The climacterium is the transitional phase from the reproductive stage to the non-reproductive stage. It is a process that begins with the decrease in ovulation frequency with ovarian insufficiency and continues until the senile period (65 years) by including a certain period after menopause. The climacterium is divided into 3 periods:
Perimenopause: The perimenopausal transition period lasts approximately 2-8 years. The most prominent clinical finding of this transition period is menstrual irregularities. The average cycle length shortens significantly as women age. Polymenorrhea dominates the clinic because of the short follicular phase at the beginning of the perimenopausal period , However, after the age of 40, anovulatory cycles become evident and luteal phase defect cycles as menopause approaches. Thus, the follicular phase begins to prolong and oligomenorrhea, which is the prominent feature of menopausal ages, occurs.
Menopause: It is the period when the menstrual cycles are completely stopped. The average age of menopause is 51. Age of menopause is determined genetically, It is not affected by age at menopause, race, socioeconomic status, number of previous ovulations and age of menarche. Ovary toxic agents are associated with early menopause. Menopause in smokers, those with a history of chemotherapy and pelvic radiotherapy, those who have had ovarian surgery and hysterectomized women appears earlier.
The spontaneous occurrence of menopause before the age of forty is called primary ovarian failure and is seen in 1% of women.
Postmenopause: It is the period after 12 months from the last menstruation.
Menopause is also examined in two groups according to the way it occurs:
Physiological Menopause: It is the picture that develops as a result of atresia of a large part of the existing oocytes.
Artificial Menopause: Surgical removal of the ovaries or loss of ovarian functions after radiotherapy and chemotherapy. After surgical menopause, vasomotor symptoms develop very rapidly and loudly. The risk of osteoporosis and cardiovascular disease is higher in patients whose ovaries have been surgically removed.
Hormonal Changes in Menopause
In the premenopausal phase, there is an increase in FSH due to decreased inhibin-B levels due to decreased ovarian reserve. Accordingly, folliculogenesis of follicles that are not yet completely depleted occurs and estrogen levels also increase, whereas LH and progesterone levels do not change. Anti-mullerian hormone levels have decreased , This is the period when the need for contraception still continues.
However, in the postmenopausal period, there is no response to increased FSH from the follicles, which are considered to be almost completely depleted, and ovarian steroids decrease.
Gonadotropins (FSH and LH) are elevated . FSH level peaks 1-3 years after menopause.
Perimenopausal transition period
FSH>20 IU/L
Inhibin-B low
LH normal
Estradiol > 80 pg/mL
postmenopausal period
FSH >40 IU/L
Iinhibin-B low
LH> 30 IU/L
Estradiol < 40 pg/mL
Contraception should be continued until FSH > 20 IU/L and LH > 30 IU/L
• Estrogen production decreases in the postmenopausal period and the amount of estrogen decreases to 10-20 pg/ml. While the main estrogen in the circulation is estradiol (E2) in the premenopausal period, the main estrogen in a postmenopausal woman is estrone (El), which is synthesized by the conversion of androstenedione in peripheral tissues. The hand/E2 ratio increases in favor of E1. After the functional depletion of the ovaries after menopause, estrogen levels become directly proportional to the amount of adipose tissue. Because fat cells are the main place where androgens aromatize into estrogens.
• In the postmenopausal period, the ovaries mainly secrete androgens. With the stimulating effect of increasing gonadotropins on stromal cells, testosterone synthesis from the postmenopausal ovary continues with a slight decrease. While this decrease is very small in spontaneous menopause, it is greater in surgical menopause. Androstenedione level is reduced by 50%.
Another source of androgens in postmenopausal women is the adrenal gland. With advancing age, DHEA (60%) and DHEA-S (80%) decrease, which is called adrenopause.
• Since ovulation does not occur in the postmenopausal period, progesterone levels are low.
Symptoms and Signs in Manopause
Menstrual Irregularities
► The first clinical symptom of menopause is menstrual function changes. Sudden cessation of menstruation is rare. The most frequently observed pattern is the decrease in both amount and duration of menstrual bleeding, and ultimately its cessation.
causes of postmenopausal bleeding
1. Endometrial atrophy ----------------------------------- ► 60% - 80%
2. Use of exogenous estrogen ---------------------------------------- 15 - 25 %
3. Endometrial polyp-------------------------------------► % 2 - 12
4. Endometrial hyperplasia -----------------------------► 5 - 10 %
5. Endometrial cancer---------------------------------► 10%
In case of uterine bleeding whether or not HRT is taken in the postmenopausal period, endometrial biopsy should be taken.
In cases where there is no bleeding, if the endometrial double wall thickness (ECWC) is 5 mm or more in the USG taken during the follow-up, endometrial biopsy should be taken again.
Vasomotor Symptoms
► It is seen simultaneously with the increase of GnRH and LH. Although the cause is not known exactly, the heat center in the hypothalamus becomes labile secondary to estrogen deficiency. It is associated with abrupt cessation of estrogen rather than a simple estrogen deficiency. It may also be due to adrenergic, serotonergic or dopaminergic activation as a result of its central effect.
► It occurs in more than 75% of perimenopausal women and affects both the central and peripheral parts of the body. It usually progresses in the form of hyperemia and sweat discharge due to cutaneous vasodilation lasting about 1-4 minutes in the upper parts of the body, head, neck and chest and recurring 5-10 times a day. It develops more severely and more often at night. There is an increased central and peripheral body temperature and tachycardia.
► Hot flashes develop earlier and are more severe after surgical menopause. It usually ends 1-2 years after menopause. In some cases, it can take more than 10 years. More vasomotor symptoms are seen in smokers and obese women.
► The most effective treatment in the treatment of vasomotor symptoms is systemic estrogen.
Alternative treatments for vasomotor symptoms
1. Conjugated estrogen + bazedoxif en combination
2. Progesterone (MPA, megestrol acetate)
3. Clonidine
4. SSRI (paroxetine, fluoxetine, escitalopram)
5. SNRI (venlafaxine, desvenlafaxine)
6. GABA analogs (Gabapentin, pregabalin)
7. Veralipride (dopamine antagonist)
8. Isoflavonoids (phytoestrogens)
9. Black cohosh
10. Soy protein
11. Dong quai, yoga, acupuncture
Urogenital Atrophy
► Vaginal dryness, itching, dyspareunia, dysuria and urgency occur due to urogenital atrophy.
► Atrophy occurs in the vulva. Dystrophic lesions and vulvar intraepithelial lesions develop more frequently.
► Vaginal rugae are flattened, epithelium thins, lubricity decreases. The maturation index deteriorates in favor of basal and parabasal cells. Dyspareunia develops due to introital and vaginal atrophy. Depending on the decrease in the number of lactobacilli, the pH rises (>4.5) and atrophic vaginitis develops accordingly.
► Cervix sizes decrease, corpus/cervix ratio which is 2:1 in adults, decreases to 1:1 in the postmenopausal period. The squamocolumnar junction is pulled towards the endocervical canal, the mucus decreases. Uterus shrinks in size. The endometrium undergoes atrophy and becomes thinner. Fibroids shrink, adenomyosis and endometriosis foci atrophy. The ovaries are reduced in size and cannot be palpated.
► Urethra tone decreases, urethral caruncle may develop. Stress incontinence occurs (urethral closure pressure decreases by 30% at menopause). Bladder tone may increase, detrusor instability (overactive bladder) may occur. Atrophic cystitis (characterized by urgency, urinary frequency and incontinence without dysuria and pyuria) develops as a result of urinary system atrophy.
► Pelvic relaxation, uterus and vaginal prolapse may develop due to decreased tone in the pelvic floor.
Ospemifene: It is a selective estrogen receptor modulator used in the treatment of genitourinary symptoms such as vaginal atrophy and dyspareunia in postmenopausal women.
Vaginal DHEA can be used in the treatment of moderate to severe dyspareunia in postmenopausal women.
osteoporosis
► Postmenopausal osteoporosis (type I osteoporosis); It occurs due to estrogen deficiency. Women lose 10-15% of their entire bone mass during the first 5 years of menopause. After the age of 30, bone destruction begins to be greater than production, and as a result, 50% reduction in trabecular bone and 30% reduction in cortical bone occurs 20 years after the last menstruation.
► The decrease in trabecular bone in the postmenopausal period is due to estrogen deficiency. Hip fractures begin to occur 10-15 years after menopause. In the postmenopausal period, the first loss and spontaneous fractures occur in vertebrae containing trabecular structure (compression fracture). The minimum estrogen blood value required to keep the bone tissue strong enough is 40-50 pg/ml.
► Dual x-ray absorptiometry (DXA) is the gold standard method for measuring bone mineral density. The most commonly used test in the diagnosis of osteoporosis is bone mineral densitometry (BMD). Bone mineral density measurement should be performed at the age of 65 and above regardless of the presence of any risk factors. It should be performed in younger postmenopausal patients if one or more risk factors are present.
► T score: It shows the standard deviation between the healthy and young (28 years old) population and the patient.
T Score
- 1 to + 1 ► Normal
- 1 to -2.5 ► Osteopenia
Less than - 2.5 ► Osteoporosis
► Women in the postmenopausal period should take 1200 mg of calcium and 800-1000 IU of Vitamin D in their daily diet to protect them from osteoporosis.
Osteoporosis risk factors;
Unchangeable factors
- Age
- Race
- Small body structure
- Early menopause
- Previous fracture history
- Family history for osteoporosis
Diseases
- Anovulation due to excessive exercise and eating disorder
- Hyperthyroidism
- Hyperparathyroidism
- Chronic renal disease
- rheumatoid arthritis
Modifiable risk factors
- Insufficient calcium and vitamin D intake
- Cigarette
- Low body weight (obese people have less osteoporosis)
- Excessive alcohol consumption
- Sedentary life
Drugs
- heparin
- Anticonvulsants,
- Systemic coricosteroids
- Thyroxine,
- SSRI
- Thiazolidinediones
Drugs Used in the Treatment of Postmenopausal Osteoporosis
Estrogen or estrogen + progesterone
0 It reduces the risk of osteoporosis and osteoporotic fractures. Estrogens increase intestinal absorption of calcium, decrease renal excretion, have a direct inhibitory effect on osteoclasts and provide osteoclast/osteoblast balance. It is not clear whether adding progesterone to estrogens produces a greater effect than that provided by estrogen.
Bisphosphonates (Alendronate, Risedronate, Ibandronate)
0 Specifically, they prevent bone loss by inhibiting bone resorption. They bind to bone minerals, making the bone resistant to osteoclastic resorption. The most important side effects are esophageal ulcers and GI problems. It reduces the risk of vertebra and hip fractures.
raloxifene
They create agonist or antagonist effects by binding to estrogen receptors.
0 While it has an estrogenic effect on bone and lipid profile; It creates an antiestrogenic effect on the breast and uterus. While it reduces the risk of vertebral fractures in women with osteoporosis and bone mass loss, it has not been shown to reduce non-vertebral fractures. Significantly reduces invasive breast cancer.
0 It reduces total cholesterol and LDL, does not increase HDL and triglycerides. It has good effects on fibrinogen and alpha lipoprotein.
0 The most important disadvantage is that it increases vasomotor symptoms and causes leg cramps. Although the most feared side effect is an increased risk of venous thromboembolism, no increased risk of fatal thromboembolism has been observed.
Bazedoxifene + Estrogen
0 Bazedoxifene is used in combination with estrogen for the treatment of hot flashes, the treatment of urogenital atrophy and the prevention of postmenopausal osteoporosis. It has positive effects on vertebra and hip. It has no adverse effects on the breast and endometrium.
Calcitonin
It regulates plasma calcium by inhibiting bone resorption. It should be combined with vitamin D and calcium.
Parathyroid Hormone (Teriparatide)
0 Unlike other agents, it does not prevent bone resorption, it strongly stimulates new bone formation. Thus, it provides a dramatic increase in whole body bone density. However, it should be preferred only in those with a very high risk of osteoporosis. There is a relationship between long-term use and the risk of developing osteosarcoma.
Monoclonal Antibody (Denosumab)
0 It is a monoclonal antibody that causes receptor activation of nuclear factor-K-B ligand and reduces bone resorption. It reduces the risk of vertebral and hip fractures in postmenopausal osteoporotic women.
Other Drugs
0 Tibolone, strontium and fluoride are used in the treatment of postmenopausal osteoporosis
cardiovascular system in Menopause
Coronary heart diseases are the leading cause of death (45%) of postmenopausal women. The relative hyperandrogenic picture, which occurs with the decrease in estrogen levels in women with menopause, increases the risk of cardiovascular disease on metabolism.
Estrogen physiologically has a positive effect on the cardiovascular system. However, it increases the risk of thromboembolism in cases with endothelial damage. Those with combined HRT have an increased risk of heart disease.
Hormone replacement therapy has no place in the prophylaxis or treatment of heart diseases.
central nervous system in Menopause
► Due to aging and estrogen deficiency, postmenopausal women experience difficulty concentrating and short-term memory problems. Although estrogen replacement therapy is started at a young age has a positive effect on cognitive functions, estrogen replacement therapy at older ages is harmful.
HORMONE REPLACEMENT THERAPY (HRT) in Menopause
• HRT is a very effective option in women with hot flashes and should be preferred especially in women who are in the first 10 years of menopause or younger than 60 years of age. In hormone replacement therapy, the lowest effective dose and the shortest duration of treatment should be aimed.
• There is no need to take a routine biopsy before HRT. However, in those at high risk for endometrial pathology, an endometrial biopsy should be taken before starting HRT.
HRT Indications and Contraindications
HRT Indications
1. Vasomotor symptoms
2. Urinary system atrophy
3. Genital system atrophy
4. Osteoporosis prophylaxis
Conditions in which estrogen should not be used
1. Undiagnosed uterine bleeding
2. Known or suspected breast cancer or having had breast cancer
3. Known or suspected estrogen-dependent neoplasms
4. Active or past DVT, pulmonary embolism
5. Active or previous (IN LAST 1 YEAR) arterial thromboembolic diseases (stroke or MI)
6. Liver diseases or liver dysfunctions
7. Hypersensitivity to estrogen
8. Known or suspected pregnancy
Conditions in which estrogen should be used with caution
1. Dementia
2. Gallbladder diseases
3. Hypertriglyceridemia
4. Previous cholestatic jaundice
5.Hypothyroidism
6. Fluid retention accompanying cardiac or renal failure
7. Severe hypocalcemia
8. Past endometriosis
9. Hepatic hemangioma
• The purpose of using progesterone is to meet the effects of estrogen on the endometrium.
Estrogen is used per te c because women who have had a hysterectomy do not have an endometrium. Progesterone is not added to this treatment because of its negative effects on lipid metabolism and an increased risk of possible breast cancer.
However, there are situations where progesterone should be added to estrogen therapy even though there is no uterus or endometrium:
1. Cases operated for endometrial cancer
2. Cases with endometriosis
3. History of endometrioid tumor in the ovaries
4. Those who have undergone supracervical hysterectomy
5. Cases undergoing endometrial ablation
HRT Complications
1. Endometrial cancer
2. Breast cancer; Risk increases for more than 5 years, especially those taking combined HRT
3. MI; The risk is increased in those taking combined HRT
4. Stroke
5. VTE (venous thrombomboli); no increased risk with transdermal preparations
6. Adverse effect on Alzheimer's, dementia and cognitive functions
7. Cholelithiasis; no increased risk with transdermal preparations
Combined hormone replacement therapy (estrogen+progesterone) reduces the incidence of colorectal cancer.
Results of the WHI study (Women's Health Initiative Study): In this study, it was planned to investigate the effects of hormone replacement therapy against heart diseases, osteoporosis, breast and colorectal cancer. Estrogen and progesterone were given to one group of women, and estrogen only to the other group that was hysterectomized, and the results were evaluated.
A) In the group receiving estrogen and progesterone
- Those with increased risk
• Coronary heart diseases
• CVA
• Thromboembolism
• Breast cancer
• Dementia
- Those with reduced risk
• Hip fracture
• Colorectal cancer
B) In the group receiving only estrogen
- Those with increased risk
• CVA
• Thromboembolism
- Those with reduced risk
• Hip fracture
- Those whose risk does not change
• Coronary heart diseases
• Invasive breast cancer
• Colorectal cancer
