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The various signs and symptoms of menopause according to their specific hormonal change

Menopause is a physiological, unavoidable and transitional period in a woman’s life when decreased and later ceased function of ovaries lead to amenorrhea and the end of fertility.  It usually occurs in midlife, in the second half of 40-ties or early 50-ties. It is a gradual, aging process when ovaries follicular activity is ceased.  The term comes from Greek word “pausis” (cessation) and “men” (month) and it means the end of monthly menstruations.

Even though menopause is considered to be physiological, many symptoms and signs are troublesome and often justify treatment.                                                                                                                                                

Some catastrophic diseases can be associated with menopause, just to mention: fractures due to osteoporosis, cancer, coronary artery disease (CAD), stroke and dementia.                                                                        

Many studies demonstrated that if estrogen replacement therapy is initiated at early stage of menopause progression of some of these diseases might be prevented.  

  1. Estrogen is a general term for three endogenously produced estrogens which are: E1-estrone, dominant form in post-menopausal period; it is produced in the ovary and in adrenal glands in small amounts but it is mostly derived from androstenedione in adipose tissue E2-estradiol is produced byovarian follicle during menstrual cycles; it has positive effect on lipids, bone density, memory, mood E3-estriol, its levels do not change much after menopause, some studies indicated that might protect against breast cancer. Significantly high levels are observed during pregnancy by placenta.           

In prevention of Coronary Artery Disease many studies observed that estrogen has an anti-atherogenic effect helping to decrease the risk of formation of atheromatous plaques. Estrogen was also found to increase HDL and decrease LDL, lipoproteins and homocysteine which adds to its cardioprotective role.                                                                                                                                                               

This positive outcome should be maximized by healthy life style including regular exercises, body weight reduction and non-smoking.  Arterial hypertension and dyslipidemia should be treated. It was concluded that cardio- protection of estrogen has its stronger effect if it is used at early stage of menopausal transition.                                                                                                                                                                    

Postmenopausal female patients who already have history of CAD, like angina or MI, sadly do not benefit from estrogen therapy.                                                                                                                                                                                                                           

Reduction of Alzheimer’s dementia is mostly seen in female patients who take estrogen therapy for a longer period.  Estrogen activates production of an enzyme choline acetyltransferase which lack may predispose to Alzheimer’s disease. 

Bone loss density (osteoporosis) already occurs in early 40-ties as the peak bone mass usually reaches the highest point at age between 25-35 years old. Many factors contribute to this problem, most important include: decreased estrogen level, hereditary factors, sex, race, lack of exercises, cigarette smoking, low calcium intake, type of menstrual cycle, body weight. Estrogen stimulates action of osteoblasts and its lack predisposes bone to react to parathyroid hormone which leads to increased stimulation of osteoclasts and bone loss.    

Sadly estrogen therapy is not risk free; the most common complications are: venous thromboembolic disease, breast, endometrial cancer and stroke.

Higher prevalence of the thromboembolic episodes is seen in obese, older women who smoke.

As for breast cancer many studies concluded that the risk of developing breast cancer in women taking estrogen is indeed increased but the risk is small and usually affects susceptible women, mostly older who take estrogen for a prolonged time. Once HRT is discontinued the risk falls to zero.                                                  

The good news is that women on estrogen therapy have lower incidence and lower mortality of colon cancer.                                                                                                                                                                                   

Strokes have moderately higher prevalence in women taking estrogen, but it seems that this finding applies to older women who take higher doses of estrogen. Recent studies demonstrated that younger women, between 50-60 years old, who have no other risk factors, do not have increased risk of cerebrovascular incidents.

The most commonly occurring symptoms and signs of menopause are due to decreased levels of estrogen and they include:

  • Amenorrhea
  • Hot flashes, night sweats
  • Mood swings, anxiety, irritability, depression, emotional instability, crying easily
  • Poor concentration, forgetfulness, decreased verbal skills
  • Vaginal dryness, dyspaurenia, urinary incontinence
  • Low libido
  • Breasts changes
  • Aging of skin
  • Alopecia
  • Migraine
  • Muscles weakness
  • Insomnia

Amenorrhea occurs due to loss of follicular activity in the ovaries. Healthy follicular cells synthesize estradiol as well as inhibins, peptides which inhibit FSH release.  Already from age of 38 there is a slow, but gradual decrease in inhibins B production which leads to elevation of FSH.                                                                         

At early stage increased FSH level stimulates ovaries to produce more estradiol, therefore often in perimenopausal period (between normal menstruations and menopause) estradiol level might be even increased. Amenorrhea usually occurs in the late menopausal transition when estradiol levels decline, reaching 50% of the level of reproductive period.  FSH remains high.

Hot flash is the most commonly reported complaint and it is usually described as a warm sensation, usually lasting few seconds to minutes, in the head and upper torso, which can be followed by increased sweating and chills.                                                                                                                                                                                              There is no consensus regarding the pathophysiology of this phenomenon. One of the theories explains a role of hypothalamic thermoregulatory zone which in menopause becomes over sensitive.  Serotonin, noradrenalin as well as withdrawal of estrogen might cause decreased threshold in that zone leading to elevation of body temperature causing cutaneous vasodilatation and flushing followed by chills.                       

BMI higher than 30, cigarette smoking, lack of exercises increase the frequency of hot flashes.                                 

Hot flashes often occur at night and cause sleep dysfunction and secondarily fatigue.

Mood swings, depression, anxiety are frequently occurring symptoms in menopause.                                                               

It is believed that estrogen has a modulatory effect on mood control as well as cognitive reactions. Women who were diagnosed with depression prior menopause are at a higher risk. Estrogen therapy might prevent depression but as per literature does not relieve symptoms of major depressive disorder

Poor concentration, forgetfulness, decreased verbal skills occur in menopause and they are mostly due to estrogen deficiency. Estrogen is a powerful hormone which regulates almost all neurotransmitters in the brain.  Estrogen is needed for proper verbal memory therefore postmenopausal women often forget words.     

Dyspaurenia, vaginal dryness, urinary incontinence, vaginal atrophy occurs due to lack of estrogen and progesterone. These deficiencies cause thinning of vaginal epithelial layer as well as decreased vascularity which induce irritation, dryness, itchy and burning sensations.  Changes of pH from acidic to alkaline predispose to infections. Ligaments of the pelvic floor become more lax leading to urinary incontinency and prolapsed of organs.

Low libido, a frequent complaint of menopausal women, has a complex pathophysiology.                            

Many factors are involved: psychological, social, physical, some medications, aging.                                               

Estrogen deficiency along with other hormonal deficiencies plays an important role.                                    

Other hormonal deficiencies include: progesterone, androgens, oxytocin as well as dopamine, serotonin, noradrenalin and acetylcholine. Dopamine is one of the most important neurotransmitter of neuropathways involved in libido.

Breasts changes are often reported by menopausal women. Firm breasts tissue is replaced by soft adipose. Estrogen controls ducts, while progesterone lobular structures.

Aging of skin becomes obvious during menopause and it is due to loss of elasticity, moisture as well as diminished collagen and elastin synthesis.  The skin becomes thin and wrinkled. Dryness is a result of decreased sebum production.

Alopecia is frequently observed in postmenopausal women. It affects the crown and spares the frontal hairline. Very seldom leads to baldness but mostly thinning of the hair. It is believed that estrogen stimulates hair growth as well as counteracts testosterone. The role of estrogen remains controversial though as there is some evidence suggesting that excess of estrogen also can cause hair loss.

Migraines are commonly associated with menstruations and estrogen fluctuation.                                                                     Estrogen influences serotonin’s metabolism, therefore it is believed that in menopause migraine can be triggered by serotonin. Progesterone has less understood role, but since it has an effect on neural activity its role should not be underestimated.

Muscles weakness is reported by up to 50% of menopausal women. Estrogen is called “energizer and builder” and its lack can lead to muscles atrophy.

Insomnia in menopause has multifactoral genesis. It is believed that elevated cortisol in menopause leads to insomnia and estrogen helps to regulate this effect stabilizing night sleep.

 

  1. Progesterone is a steroid hormone produced in the ovaries in the corpus luteum during the luteal phase of menstrual cycle. It belongs to group of hormones called progestogens.                                                          
  2. Progesterone controls many physiological reactions which are amplified by estrogen.                                                           
  3. Progesterone plays an important role in decreasing proliferation of the uterine endometrium preventing hyperplasia. By stimulation of endocervical glands decreases penetration of the sperm through the cervix. It helps to maintain pregnancy.

Symptoms and signs occurring in menopause due to progesterone deficiency are:

  • Irritability, depression, anxiety, mood swings, overreacting, stress, feelings of confusion
  • Insomnia
  • Decreased HDL
  • Pains, aches, inflammation
  • Bone loss
  • Weight gain, fluid retention
  • Alopecia
  • Hot flashes

It appears that micronized progesterone is a safe option to be used in early menopause to treat hot flashes and night sweats even without estrogen. It is believed that progesterone balances estrogen and as a GABA agonist improves sleep and emotional disturbances occurring in menopause.                                                 

It has beneficial effects on lipids (lowers cholesterol), blood pressure and metabolic rate.                                                 

It is a respiratory stimulant helping in mild cases of obstructive sleep apnea which is especially important in third trimester of pregnancy. There is no sufficient data proving that it has anti-carcinogenic effect preventing breast carcinoma.

  1. Testosterone is another steroid hormone; it belongs to the androgen group.

Symptoms related to androgen deficiency are:

  • Lack of confidence, lack of drive, low self-esteem, anxiety, fatigue
  • Weight gain, lean muscles loss
  • Low libido
  • Decreased elasticity of the skin leading to droopy eyelids, sagging cheeks and thin lips
  • Dyslipidemia: decreased level HDL

Testosterone used as a part of HRT in menopause must be used together with estrogen.

  1. DHEA (Dehydroepiandrosterone), known as androstenolone, is produced by adrenal glands, gonads as well as the brain. It is a precursor of androgen, progesterone and estrogen, but it also has many physiological effects on its own.

DHEA levels decrease in menopause and the symptoms might be:

  • Fatigue
  • Muscles weakness
  • Depression, anxiety
  • Loss of libido
  • Dry skin,
  • Alopecia

There is no general consensus regarding effects of DHEA on menopausal symptoms as some studies show beneficial effects and some do not confirm this.  The same applies for increasing muscular strength, improvement in sexual function and osteoporosis. It seems that DHEA has positive effect on helping elderly obese people to lose weight. It has antidepressant effect.  If applied topically it might help for vaginal atrophy in older women.

  1. Cortisol, another steroid hormone; it is produced by adrenal glands in zona fasciculata.    Its levels increase with aging.                                                                                                                                    Symptoms of elevated cortisol include:
  • Fatigue, irritability,
  • Night sweats
  • Muscles weakness
  • Weight gain
  • Insomnia
  • Decreased function of immune system leading to increased risks of infections
  • Osteoporosis
  • Hyperglycemia, increased insulin level, insulin resistance, sugar cravings
  • Thin skin
  • Dyslipidemia-increased TG and cholesterol
  • Hypertension

 

  1. Pregnenolone is a precursor of DHEA, testosterone, progesterone and estrogen.

Symptoms occurring due to lack of Pregnenolone are:

  • Fatigue
  • Stress
  • Poor memory
  • Depressed mood
  • Pains and aches, especially painful joints

 

  1. Thyroid hormones, T3, T4.

There is no evidence proving that menopause causes decline in synthesis of thyroid hormones.                   The production of T3 T4 decreases progressively with age and it differs from person to person.  There are two aspects to consider while treating menopause women:

  • Many symptoms of hypo or hyperthyroidism might mimic menopause (weight gain, depression, palpitations, hot flashes, dry skin and insomnia). As per some studies 10 % of women older than 40 years old have undiagnosed thyroid disease.
  • Oral estrogen therapy, as part of HRT in menopause, increases levels of TBG (thyroid-binding globulin) leading to increased binding of T4 and secondarily to decreased level of free, biologically active T4 ( fT4). Estrogen also reduces the ability of conversion from T4 to T3.  Women on oral estrogen therapy and thyroxin might need to increase the dose of T4.
  •  
  1. Melatonin is a hormone produced in pineal gland, same as thyroid hormones its synthesis declines steadily with age.

 It controls sleep-wake cycles.  As study performed in Italy in 2001 (7) showed improvement of pituitary and thyroid functions in menopausal women regularly melatonin.                                                                                                                                                                                           Melatonin is well known for initiating and perhaps maintaining sleep by blocking arousal stimulants; it is especially helpful for jet lag. Melatonin action is related to estrogen; there is a theory that a drop in estrogen levels in menopause “marks the loss of pineal and pituitary control of ovarian cyclicity “(9). Melatonin has powerful anti-oxidant properties and might prevent cancers. Some authors believe that melatonin plays a role in anti-aging treatment.

Symptoms associated with low melatonin levels are:

  • Insomnia
  • Depression, anxiety
  • Stress
  • Chronic fatigue
  • Immunological disorders
  • Headaches, including migraine and cluster headache 

 

  1. Parathyroid Hormone produced by parathyroid glands plays a very important role in calcium metabolism and its levels decrease with aging.

The symptoms of declined parathyroid function are osteoporosis as well as delayed healing of fractured bones.

In summary one should conclude that menopause is a period in woman’s life when many vital hormones decline in their action leading to many symptoms and signs.                                                                               Knowledge of these symptoms is important in order to recognize the problem and initiate an appropriate treatment.

 

References

 

  1. Burger H.G., Physiology and endocrinology of the menopause. 2006 Medicine Jan34 (1);27-30
  2. Burger H.G., The endocrinology of the menopayse. 1996 Maturitas Mar;23(2):129-36
  3. Cobin R., Futterweit R.H., Ginzburg S.P., AACE Menopause Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause 2006 Endocrine Practice 12(3):315-337
  4. Endocrine news 2013 Prior J.C., Perimenopause: The Complex Endocrinology of the Menopausal Transition press.endocrine.org Retrieved 21.02.2016
  5. Medscape 2016 Halverson J.L. Depression medscape.com Retrieved 21.02.1016
  6. Soares C.N., Depression in Peri-and Postmenopausal Women: Prevalence, Pathophysiology and Pharmacological Management, 2013 Menopause 30 (9): 677-685
  7. Bellipanni G., Bianchi P., Pierpaoli W., Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study. 2001 Experimental Gerontology Feb; 36(2):297-310
  8. Dul A., Menopausal transition 2009 Best Practice and Research in Clinical Obstetrics and Gynaecology Feb;23(1):25-32
  9. Eichling P.S., Sahni J., Menopause sleep related disorders. 2005 Journal of clinical Sleep Medicine1, No.3
  10. Medscape 2011 Sikon A.L., Migraines and Perimenopause medscape.com Retrieved 21.02.2016
  11. Levy L. L., Emer J.J., Female pattern alopecia: current perspectives. 2013 International Journal of Womens Health 5:541-556
  12. Mazer N.A., Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women 2004 ThyroidSuppl 1:S27-37
  13. The Symphony of Hormones in Women 2013 Advanced Diploma in Aesthetic Medicine Module 2 Edition 2 FPD