Menopause

Menopause

1. What every clinician should know

Menopause matters. In the United States, approximately 37 million women are at or near menopause with some 45.5 million women beyond menopause.

Menopause is the last menstrual period at the end of a woman’s normal reproductive life cycle. The diagnosis is retrospective because it is made one year after that last flow. Median age for menopause is 50 to 52 years.

Perimenopause is the endocrine transition beginning with the first irregular flow ending one year after the last menses. Duration of perimenopause is approximately five years, and the normal range of this interval for 95% of women is two to eight years. The average age of onset is 46 years with 95% occurring between 39 and 51 years.

Climacteric defines the time during which a woman passes from regular ovulatory cycles to postmenopause.

Menopause, the perimenopausal transition, and the climacteric are not pathological. They are normal endocrine transitions of aging associated with significant clinical disruptions of normal life that fall into three groups: 1. estrogen depletion, 2. estrogen excess, or 3. androgen depletion.

Clinical disruptions of perimenopausal and menopausal life are closely linked to endocrine transformations of this passage: estrogen depletion, estrogen excess, and androgen depletion.

Estrogen depletion

Results from gradual decrease in ovarian follicular competence expressed as widening intermenstrual intervals followed by total cessation of ovulation with the last menses signaling total loss of ovarian estrogen production. Estrogen withdrawal is expressed clinically as menstrual irregularities, vasomotor instability (hot flashes), pelvic atrophy, and aggravation of age-related systemic disorders.

Menstrual irregularities: As perimenopause approaches, intermenstrual intervals become shorter because follicular maturation is accelerated from early selection of aging dominant follicles. Thus, intermenstrual intervals of the 20s of 28 to 30 days generally decrease by two to four days to 24-28 days in the 40s. With continued aging, intramenstrual intervals widen as ovulations decrease in frequency and become erratic. Flows decrease in frequency, finally ending in the last menstrual flow defining menopause. With the occurrence of the last menstrual period, a diagnosis of menopause is made one year later.

Vasomotor symptoms (VMS): Hot flashes result from sudden increased blood flow in the skin over the head, neck, and chest. They are preceded with an aura, increased heart rate and perspiration, and are followed with an increase in core body temperature. Duration can be several minutes, even up to an hour. They are more frequent at night. The aura and the event are highly disruptive to the orderly conduct of a woman’s life. In addition, symptoms are associated with loss of sleep, memory lapses, irritability, mood swings, and lethargy. Flashes can disrupt life for many years and, for some women, can be highly debilitating. They decrease over the years if untreated. They occur in over half the women going through the menopausal transition. The connection between estrogen withdrawal and vasomotor symptoms is firmly established, and replacement with estrogen suppresses or ablates them in a great majority of menopausal women.

Pelvic Atrophy: Estrogen withdrawal induces atrophy in the vaginal epithelium. Vaginal dryness with increasing dyspareunia is a common effect of estrogen withdrawal. Atrophic vaginitis results in persistent vaginal irritation, pain, and discharge. Dyspareunia results in declining sexual desire. Other complications include atrophy and inflammation of the vulvar skin and urethra resulting in urinary urgency, frequency, urethritis, and cystitis.

Age-related systemic disorders: Osteoporosis with deformities and fractures result from estrogen depletion. Similarly, atherosclerotic cardiovascular disease is aggravated by and associated with estrogen depletion.

Estrogen excess may cause persistent uterine bleeding long after exhaustion of ovarian follicles. Estrogen excess is more commonly seen in women who are overweight. Androgens normally secreted by the postmenopausal ovary and adrenal gland are converted to estrogens by extraglandular aromatization in peripheral tissues, particularly body fat. Estrogen excess, without luteal progesterone results in chronic hyperstimulation of endometrium and bleeding after menopause. These same endocrine mechanisms are also associated with excessive breast cancer risk.

Erratic perimenopausal flows may persist between ovulatory cycles or cause postmenopausal bleeding because of excess extraglandular conversion of androgens into estrogens. Rare cases of congenital adrenal hyperplasia are reported to produce persistent bleeding after menopause.

Endometrial hyperplasia results directly from estrogen excess, may cause of persistent bleeding, and may evolve into endometrial cancer.

Endometrial cancer occurs with increasing prevalence in women with chronic estrogen excess. These women are usually overweight with insulin resistance. In some cases, endometrial cancer pathogenesis is not related to estrogen excess.

Androgen depletion results from diminishing testosterone secretion of the anovulatory postmenopausal ovary and from atrophy of the reticularis zone of the adrenal cortex associated with advancing age.

The premenopausal ovary secretes a mid-cycle surge of testosterone that is associated with ovulation. This surge is linked with measurable increases in sexual desire at midcycle. With menopause, the midcycle surge in testosterone is lost. Although the postmenopausal ovary does produce some testosterone, it is significantly diminished. Ovarian testosterone is believed to be important in the maintenance of normal sexual desire in women. Decreased testosterone production is a consequence of oophorectomy and is associated with loss of sexual desire.

The adrenal androgen cortex (zona reticularis) secretes an abundance of dehydroepiandrosterone sulfate (DHEA-S), a testosterone precursor. DHEA-S secretion, genetically determined, is characteristic within families. DHEA-S production reaches maximum levels during adolescent years and into the early 20s and then attenuates gradually with advancing age. It continues to decline through menopause as the adrenal reticularis continues to undergo age-related apoptosis. With some women, who are genetically inclined, the age-related apoptosis is marked and results in depressed intracellular, total system testosterone production. Loss of ovarian midcycle testosterone with menopause, or oophorectomy, further aggravates the drops in total system testosterone production associated with age-related adrenal reticular zone apoptosis.

2. Diagnosis and Differential Diagnosis

Diagnosis of menopause is not difficult, except when it is untimely. When the last menstrual flow occurs at the appropriate time in association with classic symptoms, the event is easily and correctly identified. Most women can recall the month, even the date, of their menopausal flow.

Menopause, the last menstrual flow is diagnosed retrospectively when no menstrual flow has occurred for one year at the end of the normal reproductive cycle.

Perimenopause is not so clearly defined. It diagnosed by the onset of irregular menses at the end of the normal reproductive cycle. Its onset is the first time that such an irregular flow is observed. This diagnosis is usually made by a patient’s own observation of time of her initial menstrual irregularities.

Laboratory tests are frequently not helpful. FSH and estradiol measurements are highly variable because it is nearly impossible to obtain blood at exactly the right moment in the hormonal chaos of perimenopause. A single FSH level exceeding 40 mIU/mL is considered consistent with the diagnosis of postmenopause, but an optimally timed blood sample can be difficult to obtain before the last menstrual flow. Inhibin is an index ovarian follicular mass. Its decline begins around age 35 and accelerates through age 40. There is no fixed value of Inhibin that identifies pre- or postmenopausal women. Both inhibin and anti-mullarian hormone can be undetectable during or after menopause. In general, when there have been several months of amenorrhea, a single FSH level over 40 mIU/mL is the most reliable diagnostic aid for declaring to a patient that she is postmenopausal.

Differential diagnosis

Differential diagnosis of menopause can be challenging, particularly if it is premature. Questions are most likely to occur over differential diagnosis of VMS. Causes besides hypoestrogenism can be psychological, hypothyroidism, and acute infections, pheochromocytoma, carcinoid, leukemia. and some occult malignancies. When VMS is not occurring on the perimenopausal scenario, these differential diagnoses need to be investigated.

3. Management

Ovarian failure-associated perimenopause and menopause is an inevitable, natural event. No technology is available to modify its course. Thus, the menstrual disturbances encountered in the normal perimenopause to menopause scenario follow a predictable course. Initially, menses are very regular, become more frequent, and become closer together. They then become farther apart as ovarian failure occurs, intervals widen, and flows become scanty. Management of these changes rarely requires more than an expectation setting explanation. Deviations from this pattern, however, may signal significant pathological diagnoses that include benign conditions such as adenomyosis, polyps, and myomas, or malignancies that include endometrial carcinoma or even myometrial sarcoma. When a deviation from the expected menstrual pattern is reported, diagnosis of the underlying gynecological disease is needed and specific treatment is rendered.

Management is for symptoms related to:

• estrogen depletion.

• estrogen excess.

• androgen depletion.

Managing Estrogen Depletion

Vasomotor symptoms (VMS) are directly related to withdrawal of estrogens from ovarian failure. VMS is most efficiently managed by replacing estrogens, the hormones that are deficient. During the hot flush, a woman’s body undergoes a complex autonomic thermoregulatory dysfunction that is associated with an aura, increased heart rate, flushing, perspiration, and increasing core body temperature. The symptoms are unsettling and disruptive for women during their most productive hours when they are working in public or managing complexes technical tasks. At night the hot flashes disrupt normal sleep patterns. VMS is correlated with loss of REM sleep, which is directly related to loss of memory, lethargy, and fatigue starting in the morning and persisting throughout the day. Estrogens are the most effective available for reducing VMS and associated menopausal symptoms. In 2002, concerns increased markedly over adverse reactions associated with oral estrogens because of the Women’s Health Initiative Study.

This study linked oral estrogens and progestins to cardiovascular complications including deep vein thrombosis, coronary occlusion, and strokes. There was also a small increase in breast cancer, but this was principally linked to the progestin component in the drug under investigation, which was a mixture of equine estrogens plus medroxyprogesterone acetate. These findings combined with many years of retrospective analysis led to a series of guidelines that supported continued use of estrogens for VMS but to administer them at lowest doses possible to alleviate symptoms. This logic has affected the most popular strategies, which include delivering estrogens through the skin in doses much lower that with oral administration.

Transdermal estradiol, developed over the past 20 years, includes estradiol, the exact molecular form of estrogens secreted by the premenopausal ovary, directly into the microvascular circulation. The advantage of transdermal delivery is that hepatic portal system is bypassed and liver does not metabolize estradiol through the skin. This is in contradistinction to oral estrogens where the “first-pass effect” is a mechanism by which several complications associated with oral estrogens are associated.

Estrogens, regardless of the delivery method, are highly effective in the suppression of VMS, more effective than any other therapy. The preparations differ in efficacy and side effects.

Transdermal estradiol is available as patches, gels, and sprays.

Estradiol patches currently available for clinical use are listed on Table I. Patches deliver estradiol in doses ranging from 0.14 to 0.1 mg per day, the normal range of premenopausal estradiol secretion being 0.05 to 0.06 mg on the day of menses. Two types of patches are available clinically. The reservoir patch, the earliest technology, involves dissolving the estradiol in an alcohol-retaining membrane that controls the drug release into the microcirculation of the skin. This design is associated with a high prevalence of skin reactions but is much less expensive.

The Matrix patch, a more advanced technology, utilizes a suspension of estrogen within a polymer or textile pad that is held in direct contact with the skin. The adhesive is applied only to the perimeter of the patch and makes the patches associated with fewer skin reactions. Most recent designs utilize a Dot Matrix system that combines the drugs in a single layer and can be incorporated in a small and thinner design than earlier patches. Skin reactions to these patches are even lower. Transdermal patches were designed to improve compliance to oral therapy by providing once or twice weekly dosing. Occasional skin irritation occurs. Up to 10% of the patches may fall off, become soiled, or leave behind a sticky residue or be undesirable for cosmetic reasons. Estradiol patches are highly effective for suppressing VMS in randomized clinical trials.

Estradiol gels available for clinical use are listed on Table I. Estradiol topical gels are delivered in doses ranging from 0.12 to 0.05 mg per day. These doses approximate premenopausal estradiol production in premenopausal women. Gels can be applied to the legs or other large areas of skin. Gels can be messy and must be dry before the patient dresses or washes.

Estradiol spray is currently available in the United States and is listed in Table I. First introduced in 2008, the spray delivers between 0.019 and 0.04 mg per day in proportion to one, two or three sprays applied to the arm once a day. This spray itself is estradiol dissolved in ethanol and mixed with a penetrating agent called octisalate, a binding agent used in sunscreen lotions to promote penetration through the epidermis. Estradiol is released very slowly over 24 hours. Blood levels remain stable for over 24 hours. Patients like the use of estradiol spray as no patch is visible, there are no problems with allergic reactions, they do not fall off, and the application of this spray fits in with their morning routine.