Tara K. Cooper, Oliver Milling Smith The female physiologic aging process accelerates after the menopause, particularly in the genital tract. In perimenopausal women, the ovary becomes less responsive to gonadotropins, which results in a gradual increase in the circulating levels of follicle-stimulating hormone (FSH) and later luteinizing hormone (LH) and a subsequent decrease in estradiol concentrations. FSH levels can fluctuate markedly several years before menses cease, so is an inaccurate diagnostic test, but eventually follicular development fails completely and estradiol production is no longer sufficient to stimulate the endometrium. Amenorrhea then ensues, and FSH and LH levels are persistently elevated, reaching peaks 3 to 5 years after the menopause. Thereafter, there is a gradual decline to premenopausal levels over a 20-year period.1 A loss of follicles also results in a fall in the production of antimullerian hormone (AMH). During the reproductive years, the ovary has three components for steroid biosynthesis—the maturing follicle, functioning corpus luteum, and stroma. After menopause, the stroma is the only source of estrogen. Estrone is the major postmenopausal estrogen. It is derived from the conversion of androgens, mainly androstenedione, and produced by the ovaries and adrenal glands. The efficiency of this process increases with age, and estrone levels rise to four times those found in young women. This conversion also relates to body weight because fat has the ability to aromatize androstenedione to estrone.2 The other postmenopausal estrogens include estriol, which is weak and does not seem to have a significant role, and estradiol, which although secretion is minimal, with blood levels being reduced by 90%, it has 10-fold greater biologic activity than estrone and therefore retains an important role in maintaining hormone-dependent tissues.3 Progesterone in the postmenopausal woman is derived mainly from the adrenal glands, and levels fall steadily. Production of testosterone and dehydroepiandrosterone (DHEAS) remains relatively unchanged until later life; surgical oophorectomy will, therefore, result in a decrease of serum testosterone levels of up to 50%.4 The major change is atrophy, which results in smaller and smoother structures, flattened epithelial surfaces, and fibrous stroma, with much reduced vascularization and fat content. The postmenopausal ovary is small and sclerotic, with an absence of follicular activity. The cortex involutes, and germinal inclusion cysts are found. Lipid droplets may be seen in the stroma as evidence of continuing steroidogenesis. There is a marked reduction in uterine size so that the uterine body-to-cervix ratio reverts from the 4 : 1 of reproductive life to the 2 : 1 of childhood. In the myometrium, there is interstitial fibrosis and thickened blood vessels due to obliterative and subintimal sclerosis. The endometrium becomes a single layer of cuboidal cells with a few inactive glands, which may be dilated due to blocked ducts. The cervix becomes more flush with the vaginal vault, and the squamocolumnar junction recedes into the endocervical canal; this can cause stenosis of the external os. The vagina becomes thinner, atrophic, and less elastic, which can make it more vulnerable to trauma. Reduction in estrogen inhibits lactic acid production by the vaginal flora, which raises the vaginal pH and increases the risk of fungal and bacterial infections.5 Postmenopausal changes are characterized by skin shrinkage, loss of prominent landmarks, and sparse greying hair. The epidermis is thinner, although there is increased keratinization. These features may coincide with a vulvar epithelial disorder (see later). Aging produces pelvic floor weakness. Damage to the nerve supply starts with parturition,6 and progressive denervation is found in association with prolapse7 (see later). An important element of pelvic floor support is collagen, which diminishes after the climacteric. Estrogen receptors are also present in the pelvic organs and decrease after menopause, leading to further weakness of the supporting ligaments and increased risk of prolapse.8 Menopause is the permanent cessation of menstruation in nonhysterectomized women. The cessation of ovarian function at menopause has many short- and long-term consequences. The characteristic features of reduced estrogen are systemic, including vasomotor symptoms and localized atrophy of the genital tract.9 More relevant is the prolonged effect of estrogen deficiency postmenopausally. The average age of menopause has remained around 51 years for centuries. With female life expectancy now reaching over 80 years, there has been a massive increase in the number of postmenopausal women, and the morbidity and mortality secondary to the effects of ovarian failure have become increasingly important. Long-term effects include urogenital atrophy, osteoporosis (see Chapter 70), and effects on cardiovascular function. There is continuing controversy as to whether cognitive performance is adversely affected. In postmenopausal women there is accelerated bone loss, so that by age 70 years, 50% of bone mass is lost, whereas men lose only 25% by 80 years of age.10 This is due to increased bone resorption by osteoclasts and reduced new bone formation leading to increased turnover. Altered calcium metabolism may be a contributory factor but the primary defect is generalized connective tissue loss, with reduced bone mineral content following breakdown of the organic collagen matrix.11 The resultant osteoporosis dramatically increases the older woman’s fracture rate; 50% of women aged 75 years will have sustained one or more fractures at the most common sites of the wrists, vertebral bodies (resulting in the classic so-called Dowager hump) and neck of the femur. The latter is the most significant consequence of osteoporosis because of its high morbidity and mortality; there is a 20% death rate within the first year, and 50% of survivors will fail to regain their independence.12 Two years of hormone replacement therapy (HRT) results in a 66% reduction in hip fracture in the subsequent 2 years and, taken for 10 years, produces a 60% reduction in the overall mortality rate related to osteoporotic fractures.13 However, studies have highlighted the potential risks of long-term use of HRT (see later, “Hormone Replacement Therapy”). Cardiovascular disease (CVD), which includes coronary heart disease and stroke, is five times more common in men than in premenopausal women but, by 70 years, the gender difference is lost. Overall, CVD is the most common cause of death in women. In younger women, estrogen exerts cardioprotective effects through a vasodilatory effect and an alteration in lipid metabolism. Ovarian failure causes increased levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) and a reduction in high-density lipoprotein (HDL). These changes contribute to an increased predisposition to ischemic heart disease.14 Theoretically, therefore, estrogen therapy should reverse these effects. Observational data have suggested a cardioprotective effect of HRT,15 but randomized controlled clinical trials have consistently reported that HRT does not reduce, and may slightly increase, the risk of adverse cardiac events after menopause.16 These studies may have been influenced by the type of HRT investigated and the age range of patients. Skin changes have been attributed to the aging process but estrogen deficiency and light exposure are significant factors. Skin thickness declines after menopause by 30% in the first 10 years, which is comparable to bone loss over the same time.17 When HRT is started early, there is maintenance of skin collagen and thickness. Estrogen deficiency also affects teeth; one third of U.S. women older than 65 years are edentulous. HRT may be protective. Estrogen therapy has been widely regarded as the appropriate treatment for the consequences of ovarian failure for symptom relief or prevention of long-term effects. However, the Women’s Health Initiative (WHI) study and Million Women Study (MWS) results led to considerable uncertainties among health professionals and women about the role of HRT.18,19 The British Menopause Society (BMS) published updated recommendations on HRT in 2013.20 The key recommendation is that all women should be able to obtain advice on how they can optimize their menopause transition and beyond, with particular reference to lifestyle and diet, and an opportunity to discuss the pros and cons of complementary therapies and HRT. Other key points include the following: • The HRT regimen should be individualized, with an annual review. • No arbitrary limits on the duration of usage should be established. • HRT prescribed before the age of 60 years has a favorable benefit-risk profile. Currently. most women who request HRT do so for symptom relief, and duration of use is usually less than 5 years. If HRT is to be used, it should be the lowest dose of estrogen required to relieve symptoms. There is an additional need for progesterone in nonhysterectomized women because unopposed estrogen therapy causes endometrial hyperplasia, which may lead to adenocarcinoma. Progesterone given for 12 to 14 days each month reduces these risks21 and may be administered orally or transdermally. When HRT is given in this cyclic sequential regimen, there is a withdrawal bleed at the end of each course. In women at least 1 year postmenopausal, progesterone can be given continuously, which prevents endometrial proliferation so there is no bleeding. The levonorgestrel-releasing intrauterine system (Mirena; Bayer) can fulfill this role. Women who start on cyclic HRT can be changed to a continuous combined product when they reach the age of 55 years. Common adverse effects of estrogen include nausea, headache, and breast tenderness. Unexpected bleeding requires clinical examination, and transvaginal ultrasound with biopsy as required. Oral administration is the most widely used route and is convenient, relatively inexpensive, and generally well tolerated. Many combinations are available commercially, cyclic and continuous. In perimenopausal women who do not wish frequent withdrawal bleeds, a 3-month bleed preparation can be tried. Tibolone is a synthetic steroid with estrogenic, progestrogenic, and androgenic properties and acts as a continuous combined product. It may also improve libido and may have less effect on breast tissue.22 The main disadvantage of the oral route is that estrogen passes directly to the liver, where it is inactivated and partially metabolized to the less effective estrone. This is called the first-pass effect, which means that higher doses are required than with parenteral therapy. It may also result in altered hepatic metabolism, with changes in clotting factors and increased renin substrate, which predisposes to hypertension. Transdermal patches may be matrix or reservoir in type and require changing once or twice weekly. Combination patches with progesterone are also available. Estradiol is delivered at a controlled rate, depending on surface area. The first-pass effect is avoided, and hepatic metabolism is not affected, thus reducing the risk of thrombosis. The main problems are with adhesion, and transient skin reactions can occur in up to 30% of women; the frequency is lower with matrix patches. A transdermal gel may be used instead. Low-dose vaginal creams, pessaries, tablets, and rings are used primarily for treating symptoms of urogenital atrophy. Systemic absorption and side effects are minimal and, although use may need to be prolonged, progesterone opposition is not required. In general, a short course is adequate; a 14-day course should be followed by two nights’ application each week for up to 6 weeks. A problem with this route in older women is reduced acceptability and impaired manual dexterity for self-administration. A low-dose hydrophilic vaginal tablet, which has a fine prelubricated and preloaded applicator (Vagifem; Novo Nordisk) may be acceptable for use in patients with a history of breast cancer after discussion with the oncology team. There are few contraindications to HRT, which provides estrogen replacement at a below-normal premenopausal plasma concentration and that achieved with the high-dose synthetic steroids used in the combined oral contraceptive pill. The main contraindications are estrogen-dependent breast or endometrial cancers, although women with treated breast cancer and debilitating menopausal symptoms may be given HRT under specialist supervision, and there is no evidence of increased recurrence rates.23 Oral estrogen is associated with an increased risk of venous thromboembolic disease (VTE), although the absolute risk is low for women younger than 60 years. The risk appears to be lower with transdermal estrogen, so this route is preferable for women with other risk factors, such as smoking and obesity.24 It is not necessary to stop HRT prior to surgery because most patients will fall into a moderate risk category (in regard to age) and receive antithrombotic prophylaxis. HRT may be given if there is a preexisting gynecologic condition (e.g., endometriosis, fibroids), but the latter may fail to shrink and cause heavier withdrawal bleeds. Two large studies (WHI and Million Women Study18,19) have suggested a small increase in the risk of breast cancer after 5 years of HRT usage, but current opinion has cast doubt on the ability of these studies to establish a causal association. Similarly, published data on the risk of ovarian cancer are conflicting. The risk of endometrial cancer is largely avoided by the use of combined estrogen-progestogen therapy. Changing to continuous combined HRT as soon as appropriate reduces the endometrial risk to lower than that in an untreated population.25 There is no association between HRT and cervical cancer. There may be a reduced risk of colorectal cancer. Despite extensive educational products and improved therapies, such as no bleed continuous HRT, compliance is poor. About 50% of patients do not remain on HRT 12 months after starting treatment, even when at risk of osteoporosis.26 A healthy diet, stopping smoking, and an active lifestyle should be recommended. Symptomatic relief from hot flushes can sometimes be achieved with clonidine, gabapentin, and selective serotonin reuptake inhibitors (SSRIs). There is also a growing trend toward natural products such as black cohosh, red clover, and natural progesterone cream. There are some data on the safety and efficacy of red clover27 but less so with other products. One study has shown no pharmacologic activity for progesterone cream,28 and any benefits are likely to be a placebo effect. As many as 50% to 75% of postmenopausal women will use nonpharmacologic options to treat vasomotor symptoms.29 It is important to establish what they may be taking because this may affect other medications. Vulvar epithelial disorders are important because of the severity and chronicity of symptoms—usually itching, soreness, and irritation—and their association with carcinoma. Community-based surveys have demonstrated that round 20% of women have significant vulvar symptoms.30 There have been conflicting views about the pathogenesis, diagnosis, and terminology of vulvar disorders. Lesions may be infective, inflammatory, localized variants of generalized dermatoses, premalignant or malignant. Management is often difficult, especially because patients may present to a variety of specialists, including gynecologists, dermatologists, geriatricians, and general practitioners. Treatment may therefore be improved by consultation at a dedicated vulvar skin clinic, if available. Vulvar skin is more sensitive than other epithelium because it is subjected to increased heat, friction, and occlusion. Aging is also a factor, and some chronic vulvar disorders represent an advanced stage of atrophic change. Patients with any of the myriad of diseases of the vulva may complain of symptoms such as dryness, itch, ulceration, and pain. To diagnose vulvar pathology accurately, a full history and examination are required. The history should explore symptoms at other skin sites and should include a medical and drug history. A family or personal history of autoimmune or atopic conditions should be elicited. Assessment of urinary or fecal incontinence should be made. The examination should extend to other skin and mucosal membranes. The initial investigation of a woman with vulvar symptoms could include testing for thyroid disease and diabetes if autoimmune-associated conditions are suspected. Swabs for infection should be considered, if appropriate. An initial biopsy is not necessary, especially when the diagnosis can be made on clinical basis. However, if vulvar lesions do not respond to initial treatment or doubt exists as to their cause, they should be biopsied to assist diagnosis and subsequent management. Specific common vulvar disorders and treatments are discussed below, but general measures such as following should always be discussed to try and improve symptoms: As mentioned, the vulvar skin may be affected by a variety of dermatologic conditions, including psoriasis, urticaria, and bullous diseases such as pemphigus. The more common inflammatory conditions found in older adults include dermatitis, lichen planus, premalignant conditions of lichen sclerosus, and vulvar intraepithelial neoplasia. These are described next. Women with sensitive skin or eczema can often present with vulvar symptoms and skin changes. Symptoms can include severe intractable itch, especially at night, leading to nonspecific inflammation. Scratching will lead to thickening or lichenification of the skin, termed lichen simplex. The cause of this condition may be endogenous (atopic) or exogenous (contact) in nature. In older adults, urine is a common irritant, but a history indicating a change in, for example, soap, fragrances, and underwear, should be sought. The mainstay of the management of dermatitis and lichen simplex chronic starts with general measures for vulvar care (see earlier section). Moderate or high-potency topical steroids may relieve the itch and can be of value to try and break the itch-scratch cycle. Secondary infection may complicate dermatitis, and swabs should be taken to identify treatable infection. Barrier preparations are valuable in relieving symptoms of contact dermatitis, especially in the presence of urinary or fecal incontinence. However, note that some barrier preparations can cause irritation, worsening the problem. This inflammatory condition may also affect the hair, nails, and mucous membranes. The classic lesions are purple papules, sometimes with a lacy white surface pattern (Wickham striae). The usual complaint is of soreness but itch, dyspareunia, and discharge may be present. If the patient is sexually active and concern exists over vaginal narrowing, vaginal dilators may be of benefit. A more severe presentation of lichen planus may involve an erosive vulvar lesion, leading to profuse discharge and scarring. Treatment involves general vulvar care. This includes the use of emollients and high-potency topical steroids. Premalignant conditions of the vulva include a spectrum of disorders, including vulvar intraepithelial neoplasia, lichen sclerosus, and Paget disease of the vulva. Vulvar intraepithelial neoplasia (VIN) is divided into usual and differentiated types, depending on histopathologic features. The usual type of VIN is the commoner condition and is found in younger and older women. Although the incidence of this condition is rising in younger women, most cases occur in women older than 50 years. This is associated with human papilloma virus (HPV) exposure, in particular subtype 16. Smoking represents an additional strong risk factor, as is chronic immunosuppression. There is no typical appearance of VIN, and the lesions may be unifocal or multifocal. This is rarer and more common in older women and may arise on the background of conditions such as lichen sclerosus. It has the greatest potential for malignant transformation.31 Clinically, lesions tend to be unifocal in the form of a plaque or ulcer. VIN may also be described as VIN type 1, 2, or 3. This classification was revised by the International Society for the Study of Vulvar Disease in 2004 because of a lack of evidence of a disease continuum from VIN 1 to VIN 3 (Box 85-1).32 The symptoms of pruritus can be difficult to treat but some benefit may be obtained with the use of emollients or mild steroids. No single ideal therapy for VIN exists. Surgery may be destructive, and medical treatments may be troubled by side effects. Treatment is difficult, and referral to a specialized vulvar skin clinic is advised. Surgical treatment involves local excision and is often mutilating, creates anxiety, affects sexual function, and suffers from high relapse rates. For this reason, a prudent management plan may often involve watching, with repeated biopsies to exclude carcinogenic change.
Gynecologic Disorders in Older Women
Age Changes in the Genital Tract
Hormone Changes
Anatomic Changes
Ovary.
Uterus.
Cervix and Vagina.
Vulva.
Pelvic Floor.
Menopause
Osteoporosis
Cardiovascular Disease
Skin and Dentition
Hormone Therapy
Hormone Replacement Therapy
Oral Estrogen.
Transdermal Estrogen.
Topical Estrogen.
Contraindications and Risks With Hormone Replacement Therapy
Alternatives to Hormone Replacement Therapy
Vulvar Disorders
Symptoms
Management
Common Vulvar Skin Disorders
Lichen Simplex Chronic and Vulvar Dermatitis
Lichen Planus
Premalignant Vulvar Disorders
Vulvar Intraepithelial Neoplasia
Usual Type of Vulvar Intraepithelial Neoplasia.
Differentiated Type of Vulvar Intraepithelial Neoplasia.
Management.
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Gynecologic Disorders in Older Women
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