Physiology of Menopause Timothy Rowe University of British Columbia - - PowerPoint PPT Presentation

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Physiology of Menopause

Timothy Rowe

University of British Columbia

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I have received consulting fees and honoraria for speaking from Pfizer Canada Inc. I have no other competing or potentially competing interests

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Wh What I want to talk about

• Apoptosis and the ovary
• Endocrine changes
• Neurological changes
• Bone and joint changes
• Urogenital changes
• Cardiovascular changes

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Ov Ovarian res eser erve e fr from

• m con
• ncep

eption

• n to
• men

menop

• pause

Wallace WH, Kelsey TW. PLoS One 2010 Jan 27;5(1):e8772.

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Apo Apoptosi sis s and nd ovarian n rese serve

• During fetal life, apoptosis primarily involves the
• ocyte
• After birth, and in adult life, it involves primarily

follicular granulosa cells, although oocytes in primordial follicles may also be affected

• 99.9% of follicles present at birth never reach the

stage of ovulation, but undergo atresia

• The reduction in oocyte complement < 38 years is

due to both oocyte loss and accelerated follicular growth; in women > 38 years it is solely due to faster initiation of growth

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Harlow SD et al. J Clin Endocrinol Metab 2012:97:1159-68

ST STRAW + 10 Staging System for Reproductive Aging

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Wh What I want to talk about

• Endocrine changes

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Da Daily hormone levels in women in mid-re reproductive age and older re reproductive age

Santoro N et al. J Clin Endocrinol Metab 2003;88:5502-9

22 women (either mid- reproductive age or older reproductive age) underwent daily pelvic ultrasound and blood sampling

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Age and menstrual cy cycl cle length

Treloar et al. Int J Fertil 1967;12:77-126

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Tr Trajectory of E2

2 ch

changes ( (SWAN)

Tepper PG et al. J Clin Endocrinol Metab 2012;97:2872-80

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Tr Trajectory of E2

2 ch

changes ( (SWAN)

Tepper PG et al. J Clin Endocrinol Metab 2012;97:2872-80

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FS FSH, In Inhib ibin in-B, B, AMH levels

Hale GE et al. J Clin Endocrinol Metab 2007;92:3060-7

77 women aged 21-35 or 45-55 submitted three blood samples weekly

• ver one menstrual cycle

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DH DHEA-S S levels s (SWAN)

Crawford S et al. J Clin Endocrinol Metab 2009;94:2945-51

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Te Testosterone levels (MWMH)

Burger HG et al. Menopause 2008;15:603-12

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Wh What I want to talk about

• Endocrine changes
• Neurological changes

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Ch Changes i in n neurological f function a associated wi with m menopause

• Change in cognitive function
• Mood change (chiefly

depression)

• Sleep disturbance
• Vasomotor symptoms

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De Death th from m ne neur urological or me mental di disease in n wome men n with th su surgical menopause se < < 45

Rivera CM et al. Neuroepidemiol 2009;33:32-40

Hazard ratio 5.24 95% CI 2.02-13.6 P <0.001

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Mech Mechanism sms s of es estrogen en ne neur uropr protectio tion

Scott E et al. Front Neuroendocrinol 2012;33:85-104

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Ch Change i in c cognitive f function a across m menopausal t transition

Weber MT et al. Menopause 2013;20:511-17

117 mid-life women assessed according to reproductive stage

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Change in verbal memory y across menopause

Immediate verbal memory Delayed verbal memory

Epperson CN et al. J Clin Endocrinol Metab 2013;98:3829-38

403 women monitored over 14 years

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Cogn Cognitive a agi ging i g in m mid-lif life women n (SWAN) N)

2124 participants, average age 54, followed for a median 6.5 years

• Cognitive speed declined by a mean of 4.9% over 10

years

• Verbal episodic memory (delayed testing) declined by

a mean of 2% in 10 years

• Working memory and verbal episodic memory

(immediate testing) did not decline significantly

• Possible interventions to slow cognitive aging in these

domains were not identified in this study

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De Depressive symptoms in perimenopause vs pr premeno nopaus pause and and po postmeno nopaus pause: : a meta-analy analysis is

De Kruif M et al. J Affect Disord 2016;206:174-80

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Pr Prevalence of sleep difficulty across the the me menopausal tr trans nsiti tion n (S (SWAN) AN)

Kravitz HM, Joffe H. Obstet Gynecol Clin North Am 2011;38:567-86

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Ne Neurological symptoms in th the menopausal tr transiti tion

Brinton RD et al. Nat Rev Endocrinol 2015;11:393-405

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Va Vasomotor symptoms and LH levels

Casper & Yen. J Clin Endocrinol Metab 1981:53:1056-8

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Ne Neuroki kinin B m-RN RNA e expressi ssing n g neurons be before e and and after er oopho phorect ectomy y

Rance NE et al. Front Neuroendocrinol 2013;34:211-27

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Po Postmenopausal changes in neuronal activity

Rance NE et al. Front Neuroendocrinol 2013;34:211-27

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KN KNDy ne neur urons, ns, GnRH nRH ne neur urons, ns, and nd the the he heat-de defenc nce mec mechan anis ism

Vasodilatation

heat defence effectors Rance NE et al. Front Neuroendocrinol 2013;34:211-27

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Total duration of vasomotor sym ymptoms (SWAN)

Avis NE et al. JAMA Intern Med 2015;1754:531-9

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Wh What I want to talk about

• Endocrine changes
• Neurological changes
• Bone and joint changes

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Ve Vertebral osteoporosis

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Os Osteo eocl clastogen enesi esis and and the the RANK NK/RANK NKL L in interac actio tion

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Ch Change i in b bone re resorption (S (SWAN)

Sowers MR et al. J Clin Endocrinol Metab 2013;98:2854-63

NTx = urinary type 1 collagen N-telopeptide

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Age (years) Relative BMD (BMD at age 30=100%)

Faulkner KG. J Clin Densitom 1998;1:279-85

60 70 80 90 100 30 40 50 60 70 80 90

Forearm Spine Hip and heel

Bo Bone lo loss rates es for women en

(%)

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Risk fact ctors for osteoporosis

Risk for low bone mass

Advanced age Female sex White or Asian race Thin body build (body weight <57 kg) Early menopause Estrogen deficiency Positive family history Chronic use of corticosteroids Lifestyle: inadequate calcium intake, cigarette smoking, excess alcohol intake, or lack

• f physical activity

Risk for fracture

Existing fracture Reduced BMD Positive family history of

• steoporotic fracture

Advanced age Smoking Propensity to falls Postural instability

Osteoporosis Society of Canada. Osteoporosis Update 1999

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Es Estrogen e effects o s on a articular t tissu ssues

Roman-Blas JA et al. Arthritis Res Ther 2009;11:241-55

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Pr Prevalence of osteoarthritis by age

Van Saase JLCM et al. Ann Rheum Dis 1989;48:271-80