre, which are also androgen dependent. The glands of Littre are located on the anterior surface of the urethra.

A host of structural changes and cellular dysfunctions occur in women’s genital tissues as a result of estrogen deficiency. For example, estrogen deficiency specifically in the vagina leads to vaginal atrophy. One consequence is an alteration in the normally acidic vaginal pH that discourages the growth of pathogenic bacteria. The change to an alkaline pH value in the atrophic vagina leads to a shift in the vaginal flora, increasing the likelihood of discharge and odor. In an estrogen-rich environment, glycogen from sloughed epithelial cells is hydrolyzed into glucose and then metabolized to lactic acid by normal vaginal flora. In postmenopausal women, however, epithelial thinning reduces the available glycogen.

In addition to vaginal atrophy and a reduction in organ size, other signs of a decline in sex hormones in women include: vaginal dryness; no secretions or lubrication; pale or inflamed tissue; petechiae; epithelial/mucosal thinning; organ prolapse; changes in external genitalia; decreased tissue elasticity and loss of smooth muscle. Symptoms of women’s sexual health concerns that the clinician may elicit when taking a history in a menopausal woman are: dyspareunia, vaginismus, coital anorgasmia, vaginal and/or urinary tract infections (pH imbalance), overactive bladder/incontinence.

Effects of Sex Steroid Hormones on the Vagina

The human vagina consists of 3 layers of tissue: the epithelium (composed of squamous cells), the lamina propria, and the muscularis (inner circular and outer longitudinal smooth muscle). The epithelium undergoes mild changes during the menstrual cycle. The lamina propria is replete with tiny blood vessels that become engorged with blood during sexual arousal, leading to lubrication. The smooth muscle of the muscularis enables the vagina to dilate and lengthen during penile penetration. Relaxation of that muscle leads to arousal. These 3 layers of tissue may function in an interrelated way. It is hypothesized that the blood vessels in the lamina propria that allow for lubrication are dependent on growth factors, and that the growth factors are derived from the muscularis. Postmenopausal atrophy of vaginal tissues may be due to decreased synthesis these growth factors resulting in diminished number of critical blood vessels in the lamina propria.

Controlled studies employing a rat model of vaginal atrophy demonstrated the effects of different dosages of estrogen, progestin, testosterone, and various combinations of these hormones on various physiologic and anatomic outcome parameters. These measures included organ wet weight, vaginal blood flow, epithelial height, muscularis thickness, and vaginal innervation. In each study, the effects on the vagina of different dosages of the hormone being tested were compared between rats that had undergone sham ovariectomies and rats that had actually had both ovaries removed. The hormones (or saline) were delivered through a pump inserted into the back of the neck of each animal. A Doppler probe inserted into the vagina was used to record blood flow after electrical stimulation of a nerve next to the vagina. All animals were then euthanized and vaginal tissue removed for biochemical or histologic studies. In those animal studies, removal of the ovaries reduced the wet weight of the uterus that rose with administration of estrogen because the uterus is a very estrogen-sensitive organ, much more so than the vagina.

Increased vaginal blood flow is an indicator of sexual arousal. Genital swelling and lubrication are responses to increased clitoral and vaginal perfusion; increased length and diameter of the vaginal canal and clitoral corpora cavernosa; engorgement of the vagina wall, clitoris, and labia major and minora; and transudation of lubricating fluid from the vaginal epithelium. In the animal studies just described, blood flow to the vagina was greatly reduced in the oophorectomized rats compared with the intact rats. Contrary to what one might expect, subphysiologic doses of estradiol increased vaginal blood flow in oophorectomized rats more than either physiologic or supraphysiologic doses. Ovariectomy deprived the rats of estradiol, causing the vaginal epithelium to thin down to a single layer. Subphysiologic doses of estradiol increased the thickness of the vaginal epithelium the most because the oophorectomized rats had more estrogen-alpha receptors in the epithelium than the intact animals. A small amount of estradiol delivered to tissue with many estrogen-alpha receptors produced a huge response. Thus, estradiol regulates estrogen receptors through a negative feedback system. The more estradiol that is available, the fewer estrogen receptors there are. The muscularis, the muscle that enables the vagina to lengthen and widen during sexual arousal, also atrophies without estrogen. In postmenopausal women who do not take hormone therapy, the vaginal epithelium, lamina propria blood vessels, and muscularis all decrease. Like the epithelium, the muscularis responds to estradiol by increasing in thickness.

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