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Menopause-diagnosis and management

Menopause –A biological stage in a woman’s life that occurs when she stops menstruating and reaches the end of her natural reproductive life 
( NICE 2019 )

Perimenopause –Also called climacteric ( Greek- rung of ladder ) NICE – time in which a woman has irregular cycles of ovulation and menstruation leading up to menopause and continuing until 12 months after her final period It is the time when endocrinological , biological and clinical features of approaching menopause commence Avg age 45-47 Irregular cycles of ovulation and menstruation 
( shortening follicular phase and anovulatory cycles ) Ends 12 months after the last menstrual period

Early menopause -less than 45 yrs

Premature menopause –Menopause before age of 40 yrs also called ” premature ovarian insufficiency” or “premature ovarian failure”
Causes include toxic exposure , chromosomal abnormality or autoimmune disorder , medical or surgical treatment

Postmenopause –time after menopause has occurred , starting when a woman has not had a period for 12 consecutive months ( NICE )

What happens –Menopause happens when the pool of ovarian follicles is depleted New research has shown that after age 40
- primordial follicles reduce in number rapidly
- there is a decrease in inhibin B secretion
- an increase in FSH that can maintain or increase estradiol and inhibin A secretion until follicular exhaustion happens Therefore menopause is not a central event ( changes happen in HPP hormones )- ie it is rather a primary ovarian failure Ovaries fail to respond to the pituitary hormones ( FSH and LH ) with eventual cessation of ovarian estrogen and progesterone production Since the ovarian-HPP axis is intact- FSH levels rise in response to ovarian failure and due to lack of negative feedback from the estradiol ( Bruce & Rymer , 2009 ) Cycles become irregular Three kind of estrogens exist – among them estradiol is the most important . After menopause a little amount is still produced by the fat cells which provide the supporting tissue around the ovaries ( peripheral aromatization )

Epidemiology and burden of menopause

Woman at menopause still have 3rd of life expectancy ahead of them The median age of meopause is 51 yrs ( Khaw, 1992 ; Morabia & Costanza , 1998 ) The most common troublesome symptoms of menopause include
- depressive disorders
- sleep disorders ( insomnia )
- sexual dysfunction ( e.g libido disorders , genital inflammation and painful sexual intercourse )
- discomfort associated with muscle pain
- joint aches
- osteoporosis
- characteristic hot flushes ( disabling in 10 % to 15 % cases ) Risk of depressive disorders increases in the perimenopausal and premenopausal period and decrease in the postmenopausal period Its a universal phenomenon in women who live beyond the age of 50-55 yrs Age at menopause seems to be genetically determined- it is not affected by race , socioeconomic status , age at menarche or the number of prior ovulations In the USA about 1.3 million women become manopausal each year -typically this starts between ages of 51-52. About 5 % of women suffer early menopause between ages 40-45 and 1 % of women experience premature menopause before age 
40 ( Peacock et al 2019 ) Smokers are more likely to experience menopause 2-3 yrs before non-smokers

Diagnosis of menopause – NICE

Age 45 and over with menopausal symptoms
 perimenopause based on vasomotor symptoms and irregular periods Menopause -no period for 12 months and are not using hormonal contraception Menopause based on symptoms in women without a uterus.

Tests not recommended by NICE –The following blood tests should not be used in women aged 45 and over for diagnosis of perimenopause or menopause
 ani-Mullerian hormone inhibin A and B oestradiol antral follicle count ovarian volume

The reason of this recommendation is that menopause is usually obvious by history alone.

FSH for diagnosis –women who are 40-45 yrs with symptoms of menopause , including a change in their menstrual cycle women who are less then 40 yrs in whom menopause is suspected.

Interpretation can be difficult if a woman is taking hormonal treatments for e.g for heavy periods.

Premature ovarian insufficiency –Women aged less than 40 if they have
 menopausal symptoms including no or infrequent periods and elevated FSH levels on 2 blood samples taken 4-6 weeks apart do not diagnose on the basis of a single blood test do not routinely use anti-Mullerian hormone test.

Problem-Vasomotor symptoms
♦ hot flushes- due to vasomotor instability
- episodes can last from 30 seconds to 5 minutes
- almost all perimenopausal women suffer some degree of hot flushes
- these vasomotor symptoms are more likely to occur in late peri and early menopause ( Harlow et al , 2012 )
-approximately 75 % of postmenopausal women experience hot flushes that persist for 6 months to 5 yrs and about a 3rd of this group is severely affected ( Karanth et al 2019 )-
♦ night sweats
 Urogenital symptoms-vagina has several epithelial layers ( mucosa , muscularis and adventia ) decreased estrogen causes the mucosa to become drier , thinner leading to atrophy
Vulva , vagina , urethra and trigone of bladder all have large number of estrogen receptors

♦ vaginal dryness
♦ irritation , discharge 
♦ dyspareunia
♦ postcoital bleeding
♦ prolapse
♦ recurrent UTI’s
♦ urinary frequency , urgency
♦ dysuria ,voiding difficulties
♦ urinary incontinence

Approximately 60 % of women experience urogenital symptoms
 Psychological symptoms
♦ Depression and mood change ( common )
♦ Anxiety / irritability
♦ Memory loss
♦ Poor concentration
♦ Sleep disturbance ( common )

It is estimated tha about 20 % of women have depression at some point during menopause
( Soares et al 2004 )
 Musculoskeletal symptoms ( common )
♦ joint and muscle aches and pains
 Osteoporosis – due to imbalance of osteoclastic and osteoblastic activity- more bone is being reabsorbed and overall bone loss
 Sexual disorders ( common ) DSM V classification
♦ disorders or lack of sexual desire
♦ sexual arousal disorder
♦ orgasmic disorders

 sexual disorders associated with pain
( dyspareunia )

Symptoms management

Vasomotor symptoms –NICE recommends hormone replacement therapy ( HRT ) for vasomotor symptoms It is known that HRT given continuously or cyclically is extremely effective against hot flushes ( Greendale GA et al , 1998 ) NICE states not to routinely offer SSRIs ot SNRIs or clonidine as 1st line for treatment of vasomotor symptoms only A Cochrane review Karanth et al 2019 concludes that
○ nonhormonal agents have demonstrated efficacy in reducing hot flushes and night sweats
○ SSRIs ( citalopram , paroxetine , sertraline , fluoxetine ) and SNRIs ( as desvenlafaxine and venlafaxine ) have been the most investigated group
○ they seem to be attractive alternative because fof their wide use and favorable safety profile demonstrated in various settings
○ is not clear how they work
○ studies have shown mixed results ( for eg some have demonstrated reduction in hot flushes by 50-50 % others as NAMS 2015 have reported no effect ).

Psychological symptoms –NICE recommends HRT and CBT NICE states that there is no clear evidence for SSRIs or SNRIs to ease low mood in menopausal women who have not been diagnosed with depression Studies have shown that women with previous histories of PMS or postpartum depression are at increased risk of new onset and recurrence of a major depressive episode ( Parry , 2010 )

Altered sexual function –NICE recommends testosterone supplementation if HRT alone is not effective.

Urogenital atrophy –Vaginal oestrogen is the treatment of choice Vaginal oestrogen can be given to women who are taking systemic HRT as well Vaginal oestrogen treatment can be continued for as long as needed to relieve symptoms Following advice from the menopause clinic/ specialist vaginal oestrogen can be used in women in whom systemic HRT is contraindicated Consider increasing the dose ( following advice from menopause clinic / specialist if symptoms are not relieved Lubricants and moisturizers can be used alone or in addition to vaginal oestrogens Routine monitoring of endometrial thickness during treatment for urogenital atrophy is not required.

Referral- Treatment does not improve symptoms Ongoing troublesome side effects HRT is contraindicated Uncertainty about the most suitable treatment options Women who are at high risk of breast cancer ( women who are on tamoxifen for breast cancer should not be offered paroxetine or fluoxetine ) if their is doubt about diagnosis of premature ovarian insufficiency symptoms and bloods lead to a diagnosis of premature ovarian insufficiency

References

  1. Menopause: diagnosis and management
    NICE guideline Published: 12 November 2015 www.nice.org.uk/guidance/ng23
  2. Ratner, S, and D Ofri. “Menopause and hormone replacement: Part 1. Evaluation and treatment.” The Western journal of medicine vol. 174,6 (2001): 400-4. doi:10.1136/ewjm.174.6.400 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071429/
  3. Makara-Studzińśka, Marta Teresa et al. “Epidemiology of the symptoms of menopause – an intercontinental review.” Przeglad menopauzalny = Menopause review vol. 13,3 (2014): 203-11. doi:10.5114/pm.2014.43827 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520365/
  4. Peacock K, Ketvertis KM. Menopause. [Updated 2019 Nov 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507826/
  5. Perlman, Barry; Kulak, David; Goldsmith, Laura T.; Weiss, Gerson The etiology of menopause: not just ovarian dysfunction but also a role for the central nervous system, Global Reproductive Health: June 2018 – Volume 3 – Issue 2 – p e8 doi: 10.1097/GRH.0000000000000008 https://journals.lww.com/grh/FullText/2018/06000/The_etiology_of_menopause__not_just_ovarian.1.aspx
  6. The physiology of the menopause. Barbo DM. 1987 Jan;71(1):11-22. ( Abstract )
  7. Dalal, Pronob K, and Manu Agarwal. “Postmenopausal syndrome.” Indian journal of psychiatry vol. 57,Suppl 2 (2015): S222-32. doi:10.4103/0019-5545.161483 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539866/
  8. Physiology and endocrinology of the menopause Henry G Burger Menopause and HRT

    Medicine Volume 34, Issue 1, 1 January 2006, Pages 27-30

  9. Parry, Barbara L. “Optimal management of perimenopausal depression.” International journal of women’s health vol. 2 143-51. 9 Aug. 2010, doi:10.2147/ijwh.s7155
  10. Karanth  L, Chuni  N, Nair  NS. Antidepressants for menopausal symptoms. Cochrane Database of Systematic Reviews 2019, Issue 9. Art. No.: CD013417. DOI: 10.1002/14651858.CD013417. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013417/full
  11. The Meanings of Menopause: Identifying the Bio-Psycho-Social Predictors of the Propensity for Treatment at Menopause Helena Rubinstein
    Lucy Cavendish College, The University of Cambridge https://core.ac.uk/download/pdf/20332262.pdf
  12. Laura RS. From menstruation to menopause: Have we medicalised the physiology of normalcy? (Part 1). Women Health Open J. 2017; 3(3): e27-e29. doi: 10.17140/WHOJ3-e016 

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