Menopause

Student-learning objective:

Student-learning Objectives:

At the end of this lecture the student should be able to know:

•What is menopause and climacteric period.

.Physiological changes in menopause.

•Causes, physical and psychological symptoms of menopause.

•Factors that increase the risk osteoporosis and fracture.

•The clinico-pathological features of granulosa cell and Sertoli-Leydig cell

neoplasms and teratomas

•Describe hormonal replacement therapy.

.Take history and consultation, examination before initiating HRT.

.Options for treatment of vasomotor symptoms.

.Options for osteoporosis prevention and treatment.

.Risk of hormone therapy.

.Contraindications of HRT.

MENOPAUSE

Dr. Fatin Shallal

Definitions:

Greek words menos = month

Pausos = ending

MENOPAUSE: Is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. Natural menopause is secondary amenorrhoea for more than 6 months ( some say 12 months ) in a woman aged 45 years or over without another pathological cause. The average age at which menopause occurs is 51 years. Menopause before the age of 40 years is called premature ovarian failure.

THE CLIMECTERIC: In Greek Klimakter = rung of a ladder. It is the period of time usually between 45 and 55 years of age , during which the transition from the reproductive to the non-reproductive state occurs. It is attended by a variety of signs and symptoms and metabolic adjustments due to a major reduction in circulating oestrogen level.

Physiological Changes

Hypothalamus-Pituitary-Ovarian Axis Changes:

During the reproductive life of a woman, gonadotropin-releasing hormone (GnRH) is released in a pulsatile fashion. It binds to GnRH receptors on the pituitary gonadotrophs to stimulate cyclic luteinizing hormone (LH) and FSH release. These gonadotropins, in turn, stimulate the production of the ovarian steroids: estrogen, progesterone, and also inhibin. During the reproductive years, estrogen and progesterone exert positive and negative feedback on pituitary gonadotropin production and on the amplitude and frequency of GnRH release. Produced in the granulosa cells, inhibin exerts important negative feedback influence over FSH secretion from the pituitary. This tightly regulated endocrine system leads to ovulatory menstrual cycles that are regular and predictable.

The transition from ovulatory cycles to menopause typically begins in the late 40s and in early menopausal transition . Levels of FSH rise slightly and lead to an increased ovarian follicular response with overall higher estrogen levels . There is an increase in serum estrogen levels, produced from an increased number of follicles in the stimulated cohort responding to rising FSH levels. Also, during this time ovarian follicles undergo an accelerated rate of loss until eventually, in the late menopausal transition, the supply of follicles is depleted. These changes, including the increase in FSH levels, reflect the reduced quality and capability of aging follicles to secrete inhibin . As follicular depletion continues, episodes of anovulation become more common . With ovarian failure in the menopause , ovarian steroid hormone release ceases, and the negative-feedback loop is opened. Subsequently, GnRH is released at maximal frequency and amplitude. As a result, circulating FSH and LH levels rise up to fourfold higher than in the reproductive years.

Causes of menopause:

PREMATURE OVARIAN FAILURE ( POF ): Is menopause before the age of 40 years ( some say 45 years ).

Such patients exhibit: - Low plasma oestradiol ( E2 ) usually less than 150 pmol/ L - high levels of FSH and LH and - signs and symptoms of suggestive of oestrogen deficiency.

POF may be associated with other autoimmune endocrinopathies and in about half of patients other auto antibodies are present, however the precise site of action of an antibody attack on the hypothalamo-pituitary-ovarian axis is unknown.

POF may be induced during management of malignant disease in young women through chemotherapy, pelvic radiotherapy, or creating artificial menopause to suppress oestrogen secretion from the ovary in premenopausal women treated with radiation for breast cancer.

Principle causes of premature ovarian failure:

Primary causes:

-Chromosomal anomalies e.g turner syndrome and fragile x.

-auto-immune disease e.g hypothyroidism,Addison, myasthenia gravis.

- enzyme deficiency e.g galatosaemia, 17α hydroxylase def.

Secondary causes:

-surgical menopause after bilateral oopherectomy.

- chemotherapy or radiation.

- infection e.g TB ,mump, malaria,varicella.

RESISTANT OVARY SYNDROME: Here a group of patients with premature ovarian failure have the same clinical picture but the biological appearances of the ovary are normal with abundant primordial follicles unlike those with POF in which the ovaries look like those of menopausal women.

SURGICAL MENOPAUSE: Causes:

-Following bilateral oophorectomy for any reason, this will cause immediate menopause.

-Following hysterectomy in premenopausal patients even if both ovaries are conserved, POF may supervene. The median age of menopause here is 47 – 48 years instead of the expected age of 51 years. Because of amenorrhoea due to hysterectomy , menopause here is diagnosed by symptomatology and endocrine tests.

SYMPTOMS OF MENOPAUSE: These may begin before the actual cessation of menstruation with the relative fall of oestrogen level and before the level of menopause is reached ( less than 100 pmol/L ).

1-PHYSICAL SYMPTOMS:

A-The classical vasomotor symptoms of hot flushes and night sweats: - Occur in at least 70% of perimenopausal women.

- Their frequency varies from a few to several dozens per day and the duration may be from a few weeks to many years.

- Hot flushes are a vascular response to a central disturbance of the thermoregulatory centre in the hypothalamus. There is a downshift of the set-point of this centre such that there is a frequent central misapprehension that body temperature is too high, this in turn leads to activation of the physiological mechanisms such as cutaneous flushing and perspiration which result in heat loss by radiation and by the loss of the latent heat by vaporization.

- At night these attacks may lead to frequent awakening of the patient and result in certain psychological symptoms such as irritability and short term memory impairment.

B- Tiredness

C- Insomnia

D- Vaginal dryness which leads to dyspareunia and affects the womens' relationship with their partners. With oestrogen deficiency vaginal epithelium becomes thin and poorly moisturised.

E- Urinary symptoms: menopausal women often complain of dysuria, frequency, and urgency which suggest a urinary tract infection ( UTI ) but associated with a negative urine culture. Stress incontinence may also be present.

F- Skeletal system:

About 20% of body bone is highly sensitive to oestrogen ( trabecular bone ) as found in the vertebrae, distal radius, femoral neck and the calcaneus. Oestrogen keeps the balance between bone formation and bone resorption and after menopause there will be greater bone resorption than formation. As trabecular bone is a shock-absorbing bone so it becomes more liable to fracture after minimal or moderate trauma.

The net result is that after menopause there is a progressive rise in the incidence of fracture of the trabecular sites. Traumatic fracture affects the distal radius and femoral neck, whereas non-traumatic fracture affects the vertebrae.

Factors that increase the risk of osteoporosis and fracture with minimal trauma:

-Non-modifieable :age, race, family history, history of fracture, early menopause.

-Modifiable: decrease ca. and vitamin D intake, smoking, sedentary life style, low body weight, alcohol intake.

-Anovulation during reproductive years(eg, secondary excess exercise or eating disorder)

-Early ovarian failure or bilateral oopherectomy.

-Medical conditions associated with an increased risk of osteoporosis like, thyrotoxicosis,Hyperparathyroidism,Chronic renal disease,.Diseases requiring systemic corticosteroid use.

-More than 6 months Secondary amenorrhea(excepting pregnancy).

G- Cardiovascular system:

Oestrogen has a protective effect against cardiovascular disease in premenopausal women so myocardial infarction is much lower than in men of matched ages. Oestrogen deficiency causes the following atherogenic changes in lipid profile :

-total chlestrol : ↑

-high-density lipoprotein ( HDL ) : ↓

-low-density lipoprotein ( LDL ) : ↑

-Triglycerides : ↔

Oesradiol also is known to stimulate the enzyme nitrogen synthase, whose product, nitric oxide is both a vasodilator and an oxidant for lipoprotein accumulating in the subintima of the vessel wall.

Loss of oestrogen can thus result in a promotion of both atherogenesis and vasoconstriction.

2-PSYCHLOGICAL SYMPTOMS:

-Mood swings

-Anxiety

-Loss of short-term memory

-Lack of concentration

- Loss of self-confidence

-Depression

Diagnosis of menopause:

1.cessation of menstruation for consecutive 12 months during climacteric.

2.Appearance of menopausal symptoms hot flush and night sweats.

3.vaginal cylology showing maturation index of at least 10/85/5(features of low estrogen).

4.serum estradiol:less than 20 pg/ml.

5.serum FSH and LH: more than 40 mlU/ml(three values at weekly interval).

HORMONE REPLACEMENT THERAPY (HRT):

Dr.fatin shallal

HRT should be offered when the presence of symptoms or effects of oestrogen deficiency interfere with the life, maritual or occupational welfare.

The woman herself has the final say in whether or not she will initiate and continue with such therapy.

Before initiating HRT the followings should be done:

1-HISTORY AND COSULTATION:

a-A full history with concentration on oestrogen deficiency symptoms and their impact on the personal ,domestic and occupational efficiency of woman's life.

b-A family history of :

-Cardiovascular disease particularly angina pectoris, myocardial infarction and stroke.

-Skeletal disease particularly osteoporosis manifested in relatives through height loss and low-trauma fracture to wrist, hip and other sites.

-Presence of Alzheimer's disease or other neurodegenerative disease in the family.

c-History of any gastrointestinal or liver disease that might interfere with the normal pharmacodynamics of oestrogen therapy.

d-Gynaecological history:

-Previous medical and surgical interventions particularly the presence of conditions affected by plasma oestrogen as endometriosis or leiomyomata.

-A history of benign or malignant breast disease should be sought and a review of histological report on any breast biopsy material to see whether or not cellular atypia was present as this may affect future management.

-The patient's mammographic record should be ascertained and she should be encouraged to participate in breast screening programs from age 50 to 64.

-Any heavy or persistently irregular bleeding should be further investigated by pelvic ultrasound, proceeding if required to hysteroscopy and endometrial biopsy.

2-EXAMINATION:

a-Breast examination if indicated from the history. Patients should be advised to be aware of any breast changes or masses through self-examination if necessary.

b-Pelvic examination should be done when indicated ( not routinely ) and a record is made of any uterine enlargement , the presence of fibroids, any signs suggestive of past or present endometriosis, and any adnexal mass.

c-Blood pressure should be checked.

  1. Preparation of the patient for those symptoms that mark the re-introduction of oestrogen and progestogens into the ciculation. The patient needs to be told that these start-up symptoms are likely to be temporary and to remit by 3 months. These symptoms include:

a-Breast tenderness

b-Nipple sensitivity

c-Appetite rise

d-Weight gain

e-Calf cramps

1-First critical review will be at 3 months after starting HRT where enquiry should be made about the resolution of menopausal symptoms and of start-up effects.

The incidence of vasomotor symptoms reaches baseline at 3 months and hence a critical review prior to this time may falsely indicate that treatment is failing. If no unwanted effects are encountered the patient may be reviewed 6 months later and then annually.

2-In the annual review :

a-Breast: the patient’s participation in breast screening programmes if available should be ascertained and if the patient is breast aware and performing self-examination regularly and participating in the mammographic programme then a full clinical breast examination is probably not necessary.

If there is any doubt about her breast awareness and if she complains of breast pain or swelling a breast examination should be performed.

There is evidence that long term use of oestrogen and progestogen is associated with a small but measurable increase in the risk of breast cancer.

b-Blood pressure:

This should be checked at least annually.

c-Pelvic examination:

If the patient is amenorrheoic on a continuous oestrogen/ progestogen or tibolone treatment,or if she is bleeding on time and with normal flow on a cyclic regimen then routine pelvic examination is probably not needed because it is unlikely to disclose an abnormality.

If unscheduled bleeding occurs, especially if it is prolonged or recurrent this needs a specialist consultation with a view to hysteroscopy and endometrial biopsy if indicated. Ultrasound evaluation of the pelvis preferentially transvaginally may help diagnosing a leiomyomata or endometrial polyps.

OPTIONSFOR TREATMENT OF VASOMOTOR SYMPTOMS:

1.Lifestyle changes

  • .Reducting body temperature.
  • .maintaining a healthy weight
  • .Smoking cessation
  • .Paced respiration

2.Non prescription medications.

  • .Isoflavone supplements: Phyoestrogens containing isoflavones are found to lower the incidence of vasomotor symptoms, osteoporosis and cardiovarscular disease.it reduces the risk and endometrial cancer.
  • .Soy products:is also found effective to reduce vasomotor symptoms.Soy protein acts as SERMS.
  • .Black cohosh
  • .Vitamin E.

3.Non hormonal prescription medications:

  • .Clonidine:an α adrenergic agonist may it is helpful where estrogen is contraindicated(hypertension).
  • .Selective serotonin and norepinephrine reup take inhibitors:Paroxetine, a selective serotonin reuptake inhibitors, is effective to reduce hot flushes(both the frequency and severity)
  • .Gapapentin: is an analog of gamma-aminobutyric acid.it is effective to control hot flushes.

4.Hormonal therapy:

  • .estrogon therapy:oral,transdermal,subcutaneous routes .
  • .combination estrogen and progestin therapy.
  • .progestin therapy.
  • Tibilone a synthetic hormone preparation.

Treatment of atrophic vaginitis:

1 .ESTROGEN REPLACEMENT:

Estrogen replacement restores normal pH levels and thickens and revascularizes the epithelium. Estrogen therapy may alleviate existing symptoms or even prevent development of urogenital symptoms if initiated at the time of menopause. Routes of administration include oral, transdermal and intravaginal. Dose frequency may be continuous, cyclic or symptomatic. The amount of estrogen and the duration of time required to eliminate symptoms depend greatly on the degree of vaginal atrophy and vary among patients.

Systemic administration of estrogen has been shown to have a therapeutic effect on symptoms of atrophic vaginitis. Standard dosages of systemic estrogen, however, may not eliminate the symptoms of atrophic vaginitis in 10 to 25 percent of patients. Systemic estrogen in higher dosages may be necessary to alleviate symptoms. Some women require coadministration of a vaginal estrogen product that is applied locally. Up to 24 months of therapy may be necessary to totally eradicate dryness; however, some patients do not fully respond even to this treatment regimen. Other treatment options include transvaginal delivery of estrogen in the form of creams, pessaries or a hormone-releasing ring (Estring). Treatment with a low-dose transvaginal estrogen has proved effective in relieving symptoms without causing significant proliferation of the vaginal epithelium. The genitourinary pH level is also lowered, leading to a decreased incidence of urinary tract infections. Absorption rates increase with treatment duration because of the enhanced vascularity of the treated epithelium. The advantage of transvaginal treatment may be a decreased risk of endometrial carcinoma because a lower hormone amount is required to eliminate urogenital symptoms. Negative effects of transvaginal treatment include patient dislike of vaginal manipulation, less prevention of postmenopausal bone loss and vasomotor dysfunction, decreased control of absorption with vaginal creams compared to oral and transdermal delivery, and irregular treatment intervals that may cause patients to forget to administer the treatment.

2.MOISTURIZERS AND LUBRICANTS:

Moisturizers and lubricants may be used in conjunction with estrogen replacement therapy or as alternative treatments.Some patients choose not to take hormone replacement, or they may have medical contraindications or experience hormonal side effects. Patients who wish to avoid using estrogen should not use moisturizers that contain ginseng because they may have estrogenic properties. Moisturizers help maintain natural secretions and coital comfort.

Sexual Activity:

Sexual activity is a healthful prescription for postmenopausal women who have a substantially estrogenized vaginal epithelium. It has been shown to encourage vaginal elasticity and pliability, and the lubricative response to sexual stimulation. Women who participate in sexual activity report fewer symptoms of atrophic vaginitis and, on vaginal examination, have less evidence of stenosis and shrinkage in comparison with sexually inactive women.

What treatments are available for bladder control problems:

Treatment depends on the kind of bladder control problem you have. Your doctor may recommend some of the following lifestyle changes:

1.Limiting caffeine

2 .Avoiding bladder irritants such as alcohol, carbonated beverages, and spicy foods.

3 .Strengthening pelvic muscles with Kegel exercises. These exercises strengthen your pelvic floor muscles. To do Kegel exercises, you squeeze and hold the pelvic muscles and then relax them. .

4.Training the bladder to hold more urine

If these simple treatments do not work, there are other options, including

1 .Medication such as tolterodine (Detrol®), oxybutynin (Ditropan®) etc.

2 .Biofeedback, which is a method of learning to voluntarily control certain body functions with the help of a special machine.

3.Electrical stimulation of pelvic muscles.

A device inserted in the vagina to hold up the bladder (pessary)4.

5.A device inserted directly into the urethra to block leakage

6.Surgery to lift a sagging bladder into a better position

Estrogen therapy is not FDA-approved for the treatment of incontinence, but local vaginal estrogen may reduce recurrent urinary tract infections and is recommended by national guidelines to treat minor bladder symptoms in post-menopausal women.

How will you assess her risk for having osteoporosis?

  1. History (risk factors).
  2. 2. Diagnosis:computed tomography CT and the dual-energy X-ray absorptiometry are reliable methods to assess the bone mineral density.
  3. Assessment of osteoporosis by DXA is recommended for
  • .all women aged 65 and older, regardless of risk factors.
  • .for younger postmenopausal women with 1 or more risk factors, other than being white and menopausal.

4.Biochemical parameters to detect bone loss are measurement of urinary calcium/ creatinine and hydroxyproline/creatinine ratios.