Understanding the menopausal transition, and managing its clinical challenges

Hormonal changes at the menopausal transition 

The progressive decline in follicle number produces a menstrual cycle pattern of hormones that is specific to the menopausal transition.4 Changes in the levels of gonadotropins, estrogens, and inhibins are especially noteworthy (Figure 2).

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Figure 2. Normal hormonal cycling in younger and older women. The graphs highlight changes in the levels of inhibin B, inhibin A, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P4). Reprinted with permission from Welt CK et al. J Clin Endocrinol Metab 1999;84:105-116 and the Endocrine Society.

Fluctuations in gonadotropin levels occur during the menopausal transition in both the follicular and luteal phases of the menstrual cycle.5, 6 In the early follicular and early luteal phases, FSH levels are higher in older women (ages 35 to 46) than in younger women (ages 20 to 34).6 FSH levels in the mid- and late luteal phases are comparable in both groups of women, as are luteinizing hormone (LH) levels across the entire menstrual cycle. It is presumed that reproductive aging has begun in the older subset.

Estrogen levels are elevated during the early menopausal transition. In the mid- and late follicular phases, estradiol (E2) levels are substantially higher in older women than in younger women, as defined above. In the luteal phase, E2 levels are the same in both groups.6 The study by Santoro et al, which used different age subsets to distinguish the perimenopause, showed that the overall mean menstrual cycle excretion of estrone conjugate is higher in older women (ages 43 to 47) compared with that in younger women (ages 19 to 38).7

Inhibin levels also change as women enter the menopausal transition. Compared with younger women, older women in menopausal transition exhibit lower inhibin B levels in the early follicular phase and across the entire luteal phase (Figure 2).6 Inhibin A levels are not significantly different in the two groups, except for a transient and sharp decline in the level of inhibin A in older women immediately following the LH peak.6

It is decreased negative feedback by inhibin B that causes the rise in FSH levels during the early menopausal transition.8 Inhibins are members of the transforming growth factor-β superfamily. Inhibin B is produced by granulosa cells in the ovary and serves primarily to inhibit pituitary FSH secretion. During the menopausal transition, inhibin B levels begin to decline as a result of reduced ovarian function. With decreased negative feedback by inhibin B, FSH levels increase. Higher FSH levels in the peripheral circulation drive the ovary to increase estrogen production, thus accounting for the higher estrogen levels.

Hormonal changes across the menopausal transition 

Only a few studies have examined the changes in reproductive hormone levels across the entire menopausal transition. As part of a longitudinal prospective study published in 1995, Rannevik et al monitored 160 women through the menopausal transition and postmenopause for 12 years.9 Among their findings, which are illustrated in Figure 3:

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Figure 3. Reproductive and adrenal hormone levels across the menopausal transition and postmenopause. Values are mean serum levels during the menopausal transition. FMP, final menstrual period (0) Reprinted with permission from Rannevik G et al. Maturitas 1995;21:103-139 and Elsevier Science.

Inhibin A and inhibin B levels decline across the entire menopausal transition. Burger et al published the first longitudinal study of these changes.10 Serial levels of serum inhibin A and B were prospectively measured each year in 150 women in the menopausal transition. They found that mean levels of inhibin B were 48.9 ng/L at 2.5 years prior to the FMP; inhibin B levels decreased 40% (to 28.5 ng/L) six months after the FMP. Mean inhibin A levels were 25.0 ng/mL at 2.5 years before the FMP and decreased by 50% (to 13.5 ng/mL) at the FMP.

The aging adrenal gland and ovary are responsible for changes in androgen hormone levels. However, a point of contention is whether testosterone levels change in the early postmenopause (five years after the FMP) or remain constant throughout the menopausal transition. Burger et al were able to examine this issue in a 12-year longitudinal study of total circulating testosterone levels, which were measured serially in 172 women each year, five years prior to, and seven years after the FMP.11 They found that mean total testosterone levels (1.4 nmol/L; 40.3 ng/dL) were unchanged across the menopausal transition. Others have found a decline in total testosterone levels around the FMP.9

Infertility 

The association between advancing age and decreased fecundability is well established.12 Fecundability, or the probability of achieving pregnancy in one menstrual cycle, is 20% to 25% in normal couples. The reduction in fecundability starts in a woman's early 30s and progressively declines through the menopausal transition. Infertility associated with reproductive aging is caused by both the progressive depletion of oocytes (reduced ovarian reserve) and the increase in chromosomal abnormalities in aging oocytes.

Initial assessment: Among the first signs of ovarian aging are menstrual irregularity and an elevation in FSH levels. Women with decreased ovarian reserve can be identified by measuring cycle day 3 levels of FSH and E2 and then giving 100 mg of clomiphene citrate on cycle days 5 through 9 (a clomiphene challenge test). FSH levels are then measured again on cycle day 10. FSH levels > 10 mIU/mL and/or E2 levels > 70 pg/mL are abnormal and suggestive of decreased ovarian reserve.

General treatment guidelines: All infertile couples with decreased ovarian reserve (or who are 35 or older) should be referred to a reproductive endocrinologist for evaluation and treatment. Patients with day 3 FSH levels of 10–19 mIU/mL should be offered three cycles of aggressive ovulation induction with FSH followed by intrauterine insemination or, if necessary, in vitro fertilization (IVF). Women with FSH levels > 20 mIU/mL should be advised to consider egg donation.

Biological mechanisms of ovarian aging

An important question in reproductive biology is the cause of ovarian follicle depletion that leads to reproductive aging. Two hypotheses currently under investigation are oxidative stress and apoptosis. Oxidative stress may cause cell damage within the ovary as a result of an excessive accumulation of reactive oxygen species, such as superoxide anions, hydroxyl radicals, and hydrogen peroxide.1

Apoptosis, or programmed death, is a universal mechanism underlying cell death in all types of animal cells.2 It is characterized by unique morphologic changes in the nucleus and cytoplasm. Apoptosis in the ovary has been described in several animal species. Recently, it was demonstrated that the genes bax and bcl-2 are involved in ovarian follicle apoptosis in rats, and ovarian follicle depletion was prevented in an aging bax knockout animal.3

REFERENCES 

1. 1 Behrman HR , Kodaman PH , Preston SL , Gao S . Oxidative stress and the ovary . J Soc Gynecol Investig . 2001;8:S40–S42 . MEDLINE | CrossRef

2. 2 Pru JK , Tilly JL . Programmed cell death in the ovary: insights and future prospects using genetic technologies . Mol Endocrinol . 2001;15:845–853 . MEDLINE | CrossRef

3. 3 Palumbo A , Yeh J . In situ localization of apoptosis in the rat ovary during follicular atresia . Biol Reprod . 1994;51:888–895 . MEDLINE | CrossRef

The ideal IVF stimulation protocol has not been established for poor responders; included in this category are older women (older than 40), women with decreased ovarian reserve, women with an inadequate ovarian response to controlled ovarian hyperstimulation, and women who have ultrasound ovarian antral follicle counts of <6.

Standard gonadotropin-releasing hormone (GnRH) agonist protocols may cause oversuppression in poor responders. Currently, agonist flare-up using microdoses of GnRH is the protocol of choice.13 GnRH antagonist and GnRH agonist protocols have been shown to produce similar clinical outcomes.14

Dysfunctional uterine bleeding 

Menstrual cycle irregularity occurs in over 50% of women in the menopausal transition15 and is often associated with abnormal uterine bleeding, which may present as irregular, heavy, or persistent menstrual flow. The most common cause of menstrual irregularity during the menopausal transition is anovulation.

Initial assessment: The evaluation of dysfunctional uterine bleeding should begin with a vaginal ultrasound and office endometrial biopsy. An endometrial stripe of <5.0 mm is associated with a very low risk of endometrial cancer or hyperplasia.

Management recommendations: The consensus approach to addressing anovulatory bleeding is hormone therapy. A low-dose oral contraceptive is a good first choice as long as no contraindications are present. Contraindications include thromboembolic disease, stroke, coronary artery disease, cigarette smoking, hypertension, and hypercholesterolemia.

An alternative intervention is progestin therapy. The most common regimen is cyclic medroxyprogesterone given 10 mg daily for 10 days each month. Other progestin-based therapies include norethindrone acetate, depot medroxyprogesterone acetate, and the levonorgestrel intrauterine system. An effective non-hormonal treatment for dysfunctional uterine bleeding is the use of nonsteroidal anti-inflammatory drugs (NSAIDs). A loading dose of ibuprofen (800 mg) or mefenamic acid (1,000 mg) is suggested, followed by three doses of ibuprofen (400 mg) or mefenamic acid (500 mg) daily for three days.16

Hot flashes 

The hot flash is the most common symptom of the menopausal transition. Although the biology of the hot flash is not fully understood, there is good evidence that norepinephrine, acting through α2-adrenergic receptors in the central nervous system, might be the underlying mechanism. Hot flashes have not been correlated with estrogen or gonadotropin levels.

Presentation: Hot flashes are experienced as episodes of sweating, flushing, and heat sensation. Measurable features include an increase in skin temperature, sweating, core body temperature, heart rate, and metabolic rate.17 Hot flash episodes typically last 1 to 3 minutes and recur five to 10 times per day. Hot flash frequency during the menopausal transition is greatest around the FMP. Sleep disturbances are most common in symptomatic menopausal women.

Management recommendations: Low-dose oral contraceptives (or hormone replacement therapy in small doses for a limited time) are still considered first-line treatment for vasomotor symptoms. Second-line pharmacologic treatments are typically not as effective as estrogen therapy and include agents such as clonidine (0.1 mg/d) and selective serotonin reuptake inhibitors (eg, paroxetine 12.5 to 25 mg/d).18, 19, 20

Alternative treatments, such as soy, black cohosh, and vitamin E, have not been associated with serious side effects and thus might be an option for some women. However, the efficacy of these compounds is not fully known.21

Osteoporosis 

The menopausal transition is associated with small but noteworthy losses in bone mineral density and is thus a good time to consider bone density testing, especially in women at high risk for osteoporosis. Yet few guidelines are currently available to advise clinicians on managing bone health in younger women, including those in the menopausal transition.22 The National Osteoporosis Foundation recommends an assessment of risk factors to determine the need for bone density testing and treatment.

Risk factors: Endocrine disorders that cause sex hormone deficiencies are associated with a high risk for premenopausal osteoporosis. These disorders include amenorrhea, premature ovarian failure, Turner's syndrome, hyperprolactinemic amenorrhea, athletic amenorrhea, anorexia nervosa, isolated gonadotropin deficiency, and panhypopituitarism.

Cushing's syndrome, hyperthyroidism, and hyperparathyroidism are also strongly linked to the development of osteoporosis. Medications that may decrease bone mineral density include depot medroxyprogesterone acetate and glucocorticoids, especially if they are used long-term and at high dosages.

Management recommendations: The decision of when (and whether) to treat can be difficult. Typically, women in the menopausal transition with previous fractures or documented osteoporosis (T-score lower than −2.5) should receive therapy. Appropriate first-line treatment for these women is alendronate, 10 mg/d. The management of women with osteopenia (T-score between −1 and −2.5) is more controversial.

A recommendation for treatment will strongly depend on the assessment of the patient's risk factors for fracture, with special attention to endocrine disease, low body weight, and genetics. If treatment is initiated in these patients, alendronate (5 mg/d) is a good choice. Women with T-scores between 0 and −1 do not require treatment.

Sufficient calcium consumption is recommended in women of all ages. The current, recommended daily requirement for calcium is 1,200–1,500 mg/d for adolescents, 1,000 mg/d for adults up to age 65, and 1,500 mg/d for adults older than 65. Calcium supplementation should not exceed 1,500 mg/d. For adults, the recommended daily dose of vitamin D is 200 IU/d.