Menopause

Definition and Epidemiology

Definition

Menopause is the permanent physiologic cessation of menses Menses The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle due to loss of ovarian activity determined retrospectively after 12 consecutive months of no menstrual bleeding and low estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy levels.

Epidemiology

• Average age: 51 years
• Typical range: 44–55 years of age (95% of women)
• Abnormal < 40 years of age: primary ovarian insufficiency Primary ovarian insufficiency Cessation of ovarian function after menarche but before the age of 40, without or with ovarian follicle depletion. It is characterized by the presence of oligomenorrhea or amenorrhea, elevated gonadotropins, and low estradiol levels. It is a state of female hypergonadotropic hypogonadism. Etiologies include genetic defects, autoimmune processes, chemotherapy, radiation, and infections. The most commonly known genetic cause is the expansion of a cgg repeat to 55 to 199 copies in the 5′ untranslated region in the X-linked fmr1 gene. Primary Ovarian Insufficiency
• Factors affecting age:
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
  • Ethnicity
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
  • Reproductive history
  • Chemotherapy Chemotherapy Osteosarcoma or pelvic radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Hysterectomy with ovarian conservation → post-surgical impairment in blood supply
  • Bilateral oophorectomy → surgical menopause

Physiology

Menopause is characterized by a physiologic ↓ in oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy due to progressive atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), ultimately leading to a chronic hypoestrogenic state in postmenopause. During the menopause transition, hormone levels fluctuate significantly.

Physiology of menopause transition

Normal oocyte counts:

• At birth: 1–2 million oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy
• At puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty: 400,000 oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy
• At age 30–35: 100,000 oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy
• At menopause: < 1,000 oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy

Effects of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy:

• Inhibits release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle
• Endometrial stimulation
• Vaginal lubrication
• Breast growth
• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types growth
• Modulating effects on thermoregulation Thermoregulation Body temperature can be divided into external temperature, which involves the skin, and core temperature, which involves the CNS and viscera. While external temperature can be variable, the core temperature is maintained within a narrow range of 36.5-37.5ºC (97.7-99.5ºF). Body Temperature Regulation and mood

Late reproductive years/early menopause transition:

• Perimenopause: 
  • Transitional period from reproductive to non-reproductive stage
  • Begins on average 4 years prior to last menstrual period Last menstrual period The 1st day of a woman’s last menstrual period. By convention, this date is usually used to date pregnancies. Pregnancy: Diagnosis, Physiology, and Care 
  • Usually lasts 2–8 years
  • Characterized by increasing menstrual irregularity and fluctuating hormone levels
• ↓ Oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy → ↓ estrogens → ↓ inhibition of FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↑ follicular response → ↑ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy (mid-cycle)
• Significant fluctuations in estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy throughout cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation

Late menopause transition:

• Accelerated oocyte atresia Atresia Hypoplastic Left Heart Syndrome (HLHS) 
• Severely depleted follicle supply → more anovulatory cycles 
• ↓ Oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy → ↓ estrogens → ↓ inhibition of FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle → ↓ quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of oocytes Oocytes Female germ cells derived from oogonia and termed oocytes when they enter meiosis. The primary oocytes begin meiosis but are arrested at the diplotene state until ovulation at puberty to give rise to haploid secondary oocytes or ova (ovum). Ovaries: Anatomy are unable to respond → estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy stays ↓

Primary estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy switches from estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Noncontraceptive Estrogen and Progestins (E2) to estrone Estrone An aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone, a major mammalian estrogen. It is converted from androstenedione directly, or from testosterone via estradiol. In humans, it is produced primarily by the cyclic ovaries, placenta, and the adipose tissue of men and postmenopausal women. Noncontraceptive Estrogen and Progestins ( E1 E1 An aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone, a major mammalian estrogen. It is converted from androstenedione directly, or from testosterone via estradiol. In humans, it is produced primarily by the cyclic ovaries, placenta, and the adipose tissue of men and postmenopausal women. Noncontraceptive Estrogen and Progestins):

• E2: 
  • Primary estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy in premenopausal women
  • Produced in ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy
  • ↓ Significantly at menopause
• E1 E1 An aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone, a major mammalian estrogen. It is converted from androstenedione directly, or from testosterone via estradiol. In humans, it is produced primarily by the cyclic ovaries, placenta, and the adipose tissue of men and postmenopausal women. Noncontraceptive Estrogen and Progestins: 
  • Primary estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy in postmenopausal women
  • Produced primarily in adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology

Other hormonal changes in perimenopause

Clinical Presentation

The clinical symptoms of perimenopause are caused by fluctuating hormone levels in the menopause transition period. The presentation of postmenopause results from the low estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy levels that ensue after cessation of ovarian function, which persist for the remainder of a woman’s life.

Symptoms associated with perimenopause

• Menstrual changes:
  • Late reproductive years: Menstrual cycles shorten (cycles get closer).
  • Menopausal transition: shorter cycles → longer cycles → very irregular/ sporadic Sporadic Selective IgA Deficiency cycles → final menstrual period 
• Vasomotor symptoms:
  • Hot flushes Hot Flushes Primary Ovarian Insufficiency
  • Occur in 50%–90% of women
  • Usually last 1–5 minutes, but may last up to 45 minutes
  • Night sweats Night sweats Tuberculosis: can significantly disrupt sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep → chronic fatigue Chronic Fatigue Fibromyalgia
• Emotional symptoms:
  • Mood swings and irritability
  • Stress and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
• Symptoms related to sexual function :
  • Genitourinary syndrome of menopause (GSM): vulvovaginal atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation (the physical changes of vulva Vulva The vulva is the external genitalia of the female and includes the mons pubis, labia majora, labia minora, clitoris, vestibule, vestibular bulb, and greater vestibular glands. Vagina, Vulva, and Pelvic Floor: Anatomy, vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor: Anatomy, and lower urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy due to estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy deficiency)
  • Vaginal dryness and itching
  • Dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency

Symptoms and conditions associated with postmenopause

These symptoms are a result of long-term estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy deficiency:

• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types loss:
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Fragility fractures Fragility fractures Pelvic fractures are a disruption in the cortex of a pelvic bone involving iliac wing fractures, acetabular fractures, or those causing loss of integrity of the pelvic ring (the sacrum and the 2 innominate bones). Patients often present with a history of trauma or a fall, limb length discrepancy, intense pain on palpation, and mechanical instability. Pelvic Fractures
• Cardiovascular disease:
  • Lipid profiles worsen (↑ cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism).
  • Weight gain
  • ↑ Risk for myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction and thromboembolic events
• Hair, muscle, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes:
  • Hair thins.
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions becomes drier and rougher.
  • ↓ Lean LEAN Quality Measurement and Improvement mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast and muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction
  • ↑ Fat mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
• Symptoms of GSM:
  • Dryness/ dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency
  • ↑ Risk of pelvic organ prolapse Pelvic Organ Prolapse Pelvic organ prolapse (POP) is a general term that refers to herniation of 1 or more pelvic organs (e.g., bladder, uterus, rectum) into the vaginal canal, and potentially all the way through the introitus. Weakness and insufficiency of the pelvic floor may result in POP. Pelvic Organ Prolapse
  • Incontinence issues
  • ↑ Urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (UTIs)

Mnemonic

HAVOCS:

• Hot flashes
• Atrophy of the Vagina
• Osteoporosis
• Coronary artery disease
• S leep LEEP Diagnostic Procedures in Gynecology disturbances

Diagnosis

• Primarily clinical
• Pelvic exam: Assess vaginal atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation in context of sexual complaints.
• Routine lab evaluation not indicated:
  • FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle, and estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy levels fluctuate significantly and are not clinically useful in most cases.
  • Exception: if patient is around age of menopause with abnormal bleeding, ↑ FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle may be helpful in clarifying menopausal status
• Abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding should be evaluated:
  • Endometrial biopsy Endometrial Biopsy Diagnostic Procedures in Gynecology 
  • Pelvic ultrasound
  • Hysteroscopy Hysteroscopy Endoscopic examination, therapy or surgery of the interior of the uterus. Diagnostic Procedures in Gynecology if diagnosis still uncertain
  • Possible pathologic findings: 
    • Endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation/cancer
    • Leiomyomas
    • Polyps
    • Adenomyosis Adenomyosis Adenomyosis is a benign uterine condition characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Adenomyosis is a common condition, affecting 20%-35% of women, and typically presents with heavy menstrual bleeding and dysmenorrhea. Adenomyosis
    • Ovulatory dysfunction from other causes

Management

A majority of women in perimenopause and postmenopause do not require treatment. The primary goals of management are relief of bothersome symptoms and ensuring health through appropriate screening Screening Preoperative Care.

Menopausal hormone therapy (MHT)

Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy therapy (ET):

• Effective at treating:
  • Vasomotor symptoms: hot flushes Hot Flushes Primary Ovarian Insufficiency, night sweats Night sweats Tuberculosis → sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbances
  • Mood symptoms in peri- (but not post-) menopause
  • GSM: vaginal dryness, dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency
• Routes of therapy:
  • Systemic therapy: oral, transdermal patches Patches Vitiligo, topical gels
  • Vaginal therapy: creams, vaginal tablets, ring
• Selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions of route and dosing:
  • Give continuously.
  • Transdermal is usually preferred for vasomotor symptoms.
  • Vaginal ET is preferred when treating GSM only.
• Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy stimulates endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development → progestin required if patient has uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy

Progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives:

• Higher risk of adverse events than estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy therapy
• Required for endometrial protection in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy
• Selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions of route and dosing:
  • Usually oral
  • Give cyclically if still menstruating regularly.
  • Give continuously if post-menopausal.

Candidates for therapy:

• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship within 10 years of menopause
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 60–65 years of age
• Symptoms severe enough to affect quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life
• No contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation to MHT include history of:

• Hormone-sensitive breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
• High-risk endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
• Unexplained vaginal bleeding
• Cardiovascular disease
• Venous thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus
• Stroke or transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA) ( TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA))
• Acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease

General principles:

• Use lowest dose for shortest duration required to treat symptoms.
• Should not be used for prevention of chronic disease

Risks and benefits beyond symptom relief:

• MHT ↑ risk of:
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Cardiovascular disease
  • Deep venous thrombosis Venous thrombosis The formation or presence of a blood clot (thrombus) within a vein. Budd-Chiari Syndrome and stroke
  • Gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract: Anatomy disease
• MHT ↓ risk of:
  • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • All-cause mortality Mortality All deaths reported in a given population. Measures of Health Status

Other management options for vasomotor symptoms

• Selective estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulators ( SERMs SERMs A structurally diverse group of compounds distinguished from estrogens by their ability to bind and activate estrogen receptors but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the endometrium or second generation based on their patterns of tissue specificity. Antiestrogens):
  • Modulate effects of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy 
  • Different effects (agonist vs. antagonist) in different tissue types
  • Common examples:
    • Raloxifene Raloxifene A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. Other Antiresorptive Drugs (agonist in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types, antagonist in breast and uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy)
    • Bazedoxifene Bazedoxifene Antiestrogens
    • Ospemifene Ospemifene Antiestrogens (specifically for GSM)
• Non-hormonal medications:
  • Selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants):  Paroxetine Paroxetine A serotonin uptake inhibitor that is effective in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants is the only FDA-approved SSRI.
  • Serotonin-norepinepherine reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)
  • Gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs
  • Clonidine Clonidine An imidazoline sympatholytic agent that stimulates alpha-2 adrenergic receptors and central imidazoline receptors. It is commonly used in the management of hypertension. Sympathomimetic Drugs
• Botanical and herbal remedies: not shown to be effective in clinical trials
• Lifestyle changes:
  • Layer clothing.
  • Maintain lower ambient temperature at home.
  • Avoid alcohol and caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants.
  • Stress management

Management options for GSM

• Low-dose vaginal estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy: 
  • Most effective treatment
  • Doses are low enough that progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives are not required for endometrial protection.
• Vaginal lubricants
• Vaginal moisturizers
• Regular Regular Insulin sexual activity or use of dilators

Recommended health screening Screening Preoperative Care for menopausal women

Differential Diagnosis

• Primary ovarian insufficiency Primary ovarian insufficiency Cessation of ovarian function after menarche but before the age of 40, without or with ovarian follicle depletion. It is characterized by the presence of oligomenorrhea or amenorrhea, elevated gonadotropins, and low estradiol levels. It is a state of female hypergonadotropic hypogonadism. Etiologies include genetic defects, autoimmune processes, chemotherapy, radiation, and infections. The most commonly known genetic cause is the expansion of a cgg repeat to 55 to 199 copies in the 5′ untranslated region in the X-linked fmr1 gene. Primary Ovarian Insufficiency (POI): a condition characterized by impaired ovarian function in women < 40 years of age. Symptoms are identical to menopause, including amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System, vasomotor symptoms, and vaginal dryness. The key difference is patient age. Menopause is a natural physiologic process, while POI is pathologic, and may be caused by genetic or chromosomal anomalies, an autoimmune process, or ovarian toxins. Management is with HRT HRT Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins, addressing fertility concerns, and counseling.
• Abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding ( AUB AUB Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym palm-coein, with palm representing the structural causes and coein indicating the non-structural causes. Abnormal Uterine Bleeding): preferred term for uterine bleeding outside normal parameters, and includes heavy and irregular bleeding. Common causes include leiomyomas, polyps, endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation or malignancy Malignancy Hemothorax, coagulopathy (especially in younger women), and ovulatory dysfunction. Diagnosis usually requires endometrial biopsy Endometrial Biopsy Diagnostic Procedures in Gynecology and pelvic ultrasound. Management depends on underlying etiology. Important to exclude pathologic causes of AUB AUB Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym palm-coein, with palm representing the structural causes and coein indicating the non-structural causes. Abnormal Uterine Bleeding in perimenopausal women.
• Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders: can cause hot flushes Hot Flushes Primary Ovarian Insufficiency, palpitations Palpitations Ebstein’s Anomaly, and mood symptoms, similar to menopause. Often, these conditions may co-exist with menopause. Management may include SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants, SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants, other anxiolytics, and psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy.