Giulia Palla1, Stefania Spina1, Guja Bernacchi1, Elena Cecchi1, Silvia Di Bello1, Silvia Pisaneschi1, Magdalena Montt Guevara1, Adrian Campelo1 and Tommaso Simoncini1
(1)
Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, Pisa, 56100, Italy
Tommaso Simoncini
Email: tommaso.simoncini@med.unipi.it
18.1 Definitions
Reproductive age in women is characterized by several different phases, which constitute a unique endocrinologic continuum. It starts with the beginning of fertile life, with regular, cyclic menses, typical of ovulatory cycles, and it ends with a concluding menstrual period, due to final ovarian senescence, indicated as the menopause.
An important moment in this complex process is represented by the menopausal transition (MT), the time period in the late reproductive years, which usually begins with menstrual irregularity and persists until 1 year after last menses. The menopausal transition typically starts in the late 40s or early 50s and continues for about 4–7 years.
To better understand the complexity of woman’s transit through menopause and also to simplify the nomenclature, Souls and other proposed the Stages of Reproductive Aging Workshop (STRAW) in 2001 [1].
The STRAW classification divides reproductive and postreproductive life into several periods; each one is different for the age range and duration time. The main event is the final menstrual period, FMP. Five stages are before FMP and two stages are after. Stage −5 represents the early reproductive period, stage −4 the reproductive peak, and stage −3 the late reproductive period. Stage −2 refers to the early menopausal transition (MT) and stage −1 to the late MT. In the early menopausal transition (stage −2), menstrual cycles are still regular, but the interval between cycles typically becomes shorter (7 or more days different from normal). Compared with younger women, FSH levels increase, and serum estrogen levels may be elevated in the early follicular phase. Regular ovulatory cycles may be alternated to anovulatory cycles during this transition. The late menopausal transition (stage −1) is defined by two or more skipped menses or at least one interval of amenorrhea longer than 60 days, since the periods of anovulation become more and more frequent [1].
Stage +1a refers to the first year after FMP, stage +1b identifies the years two to five postmenopause, and stage +2 refers to the later postmenopausal years until demise (Fig. 18.1).
Fig. 18.1
The STRAW staging system (adapted from Soules, MR et al., Fertil Steril 2001)
18.2 Physiological Changes
Menopausal transition is a physiological event in woman life; nevertheless, at this period, women complain about new, unexpected, and annoying symptoms; their bodies are at the mercy of intense hormonal changes, and, in addition, there is evidence of increased risk for developing depression and mood swings, due to both hormonal alterations and awareness of aging and its consequences.
Thus, menopausal transition may have a significant impact on personal, family, and professional aspects of life.
For this reason, one of the main points is to guarantee to women the best quality care from physicians during menopause, based on good communication, enough time to visit and to discuss their worries, giving information and resources to explain the basis of their physical and psychological symptoms.
In the recent past, growing evidence suggests that menopause is a primary central nervous system event, in which the aging process is probably triggered by a central pacemaker in the hypothalamus, or/and in higher brain areas, in combination with changes in several peripheral organs (ovaries and adrenal cortex) [2, 3]. This hypothesis comes from several experimental models in animals that show that ageing in the brain is associated with altered hypothalamic neurotransmitter control. In addition, getting closer to the final menstrual period, hypothalamic regulation of GnRH secretion appears desynchronized, with hormonal release at maximal frequency and amplitude and impaired gonadotropin secretory rhythm. This phenomenon starts in the late reproductive stage and in the early menopausal transition and it corresponds, clinically, with still regular menses and normal estrogen level, but levels of progesterone, Anti-Mullerian Hormone (AMH), inhibin B begin to decrease slightly [4] (Fig. 18.2).
Fig. 18.2
Endocrine consequences of follicle depletion
The Melbourne Women’s MidLife Health Project (MWMHP) and related studies have underlined that the first endocrine event, followed by the onset of menstrual irregularity, is not the increase in FSH, as stated in the past, but it is the decrease of inhibin B concentration at follicular phase, without any substantial increase in FSH and any change in estradiol or inhibin A [5]. In addition, based on the prospective determination of the moment of final menses (FMP), it has been shown that estradiol levels begin to fall and FSH levels to rise only about 2 years before FMP [6].
Nowadays, we think that the early menopausal transition begins with first menstrual irregularities and, simultaneously, inhibin B and AMH reduction due to declining follicles. As a consequence, serum FSH levels start to rise, even if estradiol levels are quite stable, but reduced amounts of progesterone are found during luteal phase [7].
In the late menopausal transition, the menstrual irregularities increase, at the same time serum FSH and estradiol are markedly variable within different cycles, with irregular ovulation.
An important aspect is that both hypothalamus and pituitary show a reduced sensitivity to estrogens and a variable loss of positive and negative feedbacks of estrogens on synthesis and release of LH. Moreover, FSH and LH in peri- and postmenopause appear to be hyperglycosylated, thus giving them prolonged half-life. This contributes to the increased FSH and LH levels and seems to be associated to decreased biological effects.
With advancing age, there is a level change in adrenal steroid production, with decline in dehydroepiandrostenedione sulfate and androstenedione. Also, the production of sex hormone-binding globulin (SHBG) decreases after menopause with an increased level of free or unbound estrogen and testosterone. This higher amount of androgens lead to an increased conversion rate of androstenedione to estrone, a weaker estrogen compared to estradiol, due to an increase of aromatase activity in adipose tissue, which characterizes the aging process [8, 9].
All those hormonal changes are accompanied together with a rapid depletion of ovarian follicles, which starts in the late 30s and early 40s and goes on until the point in which the ovary is virtually empty of follicles.
During early menopausal transition, the endometrium shows the features of the fertile period, since ovulatory cycles are still prevalent. After that, during the later stage of menopausal transition, anovulation is frequent, and the endometrium exhibit estrogen’s effect when unopposed by progesterone. Accordingly, proliferative changes or disordered proliferative changes are frequently found by endometrial biopsy samples.
18.3 Clinical Signs
The clinical signs during menopause transition are menstrual irregularities, vasomotor symptoms, sleep disruption and mood alterations, urogenital complaints, and sexual dysfunction.
As stated, altered bleeding pattern is one the most common signs during menopause: menses may be irregular in more than 50 % of women during this period [10]. This is linked to anovulation and progesterone deficit, which cause variable periods of relative hyperestrogenism that turn into breakthrough bleedings (irregular spotting), oligomenorrhea, and late cycles.
Nevertheless, in all women, regardless of menopausal status, the etiology of irregular bleeding should be thoroughly investigated.
Even if hormonal dysfunctions are frequent reason of bleeding in this period of life, endometrial hyperplasia, estrogen-sensitive neoplasms (leiomyomas and uterine polyps), should always be considered. Moreover, also pregnancy can be a reason of late cycles, since many women in their 40s quit using contraception, with the false conviction of not being fertile anymore.
Malignant precursors of endometrial cancer (complex endometrial hyperplasia with or without atypies) become more common during menopausal transition, and endometrial biopsy is needed to exclude malignancy. Endometrial cancer should be suspected in any woman in menopausal transition with abnormal uterine bleeding.
Vasomotor signs are early symptoms, often present intermittently during early perimenopause and become more common during late transition phase and during early-postmenopause. They afflict 75 % of women and usually disappear within 1–5 years, even if sometimes they persist beyond 70s.
They have been described as sudden feeling of heat to the trunk and face that quickly generalizes to the rest of the body. The duration is between seconds to 2–3 min. This change is mainly noticeable in the fingers and toes, where skin temperature can increase up to 10 °C [11]. Sweating starts on the upper body and it relates closely in time with an increase in skin conductance.
Hot flushes are usually associated to palpitations and often followed by shivering and anxiety.
Cardiovascular changes that occur during hot flushes have been deeply examined.
During hot flushes, an increase in systolic blood pressure has been described [12]. In addition, an increase in the heart rate (up to 15 beats per minute) is present, simultaneously with peripheral vasodilatation and sweating.
Temperature decreases 0.1–0.9 °C due to heat loss from increased peripheral vasodilation, after about 5 min from the beginning of the hot flush. Skin temperature slowly returns to normal and, whether the heat loss and sweating is significant enough, women may experience chills [13].
Hot flush could be 1–2/day up to 30–40/day, more frequent at night, with obvious consequences on sleep.
The pathophysiology of vasomotor symptoms is linked to dysfunction of central thermoregulatory centers in the hypothalamus. In particular, the medial preoptic area of the hypothalamus represents the thermoregulatory nucleus; it is influenced by estrogen withdrawal and neurotransmitters concentration, in particular norepinephrine, dopamine, serotonin, and β-endorphin [14]. Norepinephrine is supposed to be the main neurotransmitter responsible. When changes in core body temperature, even very subtle, happen in the woman, norepinephrine lowers the setpoint in the thermoregulatory nucleus. This is followed by the activation of heat loss mechanisms, mainly vasodilation, and increased blood stream to the skin and sweating, associated with hot flushes [15]. Interestingly, those changes are contemporary to LH pulses. After that, there is a loss of body heat and shivering takes body temperature back to normal.
Freedman and colleagues [16] have found a decrease in hypothalamic α2-adrenergic receptors related to estrogen withdrawal. The decline in presynaptic α2-adrenergic receptors causes increased norepinephrine levels, thereby provoking vasomotor symptoms.
A similar mechanism is probably activated by a reduced opioid tone and decreased serotonin levels, associated to loss of estrogens, related to menopause.
Sleep dysfunctions are due mostly to hot flushes and nocturnal sweats, which determine repeated awakening and chronic insomnia. This has been found by a cohort study in which women with a greater incidence of hot flushes are expected to experiment poor sleep more frequently, than women with fewer vasomotor symptoms [17]. Hot flushes are more frequent during early phases of sleep, while REM sleep is associated with reduced frequency. The most common complaints reported are difficulties in sleep onset and sleep maintenance, which determine daytime fatigue, mood lability, irritability, and short-term memory difficulties [18]. Moreover, other sleep disorders become more common in perimenopause and postmenopause, such as sleep–apnea syndrome and restless leg syndrome.
Also, anxiety and depressed mood contribute to sleep disruption. These clinical signs are common during perimenopause, mostly represented by irritability, nervousness, elevated anxiety, rapid mood swings, and depressive symptoms [19]. It has been described an increased risk of major depressive episode during menopausal transition that reduces after menopause. The predisposing factors are personal history of depression, PMS, postpartum depression, which can mix with other predisposing factors typical of this stage. During this period, women can experience family modifications (as empty-nest syndrome, divorce, or widowhood), problems with partner and loss of fertility, changes in social role, such as retirement and unemployment. In addition, personal or parents’ health problems can worsen the situation. However, the entity and the way of expression of mood and cognitive symptoms are clearly culture specific. In Western, beauty and youth are deeply emphasized by society, thus an elderly women can experiment a sense of loss, worthlessness, and impotence.
It has been suggested also a biological explanation of those signs, due the hormonal fluctuations. During early menopausal transition those modifications are responsible, in part, for this affective instability. In addition, it has been found that surgical menopause induces mood changes because of the quick hormonal loss.
A key component of the emotional distress during menopausal transition may be due to high and erratic estradiol levels. Ballinger and colleagues [20] have shown that stress hormones increases (and probably stress-related symptoms) are physiologically associated to relative hyperestrogenism, typical of menopausal transition. On the other hand, clinical studies also suggest that lack of estrogens, typical in women after menopause, may be related to cognitive dysfunction, such as the progression of brain degenerative diseases (Alzheimer’s disease or Parkinson’s disease), and the hypothesis that estrogen administration to postmenopausal women might decrease the progression of these conditions is enduring [21].
Also, the lack of progesterone could be involved in this process. Progesterone is needed for the production of allopregnanolone, a neurosteroid involved in the regulation of brain function. Different exogenous mediators, such as progesterone, allopregnanolone, and DHEA, but also exogenous (benzodiazepines, imidazopyridines, ethanol, and barbiturates) act on GABA receptor, regulating cellular excitability, network synchronization, and synaptic plasticity, thus provoking changes in mood, emotional state, and affectivity.
Urogenital symptoms are important aspect to consider during menopausal transition. Since vaginal, urethral, and bladder trigone are sensitive to estrogens, estrogen withdrawal determines thinner vaginal mucosa, with pale or petechial aspect and loss of mucosal folds. The reduction in glycogen and increase in pH up to 6.0–7.5 cause the growth of endogenous bacteria and this is followed by vaginal dryness, itching, bleeding, and dyspareunia. Those symptoms are present in 20 % of the women during late menopausal transition and 50 % 3 years after menopause.
Another problem reported by women is urinary incontinence, both stress and urge urinary incontinence. The main predisposing factors are the presence of a thinned urethral mucosa, which favor urine leaks, ascending infections and colonization by yeasts and bacteria, which often become recurrent. Those modifications contribute to sexual dysfunction: the loss of elasticity and the atrophy are accompanied by a decreased blood flow to vagina and vulva, decreased lubrication due to vaginal dryness. All those factors cause pain and difficult intercourse [22]. If those signs are mainly linked to estrogen withdrawal, also androgen deficit is responsible for decreased sexual interest, with a loss of libido, fantasies, and motivation, but also linked to reduced trophism and innervation of vulva and introitus. Moreover, an altered body image and reduced motivation can worsen the situation. Weight gain and fat deposition in abdomen are common in women during menopausal transition, which not only contribute to reduced self-esteem and tendency to depressive symptoms but also increase the probability of developing insulin resistance, diabetes mellitus, hypertension, and cardiovascular disease [23, 24].
18.4 Therapeutic Challenges in Menopausal Transition
During MT, physicians should guide the therapy on controlling the bleeding and the vasomotor symptoms, acting on anxiety/mood swings and improving the sexual function. Choosing the treatment in perimenopause is challenging because few randomized controlled trials have been published.
Based on the idea that menopause and perimenopause are characterized by similarly low estrogen levels, it is common practice to treat perimenopause with estrogens or oral contraceptives. This choice comes from extrapolating data from postmenopausal women and from clinical experience. To treat perimenopausal symptoms like those of menopause, however, ignores the different hormonal background between the two, mainly the higher estrogen levels and the fluctuations in hypothalamic–pituitary ovarian feedback in perimenopause.
Estrogen treatment could lead to heavier flow, getting worse mood swings, and more breast tenderness. Instead, simple actions are often quite effective. Explanation about perimenopausal hormone changes and the distinctive clinical signs accompanying them, giving idea of the perimenopause timeline, could all be very useful instruments [25].
In addition, light aerobic, continued physical exercise, increased calcium and vitamin D intake, healthy eating habits, relaxation training, and meditation can all be beneficial. These simple and everyday recommendations can help the majority of perimenopausal women. However, the 20 % are supposed to need additional therapy.
The control of cycles is a hard battle, because OCs are often contraindicated in this age group, because of the high number of women aged > 35 and smokers. Age and smoking are the major risk factors for myocardial infarction in women who may consider the OC. The increasing prevalence of obesity, high blood pressure, and diabetes in population are also important contributing factors.
Moreover, HRT could be ineffective due to the irregularity of ovarian activity.
Progesterone supplementation can be a good strategy, but it is difficult to be timed efficiently over the long term. Cyclic or daily oral micronized progesterone can help with heavy flow, hot flushes, breast tenderness, and sleep.
LNG-loaded IUD gives good results but may not be accepted. Also, endometrial ablation techniques could be an alternative, but it requires hospital stay, anesthesia and it is not possible in presence of myomas present.
Vasomotor symptoms also need frequently a well-rounded approach [26]. As stated above, OCs are often contraindicated. Even if administration of a minimal amount of estrogens is effective (25–50 mcg patches, transdermal gels or 1 mg estradiol daily usually sufficient) and does not alter cycle, this requires endometrial surveillance in long-term therapy. Thus, this could be considered a temporary measure to be replaced by standard HRT in postmenopause. In addition, a LNG-loaded IUD can be used as an add-back therapy, giving the possibility to use estrogens more liberally.
Again, some behavioral modification, like avoiding drinking caffeine and alcohol, living in cool environment, and wearing lighter clothing, may be favorable. Herbal medicines or acupuncture may offer some relief, although it has not been found much medical evidence to support these therapies. Some antidepressants (SSRIs and SSNIs) and other medicines that act on the central nervous system (clonidine and gabapentin) are also helpful strategy for hot flushes. They may also be a good choice for women with sleep or mood disturbances.
Vaginal symptoms could be faced by using local or systemic hormones, often in low dose, if need in addition to vaginal lubricants and moisturizers, typically applied prior to sexual activity [27].
In regard to sexual dysfunction, first step is to provide enough estrogen levels, usually with transdermal estrogens, in order to avoid increasing SHBG. If androgens are reduced, tibolone, oral DHEA (10–50 mg/die), or transdermal Testosterone (300 mcg/die) could be efficiently used.
18.5 Conclusions
Menopausal transition is a period of intense changes and most women experience perimenopausal symptoms and seek for medical help.
A good counseling, to provide patient-specific education and consultation, in addition to personalized therapy, based on needs, symptoms, and hormonal status, are the guiding principles for the best management in MT.
Last but not least, each moment in a woman’s life can be the starting point to quit smoking, start physical activities, and have a healthy and balanced diet. Having a healthy menopause to get a healthy life.
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