Andrea Giannini1, Andrea R. Genazzani1 and Tommaso Simoncini1
(1)
Division of Obstetrics and Gynecology, Department of Experimental and Clinical Medicine, University of Pisa, Via Roma, 67, Pisa, 56126, Italy
Tommaso Simoncini
Email: tommaso.simoncini@med.unipi.it
Natural menopause is the consequence of loss of ovarian function. This is the final step in a long and irregular cascade of events taking place both in the brain and in the ovaries.
It is well known that the interplay of genetic, biological, and environmental factors influences the timing of this process, but the key molecular pathways involved are yet unknown.
The endocrine changes of the late reproductive years thus depend on the combined dysfunction of the ovaries and of the hypothalamus; therefore, the complexity of these events determines a huge variability of changes, symptoms, and long-term implications [1–3].
As women progress to the menopause transition, their menstrual cycle length increases to 60 days or more, anovulation becomes more likely, and periods of time with little or no estrogen secretion occur. At this time, all of the commonly observed perimenopausal symptoms become usually worse. A woman is considered postmenopausal when she is over the age of 45 and has gone at least 12 months without a spontaneous menstrual period. No specific diagnostic testing is required unless the clinical presentation is atypical. A menopausal woman who has undergone at least 12 months of amenorrhea is unlikely to ever have another menstrual period, although this occurs in about 10 % of women. In this view, specific diagnostic testing for menopause is not recommended. Clinical situations may arise in which it is beneficial to document primary gonadal failure. Usually, an elevated FSH level, clinical anamnesis, and transvaginal ultrasounds examination will suffice. Measurement of estradiol during the perimenopause is not clinically useful due to the continuous variations deriving from alternate follicular recruitment [4, 5].
The menopausal transition is characterized by shortened follicular phases, which are associated with accelerated ovulation, happening with follicles of smaller size. The most common explanation for this phenomenon is the loss of inhibin B production, leading to higher FSH release and therefore to an “overshoot” of estrogen production. This would facilitate and accelerate the achievement of the LH surge [6].
With time, the age-related hypothalamic modifications determine a decrease in estrogen sensitivity and the LH surge becomes more irregular. Follicles also become less sensitive to gonadotropins, thus leading to luteal phase defect and anovulatory cycles and therefore to the first menstrual irregularities frequently resulting in dysfunctional uterine bleeding (DUB).
Most DUBs (90 %) depend on lack of ovulation due to altered hypothalamus-pituitary-ovary (HPO) axis function. Loss of normal follicle rupture and the consequent lack of progesterone production determine endometrial hyperplasia, in the absence of an adequate stromal support [7]. Breakthrough bleedings (irregular spotting), oligomenorrhea, late cycles, and abundant and sometimes hemorrhagic cycles are frequently the first clinical challenge for gynecologists during the menopausal transition. Before treating DUB, a diagnosis for exclusion of uterine myomas, endometrial polyps, or endometrial hyperplasia is required. Clinical evaluation with transvaginal ultrasound and eventually a hysteroscopic diagnosis of uterine cavity with endometrial biopsy are sufficient to obtain a correct diagnosis. There are different therapeutic options to contrast endometrial altered bleeding pattern [8]. In the presence of dysfunctional menstrual irregularities and bleeding, pharmacological treatment with oral contraceptives is the first therapeutic option with the aim of normalizing hormonal fluctuation and bleeding, and they may be effective also on vasomotor symptoms (VMS) and preventing unexpected pregnancy in perimenopausal women.
Oral contraceptives may be prescribed after accurate anamnesis and after exclusion of risk factors for thromboembolic risk, which usually increases above 35 years of age particularly in smokers and obese individuals.
In this view, supplementation with estro-progestins compounds containing 17beta-estradiol may carry a lower thromboembolic risk and effective control of bleeding, although evidence in this area is still missing.
Supplementation with natural progesterone or progestins for 14–16 days/monthly is effective in controlling dysfunctional bleeding because of the induction of direct anti-mitotic effect on glandular epithelial cells (stop mitosis in G1 phase, stop DNA synthesis, decrease ER synthesis) and secretory endometrial differentiation, but it is not contraceptive. Prolonged half-life of progestin is more important than the dose needed to protect the endometrium, additionally; longer half-life allows a single daily administration and improves compliance (Table 19.1).
Table 19.1
Characteristics of different progestins
|
Progestin |
Half-life (hours) |
Equivalent dose |
|
Cyproterone acetate |
48 |
1 mg |
|
Nomegestrol acetate |
30–50 |
(1.5) 2.5–5 mg |
|
Chlormadinone acetate |
34–39 |
3 mg |
|
Drospirenone |
30 |
3 mg |
|
NETA |
8–26 |
(1) 2.5–5 mg |
|
MPA |
14 |
10 mg |
|
Dienogest |
11 |
2–3 mg |
|
Dihydrogesterone |
2.5–6 |
10–20 mg |
|
Micronized progesterone |
2 |
200/300 mg |
The use of the intrauterine device releasing Levonorgestrel (LNG-IUD) may be an alternative and effective approach, thus recent studies suggest higher rate of regression in the presence of complex endometrial hyperplasia (with or without atypias) and less hysterectomies compared to oral progestins.
Tranexamic acid, non-steroidal anti-inflammatory drugs (NSAIDs), Danazol, GnRH analogues, and selective progesterone receptor modulators (SPRMs) may be other pharmacological compounds in symptomatic patients presenting persistent dysfunctional bleeding. Surgical endometrial ablation may be effective in patients who are not responsive to pharmacological strategies [9–13].
Vasomotor symptoms (VMS) such as hot flushes and cold or night sweats are common transitional symptoms, which usually decline throughout the postmenopausal life; however, they are bothersome symptoms that affect nocturnal sleep and deteriorate quality of life.
Hot flushes are more frequent during the early phases of sleep and contribute to sleep disruption and long-term onset of anxiety, depressed mood, and sexual dysfunction. VMS and consequent sleep disturbance are bothersome symptoms and are often common reasons for midlife women to seek for the first time medical attention on menopausal transition problems.
Hypothalamic insensitivity to estrogens also explains why menopausal symptoms commonly appear during this transition, when women have rather high levels of estrogens, as well as why exogenous estrogens are effective in reducing the symptoms [12].
Estrogen withdrawal also results in higher frequency of osteopenia, osteoporosis, urogenital symptoms and, in the long term, in increased risk of cardiovascular diseases (CVD), metabolic syndrome, and cognitive decline [14].
Estrogen deficiency is the principal pathophysiologic mechanism that underlies the spectrum of these menopausal symptoms, and various estrogen formulations are prescribed as hormonal replacement therapy (HRT), which remains the most efficacious of available therapeutic options for alleviating the symptom burden of menopause. The addition of progesterone to estrogen in HRT aims to protect women with intact uteri against endometrial pathologies, including hyperplasia and cancer.
A potential for symptomatic benefit with any treatment option must take into consideration the nature and severity of a woman’s problems and be weighed against assessed treatment-related risks, individualized from the perspective of each patient’s exclusive health profile. Choice of therapy should additionally take into consideration an individual woman’s perspective and preferences (Tables 19.2and 19.3).
Table 19.2
Treatment options and clinical indications
|
Treatment option |
Benefits |
|
Systemic estrogen alone |
Symptom relief Fracture risk reduction Osteoporosis prevention Improved QOL |
|
Systemic estrogen and progestogen |
Symptom relief Fracture risk reduction Osteoporosis prevention Improved QOL Colon cancer risk reduction |
|
Low-dose vaginal estrogen |
Relief from genitourinary syndrome of menopause |
|
Ospemifene (SERM) |
Reduction of moderate to severe dyspareunia due to vulvo-vaginal atrophy |
|
TSEC combination of conjugated equine estrogen and BZA (SERM) |
Symptom relief |
|
Tibolone (synthetic steroid with estrogenic, progestogenic and androgenic activity) |
Symptom relief Fracture risk reduction Osteoporosis prevention Improved QOL Colon cancer risk reduction |
|
Selective serotonin reuptake inhibitors |
Relief of vasomotor symptoms and anxiolytic |
|
Selective norepinephrine reuptake inhibitor |
Relief of vasomotor symptoms |
|
Clonidine, an alpha adrenergic receptor agonist |
Relief of vasomotor symptoms |
|
GABA-ergics |
Relief of vasomotor symptoms |
Table 19.3
Pharmacological options for management of menopausal symptoms
|
Therapy |
Formulations |
|
Systemic hormonal therapy |
|
|
Estrogen |
Oral, transdermal (patch, gel, spray), vaginal (ring), implant; as estradiol or synthetic estrogens |
|
Progestogen |
Oral, vaginal, intrauterine; as progesterone or progestin (synthetic) |
|
Estrogen + progestogen |
Combination (pill, patch) |
|
Tissue-selective estrogen receptor complex (TSEC) (conjugated equine estrogen + bazedoxifene [BZA], a selective estrogen receptor modulator [SERM] |
Oral |
|
Ospemifene (SERM) |
Oral |
|
Tibolone |
Oral |
|
Androgen therapy Testosterone |
Oral, vaginal Topical, oral, implant |
|
Nonhormonal therapies |
|
|
Selective serotonin reuptake inhibitor class |
Oral |
|
Selective norepinephrine reuptake inhibitor class |
Oral |
|
Anti-seizure (Gaba-ergics) |
Oral |
|
Alpha adrenergic receptor agonist class |
Oral; transdermal |
|
Sedatives and hypnotics |
Oral |
|
Complementary or alternative therapies (consistent benefit over placebo effects not demonstrated) |
|
|
Soy/isoflavones |
Oral |
|
Black Cohosh |
Oral |
|
Vitamin E |
Oral |
|
Acupuncture |
|
|
Local vaginal therapy |
|
|
Estrogen |
Low-dose estradiol, estriol and conjugated estrogen creams, rings, and pessaries |
|
Dehydroepiandrosterone (DHEA) |
Undergoing research trials, not approved |
|
Testosterone |
Undergoing research trials, not approved |
|
Nonhormonal vaginal moisturizers |
Various over-the-counter products |
|
Lubricants |
Various over-the-counter products |
Available data indicate that transdermal estradiol does not increase the risk of venous thromboembolic events (VTE). Standard dose of oral estrogens increases SHBG affecting the amount of estrogens and testosterone in the circulation while transdermal estrogens do not. Therefore, transdermal estrogen therapy is considered the first choice of treatment in women at increased risk of VTE, such as obese women and smokers. Transdermal estradiol also does not increase gallbladder disease [15, 16].
When patients report lack of energy, sexual dysfunction, and androgen deficiency symptoms, Tibolone, oral DHEA (10–50 mg/die), or transdermal testosterone (300 mcg/die) is the therapeutic option [17].
While VMS usually decline throughout the postmenopausal life, on the contrary, urogenital symptoms including sense of vaginal dryness, painful intercourse, vulvar pruritus, burning, and discomfort, as well as recurrent urogenital infections persist and may have a serious impact on sexual health and quality of life [18, 19].
Within the last 2 years, two new pharmaceutical preparations have gained the US Food and Drug Administration (FDA) approval for addressing needs of menopausal women, thus expanding the spectrum of available hormonal and hormone-like options; an oral selective estrogen receptor modulator (SERM, ospemifene) has been approved for the treatment of moderate to severe dyspareunia associated with vulvo-vaginal atrophy, and a tissue-specific SERM-estrogen complex (a combination of 0.45 mg of oral conjugated equine estrogen and 20 mg bazedoxifene (a SERM)) has been approved for the management of moderate to severe VMS in women with a uterus in the USA and in Europe. The concept of ‘tissue selective’ estrogens involves the concurrent use of estrogen treatment and a SERM, which replaces a progestogen and selectively blocks undesirable actions of estrogen. In the case of conjugated equine estrogen/bazedoxifene, the proliferative effects of estrogen are blocked at the level of the uterus, while the bone sparing actions of estrogen are preserved [20].
While the place of testosterone therapy for the treatment of postmenopausal sexual disorder and the long-term health implications of testosterone use by postmenopausal women are unclear, this strategy may offer benefit to a select subset, such as for the surgically menopausal women who have persistent sexual symptoms despite optimization of HRT regimen [21, 22].
Urogenital symptoms are effectively treated with either local (vaginal) or systemic estrogen therapy, thus estrogen therapy restores normal vaginal flora with a concomitant lowering of the pH and thickens and re-vascularizes the vaginal lining. The number of superficial epithelial cells is increased, and symptoms of atrophy are alleviated. Importantly, low-dose vaginal estrogen improves vaginal atrophy without causing proliferation of the endometrium [23].
Additionally, menopause appears to be associated with changes in cognition, but it cannot be assumed that estrogen therapy will prevent cognitive decline; therefore, there is general consensus that oral estrogen therapy should not be prescribed to prevent or treat cognitive decline [24, 25].
A number of nonhormonal pharmacological therapies against VMS are now available for those women who do not wish to take estrogen or present contraindications for HRT such as women with personal history of breast cancer or VTE and stroke.
For VMS, paroxetine, fluoxetine, and citalopram (selective serotonin reuptake inhibitors); venlafaxine and desvenlafaxine (selective norepinephrine reuptake inhibitors); clonidine (alpha adrenergic receptor agonist); and anticonvulsants (gabapentin and pregabalin) have demonstrated efficacy in several studies. Paroxetine and fluoxetine are potent cytochrome P450 2D6 (CYP2D6) inhibitors and decrease the metabolism of tamoxifen and may reduce its anticancer effect and thus should be avoided in tamoxifen users [26, 27].
Alternatives to vaginal estrogens are vaginal lubricants and moisturizers that lower vaginal pH and may normalize vaginal cell composition, providing relief of symptoms. However, many studies indicate that these preparations are less effective than estrogens. Vaginal moisturizers do not reduce urinary tract symptoms or asymptomatic bacteriuria, but they are able only to alleviate dryness during intercourse and do not treat the underlying problems [28].
With the increasing life span of women worldwide, the impact of the menopausal transition increases and needs to be better understood, thus identifications of such factors would be important to set new strategies to treat reproductive dysfunction and menopause-associated diseases.
Throughout perimenopausal transition, women should be encouraged to maintain or achieve a normal body weight, be physically active, adopt a healthy diet, limit alcohol intake, and avoid smoking in order to reduce VMS and cardiovascular risk, diabetes, urinary incontinence, breast, endometrial cancer, and cognitive decline. Regular physical activity and supplementation with vitamin D are to be encouraged to maintain muscle mass and balance and to prevent osteopenia and osteoporosis. All women at midlife should be encouraged to perform annual cardiovascular, oncologic, and gynecological prevention screenings [29].
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