Menopause

Menopause is a physiologic process in women characterized by the permanent

cessation of menstruation that occurs after the loss of ovarian activity. Menopause
can only be diagnosed retrospectively, after 12 months without menstrual bleeding.
During the menopausal transition, reproductive hormones can fluctuate significantly,
leading to symptoms that include hot flushes, sleep and mood disturbances, and
vaginal dryness. In postmenopausal woman, low estrogen levels contribute to an
increased risk for cardiovascular disease, osteoporosis, and sexual dysfunction due
to vulvovaginal atrophy. For some women, symptoms negatively affect their quality of
life and treatment is warranted. Management usually involves menopausal hormone
therapy (MHT), but other treatment options also exist.

Last updated: September 29, 2022

CONTENTS

Definition and Epidemiology

Physiology
Clinical Presentation
Diagnosis
Management
Differential Diagnosis
References
Definition and Epidemiology
Definition
Menopause is the permanent physiologic cessation of menses due to loss of
ovarian activity determined retrospectively after 12 consecutive months of no
menstrual bleeding and low estrogen levels.

Epidemiology
Average age: 51 years
Typical range: 44–55 years of age (95% of women)
Abnormal < 40 years of age: primary ovarian insufficiency
Factors affecting age:
Genetics
Ethnicity
Smoking
Reproductive history
Chemotherapy or pelvic radiation
Hysterectomy with ovarian conservation → post-surgical impairment in
blood supply
Bilateral oophorectomy → surgical menopause

Physiology
Menopause is characterized by a physiologic ↓ in oocytes due to progressive
atresia, ultimately leading to a chronic hypoestrogenic state in postmenopause.
During the menopause transition, hormone levels fluctuate significantly.
 The primary hormonal changes seen in perimenopause/menopause are a decrease in estrogen
and progesterone and an increase in follicle-stimulating hormone (FSH) and luteinizing hormone
(LH).
GnRH: gonadotropin-releasing hormone

Image by Lecturio.

Physiology of menopause transition

Normal oocyte counts:
At birth: 1–2 million oocytes
At puberty: 400,000 oocytes
At age 30–35: 100,000 oocytes
At menopause: < 1,000 oocytes
Effects of estrogen:
Inhibits release of FSH
Endometrial stimulation
Vaginal lubrication
Breast growth
Bone growth
Modulating effects on thermoregulation 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
Usually lasts 2–8 years
Characterized by increasing menstrual irregularity and fluctuating hormone
levels
↓ Oocytes → ↓ estrogens → ↓ inhibition of FSH → ↑ FSH → ↑ follicular response
→ ↑ estrogen (mid-cycle)
Significant fluctuations in estrogen throughout cycle
Late menopause transition:
Accelerated oocyte atresia
Severely depleted follicle supply → more anovulatory cycles
↓ Oocytes → ↓ estrogens → ↓ inhibition of FSH → ↑ FSH → ↓ quality of oocytes
are unable to respond → estrogen stays ↓
Primary estrogen switches from estradiol (E2) to estrone (E1):
E2:
Primary estrogen in premenopausal women
Produced in ovaries
↓ Significantly at menopause
E1:
Primary estrogen in postmenopausal women
Produced primarily in adipose tissue
Oocyte counts over lifespan of a woman:
Oogenesis is mostly completed by birth and viable oocyte counts continue to decrease through
a woman’s life.
Image by Lecturio.

Other hormonal changes in perimenopause

 Table: Other hormonal changes in perimenopause

Hormone Change Explanation

Anti-Müllerian ↓ Secreted by premature follicles

hormone (AMH) Marker of ovarian reserve
Begins to decrease 5 years prior to
last menstrual period
May lead to increased risk for twin
pregnancies

Inhibin B ↓ Inhibits FSH secretion

May begin to ↓ around age 35
(earliest measurable marker) → ↑
FSH

LH and FSH ↑ Inhibin B has an inhibitory effect on

LH and FSH, so during menopause
their levels increase.

Testosterone ↓ Primary source of production shifts

from ovaries to adrenals.
Hypoplasia of adrenal cortex leads
to a 25% decrease in testosterone.

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 levels that ensue after cessation of ovarian
function, which persist for the remainder of a woman’s life.
Symptoms of menopause that can also be seen in primary ovarian insufficiency

Image: “Symptoms of menopause” by Mikael Häggström. License: CC0

Symptoms associated with perimenopause

 Menstrual changes:
Late reproductive years: Menstrual cycles shorten (cycles get closer).
Menopausal transition: shorter cycles → longer cycles → very irregular/
sporadic cycles → final menstrual period
Vasomotor symptoms:
Hot flushes
Occur in 50%–90% of women
Usually last 1–5 minutes, but may last up to 45 minutes
Night sweats: can significantly disrupt sleep → chronic fatigue
Emotional symptoms:
Mood swings and irritability
Stress and anxiety
Symptoms related to sexual function :
Genitourinary syndrome of menopause (GSM): vulvovaginal atrophy (the
physical changes of vulva, vagina, and lower urinary tract due to estrogen
deficiency)
Vaginal dryness and itching
Dyspareunia

Symptoms and conditions associated with

postmenopause
These symptoms are a result of long-term estrogen deficiency:
Bone loss:
Osteoporosis
Fragility fractures
Cardiovascular disease:
Lipid profiles worsen (↑ cholesterol).
Weight gain
↑ Risk for myocardial infarction and thromboembolic events
Hair, muscle, and skin changes:
Hair thins.
Skin becomes drier and rougher.
↓ Lean mass and muscle tone
↑ Fat mass
Symptoms of GSM:
Dryness/dyspareunia
↑ Risk of pelvic organ prolapse
Incontinence issues
↑ Urinary tract infections (UTIs)

Mnemonic
HAVOCS:
 Hot flashes
Atrophy of the Vagina
Osteoporosis
Coronary artery disease
Sleep disturbances

Diagnosis
Primarily clinical
Pelvic exam: Assess vaginal atrophy in context of sexual complaints.
Routine lab evaluation not indicated:
FSH, LH, and estrogen levels fluctuate significantly and are not clinically
useful in most cases.
Exception: if patient is around age of menopause with abnormal bleeding,
↑ FSH may be helpful in clarifying menopausal status
Abnormal uterine bleeding should be evaluated:
Endometrial biopsy
Pelvic ultrasound
Hysteroscopy if diagnosis still uncertain
Possible pathologic findings:
Endometrial hyperplasia/cancer
Leiomyomas
Polyps
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.

Menopausal hormone therapy (MHT)

Estrogen therapy (ET):
 Effective at treating:
Vasomotor symptoms: hot flushes, night sweats → sleep disturbances
Mood symptoms in peri- (but not post-) menopause
GSM: vaginal dryness, dyspareunia
Routes of therapy:
Systemic therapy: oral, transdermal patches, topical gels
Vaginal therapy: creams, vaginal tablets, ring
Selection of route and dosing:
Give continuously.
Transdermal is usually preferred for vasomotor symptoms.
Vaginal ET is preferred when treating GSM only.
Estrogen stimulates endometrium → progestin required if patient has uterus
Progestins:
Higher risk of adverse events than estrogen therapy
Required for endometrial protection in patients with uterus
Selection of route and dosing:
Usually oral
Give cyclically if still menstruating regularly.
Give continuously if post-menopausal.
Candidates for therapy:
Patients within 10 years of menopause
Patients < 60–65 years of age
Symptoms severe enough to affect quality of life
No contraindications
Contraindications to MHT include history of:
Hormone-sensitive breast cancer
High-risk endometrial cancer
Unexplained vaginal bleeding
Cardiovascular disease
Venous thromboembolism
Stroke or transient ischemic attack (TIA)
Acute liver 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
Cardiovascular disease
Deep venous thrombosis and stroke
Gallbladder disease
MHT ↓ risk of:
Osteoporosis
Colorectal cancer
All-cause mortality

Other management options for vasomotor symptoms

Selective estrogen receptor modulators (SERMs):
Modulate effects of estrogen
Different effects (agonist vs. antagonist) in different tissue types
Common examples:
Raloxifene (agonist in bone, antagonist in breast and uterus)
Bazedoxifene
Ospemifene (specifically for GSM)
Non-hormonal medications:
Selective serotonin reuptake inhibitors (SSRIs): Paroxetine is the only FDA-
approved SSRI.
Serotonin-norepinepherine reuptake inhibitors (SNRIs)
Gabapentin
Clonidine
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.
Stress management

Management options for GSM

Low-dose vaginal estrogen:
Most effective treatment
Doses are low enough that progestins are not required for endometrial
protection.
Vaginal lubricants
Vaginal moisturizers
Regular sexual activity or use of dilators

Recommended health screening for menopausal women

 Table: Health screening tests for menopausal women

Test Frequency

Cervical cytology Up to age 65/every 3 years

Diabetes testing At age 45/every 3 years

Colonoscopy At age 50 (45 if at high risk)/every 10 years

Mammography At age 40/annually

Bone mineral At age 65/every 2 years if risk factors are

density present

Differential Diagnosis
Primary ovarian insufficiency (POI): a condition characterized by impaired
ovarian function in women < 40 years of age. Symptoms are identical to
menopause, including amenorrhea, 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,
addressing fertility concerns, and counseling.
Abnormal uterine bleeding (AUB): preferred term for uterine bleeding outside
normal parameters, and includes heavy and irregular bleeding. Common causes
include leiomyomas, polyps, endometrial hyperplasia or malignancy,
coagulopathy (especially in younger women), and ovulatory dysfunction.
Diagnosis usually requires endometrial biopsy and pelvic ultrasound.
Management depends on underlying etiology. Important to exclude pathologic
causes of AUB in perimenopausal women.
Anxiety disorders: can cause hot flushes, palpitations, and mood symptoms,
similar to menopause. Often, these conditions may co-exist with menopause.
Management may include SSRIs, SNRIs, other anxiolytics, and psychotherapy.
References

1. Casper, R.F. (2020). Clinical manifestations and diagnosis of menopause. In Martin, K. A. (Ed.),
UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/clinical-
manifestations-and-diagnosis-of-menopause
2. Martin, K. A., and Barbieri, R. L. (2020). Treatment of menopausal symptoms with hormone
therapy. In Mulder, J.E. (Ed.), UpToDate. Retrieved February 4, 2021, from
https://www.uptodate.com/contents/treatment-of-menopausal-symptoms-with-hormone-therapy
3. Martin, K. A., and Barbieri, R. L. (2020). Menopausal hormone therapy: benefits and risks. In
Mulder, J.E. (Ed.), UpToDate. Retrieved February 4, 2021, from
https://www.uptodate.com/contents/treatment-of-menopausal-symptoms-with-hormone-therapy
4. Welt, C. K. (2019). Ovarian development and failure (menopause) in normal women. In Martin, K. A.
(Ed.), UpToDate. Retrieved February 4, 2021, from https://www.uptodate.com/contents/ovarian-
development-and-failure-menopause-in-normal-women

5. Schorge J.O., Schaffer J.I., et al. (2008). Williams Gynecology (1st ed. pp. 468-491).
6. Kaunitz, A.M., Manson, J.E. (2015). Clinical expert series: Management of menopausal symptoms.
Obstetrics & Gynecology. Vol. 126(4), pp. 859-876.

7. Committee on Practice Bulletins-Gynecology. (2014). Practice bulletin: Management of

menopausal symptoms. Obstetrics & Gynecology.