Menopause Professor Susan Davis Women’s Health Program Department of Medicine Alfred Hospital, Monash University.

Menopause The last menstrual bleed in a woman with an intact uterus Permanent loss of ovarian follicular development Loss of cyclical production of estradiol, progesterone and testosterone.

Primordial follicles Fundamental reproductive units of the ovary pool of non-growing follicles from which all dominant preovulatory follicles are selected – formed between 6-9 months of gestation – Only 400 will complete development and undergo ovulation/corpus luteum formation → others die by atresia – Continued decline in number - by menopause primordial follicles difficult to find

7.5 MILLION 20 WEEK FETUS 300,000BIRTH 25,00037 YEARS 51 YEARS1000 Age of reaching critical threshold of 25,000 varies from late 20’s to 40’s → age alone has limited predictive value for determining ovarian reserve AFTER MENOPAUSE FEW/ NONE LEFT FOLLICULAR DEPLETION AND AGE

B B B B B J H HHH F F F F F F F Age in Years J Richardson et al., J.C.E.M., Autopsy data, women 7-44yrs Women in menopausal transition with regular menses Perimenopausal women Postmenopausal women Primordial Follicles / Ovary Natural menopause is a consequence of follicular depletion

Follicular health Every month ~ 500 ova develop activated by BMP15 and GDF9 Ova go through phase of growth, then atresia As oocyte numbers decline so does the oocyte quality. The ANTRAL follicle count in the follicular phase is a good predictor of IVF outcome AGE predicts fertility

Growth differentiation factor (GDF)9 bone morphogenetic protein-15 (BMP-15) + - AMH produced by small preantral follicles Puts a “break” on follicluar development

Endocrinology of Menopause Ovarian follicle number falls Inhibin B secretion decreases FSH secretion increases and maintains or increases estradiol and inhibin A secretion

Progressive decline in follicle numbers, inhibin B Progressive rise in FSH Late fall in E2, inhibin A Pre-menopausal fall in testosterone, but maintenance across menopausal transition The Aging Female Reproductive Axis

Copyright ©1999 The Endocrine Society Burger, H. G. et al. J Clin Endocrinol Metab 1999;84: The fall in inhibin B and the increase in FSH constitute markers of ovarian aging.

Anti-Müllerian Hormone (AMH) Produced by fetal testes Inhibits the development of the mullerian tract in utero ( the default option) A product of growing ovarian follicles

AMH is a principal regulator of early follicular recruitment from the primordial pool The concentration of AMH in blood may also reflect the non- growing follicle population, i.e. the ovarian reserve AMH concentrations are relatively stable across the menstrual cycle but decline with age -the rate of decline is unknown in an individual. Low levels indicate diminished ovarian reserve Low levels predict approaching menopause. Anti-Müllerian Hormone (AMH)

Earliest signs of the menopause transition Irregular menses Lighter menses Symptoms of estrogen insufficiency Symptoms of estrogen excess

Hormonal patterns through the menstrual cycle in a woman providing samples three times weekly on an annual basis (36, 25, 17, and 7 mo before final menses). The hormone levels in the top left panel are typical of an anovulatory cycle. E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, progesterone. Copyright © 2014 Menopause. Published by Lippincott Williams & Wilkins. 14 Cycle and hormone changes during perimenopause: the key role of ovarian function Cycle and hormone changes during perimenopause: the key role of ovarian function Burger, HG et al Menopause 2005;12:

Schematic luteal-out-of-phase(LOOP)event Hale GE et al Menopause 2009

Menopause Average age 51.5 years 1 in 10 women reach menopause before the age of 45

Definitions MENOPAUSE is – the last menstrual period in a woman who has not had a hysterectomy Perimenopause is – the time from the onset of cycle irregularity through until 12 m after the last menstrual period Surgical menopause is – Removal of both ovaries

Definitions Menopause is diagnosed after hysterectomy – on the basis of a symptoms/blood tests on occasion. Premature ovarian insufficiency is defined – as cessation of ovarian function occurring before the age of 40 years.

Premature ovarian insufficiency CAUSES: Genetic/cytogenetic – Fragile X syndrome Enzymatic defects Immune disturbances Defects in gonadotropin structure or actions Physical insults Ionizing radiation Chemotherapy Viral infection Cigarette smoking Surgery Idiopathic – most common

Premature ovarian insufficiency AMH serum levels in women with autoimmune- POI, idiopathic POI, postmenopausal women, and healthy control women. La Marca A et al. JCEM 2009;94: Error bars represent 10th and 90th percentiles

Fragile X syndrome One of the most common causes of mental retardation characterized by hyperactivity, autism-like behavior, attention deficits, elongated face, prominent jaw and large ears. Expansion of an unstable CGG repeat in the 5′ untranslated region of the fragile X mental retardation (FMR)1 gene on X chromosome – 7-44 repeats normal; repeats “gray zone” or borderline risk, – repeats is pre-mutation; – >200repeats=full syndrome). 1 in 4000 males and 1 in females worldwide have Fragile X Cronister Obstet Gynecol 2008

∼ up to 28% of female fragile X pre-mutation carriers develop premature ovarian failure. 1 in 10 women with premature ovarian insufficiency had a FMR1 mutation in a US study. paternally inherited pre-mutations (PIP) were more likely to give rise to POF than were maternally inherited pre-mutations (MIP). Fragile X syndrome

Consequences of the menopause Loss of ovarian cyclical oestrogen, progesterone and testosterone production. following menopause, adipose tissue continues to produce some oestrogen from androgen precursors primarily of adrenal gland origin.

Ethnic differences AGE OF MENOPAUSE Same age at menopause Asian + Caucasian women Earlier menopause African-American / Latina women / Filipino / Malay women in developed countries Developing countries Rural women High altitudes SYMPTOMS Higher frequency African-American + Hispanic – vaginal dryness Lower frequency Asian women ( less flushes and more joint pain)

2. Clinical consequences of the menopause These are due primarily to the loss of ovarian oestrogen production Symptoms can be debilitating Tissue oestrogen insufficiency contributes to the pathophysiology of – central weight gain, – insulin resistance, – cardiovascular disease risk, – dementia and – osteoporosis.

Symptoms These can start several years before menopause Even whilst regular menstruation is occurring Due to changing hormone levels Symptoms may last for MANY years in some women THERE IS NO CUT-OFF AGE AT WHICH SYMPTOMS BEGIN OR END

Commonly reported menopausal symptoms include hot flushes night sweats crawling sensations on skin anxiety irritability sleep disturbances lessened memory lessened concentration vaginal dryness Low libido fatigue muscle/joint pains overall diminished wellbeing depression Vasomotor symptoms (VMS)

Vasomotor symptoms- hot flushes and night sweats A sensation of heat/sweating – head, neck, chest + face /chills/clamminess/anxiety; → many have premonition of flush occurring Duration 1-5 minutes Triggered by small elevations in core body temperature acting within a reduced thermoneutral zone in symptomatic menopausal women. Different from response to warming May be provoked by warming When measured objectively, women under-report flushes

Sweating threshold Shivering threshold ASYMPTOMATICSYMPTOMATIC Hot flush Sweating threshold Thermoneutral zone Shivering threshold TcTc Tc Tc Freedman RR. Semin Reprod Med 2005;23:117 Thermoneutral zone Small core body temperature (Tc) elevations acting within a reduced thermoneutral zone trigger hot flushes in symptomatic postmenopausal women

Skin temperature The mean skin temperature increases a few degrees centigrade during the few minutes surrounding the hot flushes Peripheral vasodilatation, as evidenced by increased skin temperature, occurs in all body areas that have been measured These areas include fingers, toes, cheek, forehead, forearm, upper arm, chest, abdomen, back, calf and thigh Finger blood flow, hand, calf and forearm blood flow increase during hot flushes Freedman RR. Fertil Steril 1998;70:332–7; Freedman RR. Fertil Steril 2000;74:20–3

Other changes There is a small core temperature elevation preceding the hot flushes in 65% of symptomatic women Metabolic rate is increased during the period surrounding the hot flush Sweating occurs during 90% of hot flushes Heart rate increases by approximately 7–15 beats/min Freedman RR. Fertil Steril 1998;70:332–7; Freedman RR. Fertil Steril 2000;74:20–3

Mechanism of flushing Estrogen deficiency? But flushes do not occur in: pre-pubertal girls Turner’s syndrome (unless primed with estrogen) 25% of menopausal women older postmenopausal women

E strogen withdrawal does not explain the etiology of hot flushes There are no correlations between hot flush occurrence and plasma, urinary and vaginal levels of estrogens plasma levels between asymptomatic and symptomatic women not different Clonidine reduces hot flush frequency without changing circulating estrogen levels Estrogen withdrawal is necessary to explain the occurrence of hot flushes, but is not, by itself, sufficient to do so

Duration vasomotor symptoms Duration vasomotor symptoms Politi et al 2008

Bone loss Increased bone reabsorption Due to fall in estrogen production

Osteoporosis in Postmenopausal Women Osteoporosis is a consequence of disordered bone remodeling that results in bone loss and destruction of bone architecture Agents that reduce bone turnover to premenopausal levels have been shown to prevent bone loss and, in women with osteoporosis, to reduce fracture risk.

Physical consequences: Urogenital : – Stress and urge incontinence – Vaginal atrophy

Genito-urinary symptoms Vaginal – Dryness – Loss of lubrication – Dyspareunia (painful intercourse) – Vaginitis – Discharge – Vulval itching and burning Urological – Frequency of urination – Recurrent cystitis (bladder infections) – Dysuria (pain or burning on urination) – Urge incontinence – Stress incontinence – Mixed incontinence

Physical consequences: Bone loss – Increased bone reabsorption Stress and urge incontinence Central abdominal weight gain Conversion to a more adverse lipid profile

Weight gain at midlife is NOT due to hormonal changes of the menopause  Body mass index (BMI) does not differ between premenopausal and postmenopausal women, after adjusting for age and other covariants (Matthews KA et al. Int J Obes Relat Metab Disord 2001;25:863–73)  The steady weight gain in women (approx 0.5 kg/year) is due to age rather than the menopause (Sternfeld B et al. Am J Epidemiol 2004;160:912–22)

Change in body fat distribution at menopause. Carr M C JCEM 2003;88:

Menopause and lipids Cholesterol Triglycerides LDL HDL HDL 2 HDL 3 Apo B Apo AI Lipoprotein(a) Stevenson et al. Atherosclerosis 1993;98:83–90

Endothelial function is impaired by loss of oestrogen at menopause Menopausal Flow-mediated dilatation (FMD) *p < 0.01 Arrowood, et al. Circulation 2000;A514 *

Consequences of obesity in women at midlife Increased risk of cardiovascular disease including coronary artery disease, hypertension and stroke Increased risk of dementia Increased risk of breast, uterine and colon cancer Increased likelihood of depression Greater likelihood of sexual dysfunction

Menopause and depression 1 in 3 women experience severe psychological symptoms (depression, anxiety) at menopause The average lifetime prevalence of depression in women is approximately 20% and 13% of middle aged Australian women report having had a diagnosis of depression by a doctor Women with a history of depression are 5x as likely to be diagnosed with depression during the perimenopause, Women with no history of depression are 2-4x more likely to have a diagnosis compared with premenopausal women Pattern of depression different to that of major depression

Conclusions Menopause is a natural event but it has serious pathophysiological consequences: Vasomotor instability Mood effects Adverse effects on body composition result in – CVD – Diabetes – Dementia – Osteoarthritis – Cancer- breast, endometrial and colon – Depression