Primary Care Reports – Managing Menopausal Symptoms and the Role of Hormone Replacement Therapy by Global Business Media

SPECIAL REPORT

Managing Menopausal Symptoms and the role of Hormone Replacement Therapy

Effectiveness of Transdermal Estradiol and Natural Micronised Progesterone for Menopausal Symptoms Glands and Hormones Part 1 – The Pituitary and the Pineal Glands and Hormones Part 2 – The Thymus, Thyroid, and Pancreas Testes Glands and Hormones Part 3 – The Testes and Ovaries The Skin as a Mechanism to Deliver Hormone Replacement Therapy (HRT) and as a Beneficiary

Published by Global Business Media

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

SPECIAL REPORT

Managing Menopausal Symptoms and the role of Hormone Replacement Therapy

Contents Foreword

John Hancock, Editor

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org

The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles. © 2017. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

Effectiveness of Transdermal Estradiol and Natural 4 Micronised Progesterone for Menopausal Symptoms Dr Louise R Newson BSc(Hons) MBChB(Hons) MRCP FRCGP GP and Menopause Expert, Spire Parkway Hospital, Damson Parkway, Solihull B91 2PP

HRT ‘Scares’ are Unfounded Evidence to support HRT Contraindications to HRT Type of HRT Transdermal Oestrogen Type of Progestogen Endometrial Protection Adherence Oestrogel® and Utrogestan® 100 mg Summary

Glands and Hormones Part 1 – 10 The Pituitary and the Pineal Joanna Fischer, Medical Correspondent

The Pituitary Gland and the Hypothalamus The Pineal Gland - Let There Be Light Summary

Glands and Hormones Part 2 – The Thymus, Thyroid, and Pancreas Testes

Dr Charles Easmon, Editor

The Thymus The Thyroid The Adrenal Glands The Pancreas Summary

Glands and Hormones Part 3 – The Testes and Ovaries 14 Joanna Fischer, Medical Correspondent

The Testes The Ovaries What Makes a Man a Man and a Woman a Woman – Transgender and Non-‘Binary’ The Menopause Summary

The Skin as a Mechanism to Deliver Hormone 16 Replacement Therapy (HRT) and as a Beneficiary John Hancock, Editor

The Skin as a Safe Vehicle for HRT Perfect Skin Summary

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Foreword T

HE JOB of a messenger is to get a message

expect to feel more tired, gain weight, suffer mood

from point A to point B in the most effective

swings, depression and anxiety as a minimum.

way possible with minimal damage to the content

As a General Practitioner you should ideally

and the ‘carrier’ as possible. Skin is an effective

follow the National Institute for Health and Care

and safe way of getting hormone replacement into

Excellence (NICE) Guidance based on the symptoms

the female body.

of any women 452 or over without the need for

Hormones are messengers. They are mainly secreted from glands. If all our glands were collected,

inconclusive blood tests. If she tells you she is suffering then treat.

bagged up and thrown away we would be talking of

Despite seeing the value of HRT, we must also ask

a small bag under a kilogram but the effect would

is it safe3 and if not what should we do? As clinicians,

be devastating to our functioning and quality of

we are used to asking personal and family history

life in ways predictable and unpredictable. As they

and for HRT this is, itself, our risk assessment. If the

age, women have a significant reduction in their

women has a clear history of breast cancer4 or family

oestrogen and progesterone levels and the debate

history of blood clots then HRT’s risk/benefit analysis

will always rage about does this matter and if it’s

is not likely to be favourable and if surgery is required

a natural process why disrupt it? The best answer,

whilst on HRT it must be considered as a risk factor

backed up by hundreds of scientific studies, is to

for blood clots5. Skin-based HRT reduces these risks

ask a woman who has had hormone replacement

and this should be your preferential recommendation.

therapy how she felt before and after1. The answer is usually positive or very positive in that, without higher levels of progesterone and oestrogen, women can

Dr Charles Easmon Editor

References: 1

https://www.nice.org.uk/guidance/ng23/chapter/Recommendations#individualised-care Accessed 11/6/17

https://www.nice.org.uk/guidance/qs143/chapter/Quality-statement-1-Diagnosing-perimenopause-and-menopause Accessed 11/6/17

https://www.nice.org.uk/news/press-and-media Accessed 11/6/17

4 5

http://bit.ly/2rNFrsz Accessed 11/6/17 https://www.nice.org.uk/guidance/cg92/chapter/1-Recommendations#assessing-the-risks-of-vte-and-bleeding-2 Accessed 11/6/17

WWW.PRIMARYCAREREPORTS.CO.UK | 3

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Effectiveness of Transdermal Estradiol and Natural Micronised Progesterone for Menopausal Symptoms Dr Louise R Newson BSc(Hons) MBChB(Hons) MRCP FRCGP GP and Menopause Expert, Spire Parkway Hospital, Damson Parkway, Solihull B91 2PP This article discusses the role of hormone replacement therapy (HRT) in the management of menopausal symptoms, and specifically considers the advantages of different types and preparations of HRT, based on the current medical evidence.

Around 75% of menopausal women experience symptoms, with around one third of these experiencing severe symptoms

4 | WWW.PRIMARYCAREREPORTS.CO.UK

HE MENOPAUSE is a normal life event for women, not an illness or a medical condition. However, the effects of the menopause often have a negative impact on women’s wellbeing and quality of life, and are frequently underestimated. Furthermore, the low oestrogen levels and other biological changes that occur in these women are also associated with an increased risk of cardiovascular disease,1 osteoporosis,1 diabetes2 and dementia.3 Menopausal and perimenopausal symptoms vary tremendously between women. The most common are the vasomotor symptoms (i.e. hot flushes and night sweats). Other symptoms include mood changes, memory loss, urogenital atrophy, a lack of interest in sex, sleep disturbances, and joint and muscle stiffness.1,4 These symptoms can be non-existent, last for a few years, or for some women they can last for decades.1 Around 75% of menopausal women experience symptoms, with around one third of these experiencing severe symptoms.5 The average age of the menopause in the UK is 51 years.1 However, perimenopausal symptoms commonly occur from age 45 years.6 Around one in a hundred women under 40 years have an early menopause, termed premature ovarian insufficiency (POI).7 Oestrogen is known to have an effect on many different systems in the body, including the brain, skin, bones, heart, blood vessels, urinary tract, vagina and breast.

Over the past century, life expectancy has increased hugely. This has resulted in many more women being affected by menopausal symptoms, which often adversely impact their work and daily life.8,9 Many women suffer in silence, and do not realise how effective HRT can be at improving both their symptoms and quality of life.

HRT ‘Scares’ are Unfounded Much of the negative publicity surrounding HRT stems from misinterpretation by the media of the findings from the Women’s Health Initiative (WHI) study,10 published more than a decade ago, and Million Women study.11 This has led to concerns among many women and healthcare professionals (HCPs) about the potential risks of HRT. As a result, numerous women have needlessly endured menopausal symptoms, and have also potentially increased their future risk of osteoporosis, cardiovascular disease and diabetes by not taking HRT.

Evidence to support HRT HRT is not a “one size fits all” treatment. The benefits and risks of HRT vary by dosage, route of administration, and timing of initiation.12,13 Data accumulated from numerous studies have shown that, in women under the age of 60 years with symptoms or other indications, initiating HRT near their menopause provides a favourable benefit:risk ratio. This is reflected in current

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

p-value for trend: 0.16

Absolute excess risk of CHD per 10,000 person-years

n=27,347 19

20 15 10 5 0 –5

–1

–2 50–59

60–69

70–79

Age at randomisation (years) WOMEN’S HEALTH INITIATIVE (WHI) STUDIES: HRT AND CHD – ABSOLUTE RISK BY AGE21

National Institute for Health and Care Excellence (NICE) and International Menopause Society (IMS) guideline recommendations.1,14 There is wide consensus about the positive safety profile of HRT, when taken by healthy perimenopausal or early postmenopausal women. Numerous studies have been published since the WHI study, which have confirmed the benefits of taking HRT. Symptoms of the menopause, such as hot flushes, mood swings, night sweats, sleep disturbances and reduced libido, all improve with HRT. There is also robust and compelling evidence to suggest that, in addition to a benefit on symptoms, HRT can also play a role in quality of life improvement, the prevention of coronary heart disease, osteoporosis and fracture risk, and reduction in mortality.10,15-17 No other treatments for menopausal symptoms have demonstrated a similar role. HRT preserves or even increases bone mineral density (BMD).18 HRT is associated with a reduced risk of total, hip, and vertebral fractures.19 Years since the menopause and age are now known to be important variables affecting the benefit: risk profile of HRT.20 Starting HRT less than 10 years after the menopause is associated with a reduction in death and cardiovascular disease, including CHD.15 Similarly, there is a trend for reduced risk of CHD associated with starting HRT at a younger age.15 I m p o r t a n t l y, H R T u s e i n y o u n g e r postmenopausal women also increases qualityadjusted life-years (QALYs) and is cost-effective.22

Contraindications to HRT As stated in the NICE guideline (NG23), consider referring women to a healthcare professional with expertise in menopause if: • T hey have menopausal symptoms and contraindications to HRT or

• There is uncertainty about the most suitable treatment options for their menopausal symptoms. As per the Summary of Product Characteristics of all HRTs, HRTs are contraindicated in patients with: • Known, past or suspected breast cancer • Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer) • Undiagnosed genital bleeding • Untreated endometrial hyperplasia • Previous or current venous thromboembolism (VTE) (e.g. deep venous thrombosis, pulmonary embolism) • Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency) • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal • Known hypersensitivity to the active substances or to any of the excipients • Porphyria.

Much of the negative publicity surrounding HRT stems from misinterpretation by the media of the findings from the Women’s Health Initiative (WHI) study

Type of HRT HRT is available mainly as oral or transdermal preparations, all of which contain oestrogen, either alone or combined with progestogen. The various types of HRT can differ with respect to the cardiovascular risks associated with their use, particularly oral versus transdermal preparations,1 and therefore the benefits and risks of taking HRT need to be carefully considered for each woman. Risk-benefit balance for symptomatic women treated with an optimised HRT delivering estradiol by the transdermal route in combination, if appropriate (women with an intact uterus), with micronised progesterone as the progestogen WWW.PRIMARYCAREREPORTS.CO.UK | 5

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

No increased risks of: Breast cancer Stroke Thromboembolism Gall bladder disease

Benefits: Improved quality of life Cardioprotection Fracture prevention

RISK-BENEFIT BALANCE OF HRT IN WOMEN EXPERIENCING CLIMACTERIC SYMPTOMS12

The various types of HRT can differ with respect to the cardiovascular risks associated with their use, particularly oral versus transdermal preparations,1 and therefore the benefits and risks of taking HRT need to be carefully considered

required for endometrial protection. This ratio remains favourable in asymptomatic women despite the lack of improved quality of life.

Transdermal Oestrogen Risk of venous thromboembolism The incidence and prevalence of VTE strongly increases with age.23 Risk factors for VTE include previous or family history of VTE, obesity and inherited thrombophilias, such as factor V Leiden or prothrombin gene mutations.24 The overall VTE risk increases about two-fold in women who take oral oestrogens.25 Even low-dose oestrogen use results in an increased VTE risk. High levels of oral oestrogen concentrate in the liver, which results in activation of the coagulation and activation factors of the renin angiotensin aldosterone cascade.26 In addition, oral (but not transdermal) oestrogens induce resistance to activated protein C, which is also a known risk factor for VTE.25 In contrast, data from observational studies have shown no association between VTE risk and use of transdermal oestrogens.27

for each woman

*Adjusted for family history of VTE and varicose veins and body mass index (BMI); †adjusted for BMI, history of or treatment for varicose veins, inherited thrombophilia, antiphospholipid syndrome, known or diagnosed cancer in the year before the index date, myeloproliferative disorders, inflammatory bowel disease, nephrotic syndrome, hypertension, cardiovascular and cerebrovascular diseases, smoking status and use of non-steroidal anti-inflammatory drugs or tamoxifen; ‡adjusted for confounding factors (BMI, parity, education level, and time period).

6 | WWW.PRIMARYCAREREPORTS.CO.UK

Odds ratio (95% CI)

Risk of VTE in women receiving oral oestrogens versus transdermal estradiol in the ESTHER study, the UK GPRD and the E3N cohort.28 The combination of oral oestrogen use and being overweight or obese is known to further increase a woman’s VTE risk.27 However, obese women who use transdermal oestrogen have a comparable VTE risk to women with a similar body mass index (BMI) who do not take HRT.29 One study has shown that women with a greater risk of VTE due to the factor V Leiden or prothrombin G20210A mutations had no significant increase in their risk of VTE when using transdermal oestrogen, compared to women with a mutation who did not use oestrogen.30 This was in contrast to women with these prothrombotic mutations taking oral oestrogens, who had a 25fold increased risk of VTE.30 Guidelines recommend transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.1 In addition, NICE states that transdermal oestrogen does not need to be discontinued prior to elective surgery, especially

4.5 (2.6–7.7)

Oral oestrogens Transdermal oestradiol

4 3 1.49 (1.37–1.63)

2 1 0

1.1 (0.7–1.7) ESTHER*

1.01 (0.89–1.16) UK GPRD†

1.7 (1.1–2.8)

1.1 (0.8–1.8) E3N‡

RISK OF VTE IN WOMEN RECEIVING ORAL OESTROGENS VERSUS TRANSDERMAL ESTRADIOL IN THE ESTHER STUDY, THE UK GPRD AND THE E3N COHORT28

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

when the surgery is minor and will not involve immobility.1 This is important as some women are needlessly being informed to discontinue their HRT prior to surgery, which can be detrimental for their health. This is because stopping HRT can lead to a significantly increased risk of cardiac and strokerelated death within the first-year posttreatment.31 Risk of stroke Oral HRT containing oestrogen at either high or low doses is associated with an increased risk of ischaemic stroke, compared with non-users.32 In contrast, transdermal preparations containing low doses of oestrogen have not been shown to be associated with an increased risk of stroke.32 Other advantages of transdermal oestrogen Oral oestrogen has been associated with a small but significant increase in total body fat and a decrease in lean body mass, whereas transdermal oestrogen has no significant effects on either parameter.33,34 The differences observed between these two routes of administration may be due to the effects of oral versus transdermal oestrogen on growth factors and substrate oxidation.33 In addition, low-dose transdermal oestrogen appears to be linked to a lower risk of cholecystitis compared with oral oestrogen.20

Type of Progestogen The chemical structures of progestogens vary widely. Each of the progestogens used in HRT have distinctive biological and clinical profiles. This has been demonstrated by the differing clinical outcomes observed in epidemiological studies of oestrogen alone compared with combined oestrogen and progestogen regimens.35 Observational studies have shown that HRT containing micronised progesterone may be associated with a lower risk of breast cancer, cardiovascular disease and thromboembolic events.20,36 Compared with non-use of HRT, a significant reduction in the risk of new-onset diabetes has been demonstrated in women who receive transdermal oestrogen and micronised progesterone, and this effect is greater when compared with other progestogens.37 Risk of venous thromboembolism (VTE) The type of progestogen used in HRT has an effect on VTE risk.38 The risk of VTE is greater in women using medroxyprogesterone acetate than in those receiving other progestins. Based on observational data, progesterone demonstrates a favourable safety profile with respect to VTE.38 Studies have shown that the risk of VTE increased by about 50% in women using oestrogen plus progestogens, compared with oral oestrogen

alone.38 There does not appear to be a change in oestrogen-related VTE risk in women using progesterone.29,39 Cardiovascular risk Progestogens have differing effects on cardiovascular risk. In general, those progestogens more similar to progesterone have been associated with a lower cardiovascular risk than more androgenic progestogens.35 Micronised progesterone seems to have a neutral effect on blood pressure in postmenopausal women.40 In contrast to other progestogens, progesterone has been shown to antagonise the effect of aldosterone, causing natriuresis and a reduction in blood pressure.41 This is important as hypertension is a major risk factor for coronary heart disease and stroke. Risk of breast cancer Women taking oestrogen-only HRT do not have an increased risk of breast cancer.35 It is only when a progestogen is added to the oestrogen-primed breast tissue that there is an increased risk. Epidemiological data support the hypothesis that progestogens are not a uniform class and that progesterone and progestogens have different effects on the risk of breast cancer in menopausal women using HRT.35 The French E3N Cohort Study assessed the association between different HRT regimens and breast cancer risk in postmenopausal women. Results showed that the combination of oestrogen with micronised progesterone was associated with no increased risk of breast cancer, whereas all other oestrogen and progestogen combinations showed substantially increased risks.42 In addition, the Finnish Cohort Study did not show a significant association between micronised progesterone and breast cancer.43 The currently available data do not demonstrate any difference in risk of breast cancer between oral and transdermal routes of oestrogen administration.44

There is wide consensus about the positive safety profile of HRT, when taken by healthy perimenopausal or early postmenopausal women

Endometrial Protection Oral micronised progesterone (taken for 12 out of 28 days) provides endometrial protection comparable to that given by other progestogens.45 In addition, taking oral micronised progesterone daily has been shown to effectively protect the endometrium from the stimulatory effects of oestrogen.46

Adherence Adherence with HRT is fundamental because the beneficial effects of hormones will be reduced or lost if women stop taking HRT. Some women experience side effects related to taking HRT,1 WWW.PRIMARYCAREREPORTS.CO.UK | 7

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Oestrogen plus Utrogestan® 100 mg/day

100 mg/day at bedtime

or Utrogestan® 200 mg/day

2 x 100 mg/day at bedtime

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Days of cycle HRT IN WOMEN WITH A UTERUS

The combination of oral oestrogen use and being overweight or obese is known to further increase a woman’s VTE risk

and this can affect their adherence. Side effects can include breast tenderness, vaginal bleeding or spotting, fluid retention, leg cramps and nausea. Although some side effects may improve with time, for many women the presence of side effects leads to them stopping HRT use. Side effects are less common in transdermal preparations of oestrogen and current recommendations are to change the mode of administration, e.g. from oral to transdermal if side effects occur.1 Among all continuous combined oestrogen and progestogen regimens, those using micronised progesterone have been shown to give the greatest percentage of completely amenorrhoeic cycles (>90%),12 which is likely to improve patient adherence.

Oestrogel® and Utrogestan® 100 mg Oestrogel® (17β-estradiol) is a transdermal gel containing 17β-estradiol, identical to the hormone produced by the body.47 Oestrogel® effectively: • Reduces vasomotor symptoms such as hot flushes and sweats, and alleviates vaginal atrophy48 • Helps to prevent osteoporosis in postmenopausal women at high risk of future fractures who are unable to take other medication approved for prevention of osteoporosis.47 It is the only transdermal gel available in a pumppack format, allowing clinicians to tailor their dosing according to symptoms.47 The usual starting dose of Oestrogel® is two measures or two pumps (equivalent to 2.5 g of gel, containing 1.5 mg estradiol) once daily applied on the arms, shoulders or inner thighs. In the majority of women, this dose will provide effective relief of menopausal symptoms. If after one month’s treatment, effective relief is not obtained, the dosage may be increased accordingly to a maximum of four measures (5 g of gel, containing 3.0 mg estradiol) once daily.47 8 | WWW.PRIMARYCAREREPORTS.CO.UK

For postmenopausal women with an intact uterus, a progestogen needs to be added for adjunctive use with oestrogen as HRT. Utrogestan® 100 mg (natural micronised progesterone) is the only natural micronised progesterone licensed in the UK for HRT use, providing endometrial protection to women who have not had a hysterectomy.49 Utrogestan® 100 mg can be given sequentially with 200 mg daily (equivalent to 2 oral capsules) at bedtime, for 12 days in the last half of each therapeutic cycle (beginning on day 15 of the cycle and ending on day 26). Withdrawal bleeding may occur in the following week. Alternatively, 100 mg (equivalent to 1 capsule) can be given at bedtime from day 1 to day 25 of each therapeutic cycle, with withdrawal bleeding being less using this treatment schedule.49

Summary It is very important that broad, sweeping conclusions concerning HRT are not made. It is essential that HCPs, women, and also the media are aware that various HRT products are available and there are important differences between these. An individualised approach should be taken at all stages of diagnosis, investigation, and management of the menopause.1,14 Women should receive appropriate information to enable them to make informed choices regarding treatment, and HRT should only be prescribed after considering each woman’s individual risk profile. There is robust evidence demonstrating that transdermal oestrogen in association with natural micronised progesterone could represent the optimal HRT regimen, particularly in women at risk of cardiovascular events.12,28 Prescribing information of Oestrogel® and Utrogestan® 100 mg is available on the inside cover advertisement of this report. This advertorial was funded by Besins Healthcare (UK) Ltd. OES/2017/032 – May 2017

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

References: National Institute for Health and Care Excellence. NICE guideline NG23 – Menopause: diagnosis and management 2015 [May 2017]. Available from: https://www.nice.org.uk/guidance/ng23 2 Kim C. Does menopause increase diabetes risk? Strategies for diabetes prevention in midlife women. Womens Health (Lond) 2012;8:155-67 3 Au A, Feher A, McPhee L, Jessa A, Oh S, Einstein G. Estrogens, inflammation and cognition. Front Neuroendocrinol 2016;40:87-100 4 Maki PM. Verbal memory and menopause. Maturitas 2015;82:288-90 5 Hamoda H, Panay N, Arya R, Savvas M. The British Menopause Society & Women’s Health Concern 2016 recommendations on hormone replacement therapy in menopausal women. Post Reproductive Health 2016;22:165-83 6 Falconi AM. Sex-Based Differences in the Determinants of Old Age Life Expectancy: The Influence of Perimenopause. Biodemography Soc Biol 2017;63:54-70 7 Maclaran K, Panay N. Current concepts in premature ovarian insufficiency. Womens Health (Lond) 2015;11:169-82 8 Groeneveld FP, Bareman FP, Barentsen R, Dokter HJ, Drogendijk AC, Hoes AW. The climacteric and well-being. J Psychosom Obstet Gynaecol 1993;14:127-43 9 Kopenhager T, Guidozzi F. Working women and the menopause. Climacteric 2015;18:372-5 10 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33 11 The Million Women Study Collaborative Group. The Million Women Study: design and characteristics of the study population. Breast Cancer Res 1999;1:73-80 12 L’Hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric 2013;16 Suppl 1:44-53 13 Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis 2016;254:282-90 14 Baber RJ, Panay N, Fenton A, Group IMSW. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19:109-50 15 Boardman HM, Hartley L, Eisinga A, Main C, Roque i Figuls M, Bonfill Cosp X, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015:CD002229 16 Langer RD. The evidence base for HRT: what can we believe? Climacteric 2017;20:91-6 17 Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol 2017;13:220-31 18 Gambacciani M, Levancini M. Hormone replacement therapy and the prevention of postmenopausal osteoporosis. Prz Menopauzalny 2014;13:213-20 19 Gambacciani M, Levancini M. Management of postmenopausal osteoporosis and the prevention of fractures. Panminerva Med 2014;56:115-31 20 Sood R, Faubion SS, Kuhle CL, Thielen JM, Shuster LT. Prescribing menopausal hormone therapy: an evidence-based approach. Int J Womens Health 2014;6:47-57 21 Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77 22 Salpeter SR, Buckley NS, Liu H, Salpeter EE. The cost-effectiveness of hormone therapy in younger and older postmenopausal women. Am J Med 2009;122:42-52 e2 23 Montagnana M, Favaloro EJ, Franchini M, Guidi GC, Lippi G. The role of ethnicity, age and gender in venous thromboembolism. J Thromb Thrombolysis 2010;29:489-96 24 Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007;44:62-9 25 Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671-6 26 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071-8 27 Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336:1227-31 28 Mueck AO. Postmenopausal hormone replacement therapy and cardiovascular disease: the value of transdermal estradiol and micronized progesterone. Climacteric 2012;15 Suppl 1:11-7 29 Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-5 30 Straczek C, Oger E, Yon de Jonage-Canonico MB, Plu-Bureau G, Conard J, Meyer G, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 2005;112:3495-500 31 Mikkola TS, Tuomikoski P, Lyytinen H, Korhonen P, Hoti F, Vattulainen P, et al. Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy. J Clin Endocrinol Metab 2015;100:4588-94 32 Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 2010;340:c2519 33 Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D, et al. Understanding weight gain at menopause. Climacteric 2012;15:419-29 34 dos Reis CM, de Melo NR, Meirelles ES, Vezozzo DP, Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen. Maturitas 2003;46:59-68 35 Stanczyk FZ, Hapgood JP, Winer S, Mishell DR, Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34:171-208 36 Panay N. Body identical hormone replacement. Post Reprod Health 2014;20:69-72 37 de Lauzon-Guillain B, Fournier A, Fabre A, Simon N, Mesrine S, Boutron-Ruault MC, et al. Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Generale de l’Education Nationale (E3N) cohort. Diabetologia 2009;52:2092-100 38 Scarabin PY. Hormone therapy and venous thromboembolism among postmenopausal women. Front Horm Res 2014;43:21-32 39 Canonico M, Fournier A, Carcaillon L, Olie V, Plu-Bureau G, Oger E, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010;30:340-5 40 Honisett SY, Pang B, Stojanovska L, Sudhir K, Komesaroff PA. Progesterone does not influence vascular function in postmenopausal women. J Hypertens 2003;21:1145-9 41 Boschitsch E, Mayerhofer S, Magometschnigg D. Hypertension in women: the role of progesterone and aldosterone. Climacteric 2010;13:307-13 42 Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005;114:448-54 43 Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol 2009;113:65-73 44 Bakken K, Fournier A, Lund E, Waaseth M, Dumeaux V, Clavel-Chapelon F, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2011;128:144-56 45 The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;275:370-5 46 Eden J. The endometrial and breast safety of menopausal hormone therapy containing micronised progesterone: A short review. Aust N Z J Obstet Gynaecol 2017;57:12-5 47 Besins Healthcare (UK) Ltd. Summary of Product Characteristics: Oestrogel® (17β-estradiol) 2014 [May 2017]. Available from: http://www.medicines. org.uk/emc/medicine/19898 48 Archer DF, Pickar JH, MacAllister DC, Warren MP. Transdermal estradiol gel for the treatment of symptomatic postmenopausal women. Menopause 2012;19:622-9 49 Besins Healthcare (UK) Ltd. Summary of Product Characteristics: Utrogestan® 100 mg capsules (natural micronised progesterone) 2016 [May 2017]. Available from: https://www.medicines.org.uk/emc/medicine/19895 1

WWW.PRIMARYCAREREPORTS.CO.UK | 9

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Glands and Hormones Part 1 – The Pituitary and the Pineal Joanna Fischer, Medical Correspondent

Hormone: A chemical substance produced in the body that controls and regulates the activity of certain cells or organs. Many hormones are secreted by special glands, such as thyroid hormone produced by the thyroid gland. Hormones are essential for every activity of life, including the processes of digestion, metabolism, growth, reproduction, and mood control. Many hormones, such as neurotransmitters, are active in more than one physical process1.

An organ of the body can have a function to produce hormones (its endocrine function) but it can also have a function to produce enzymes (its exocrine function – such as the digestive enzymes of the pancreas)

OST GLANDS are like the Post Office, the Jaguar car factory and Amazon combined. The Post Office part is the messaging system (hormones). The Jaguar car factory part is the production of a series of products that roll off the product line (sperm from the testes, eggs from the ovaries etc.). The Amazon part is the efficient stock storage and delivery. We are multi-functional beings and our organs are also multi-functional. Even if we might think that an organ only does one thing, as science progresses we will almost undoubtedly find that it does more. The interconnectedness of the organs, blood, lymph and chemical and neuro transmitters is mind boggling in its elegant 10 | WWW.PRIMARYCAREREPORTS.CO.UK

simplicity, which amounts to complexity of function and interactions. In the simplest terms, everything is interdependent and hormones play a key role as messengers and regulators. An organ of the body can have a function to produce hormones (its endocrine function) but it can also have a function to produce enzymes (its exocrine function – such as the digestive enzymes of the pancreas). Imagine if you did not grow or failed to develop adult features. Imagine if you ate food but could extract no energy or nutrition from it. Imagine if you had no sexual function, no desire and could not reproduce. Imagine you had no mood variations. Lack of hormones would make you no better than a machine. We are human because we have

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

hormones. They are produced in various parts of the body (mostly glands) and then transported in the blood stream to tissue and organs. They have no instant magic wand and may take days or weeks to act and they may affect many different processes at the same time. Excesses and deficiencies of hormones have predictable effects such as illustrated by the gigantism of acromegaly (in growth hormone excess) versus the dwarfism of a lack of growth hormone. The protuberant eyes (Grave’s disease) and over activity associated with an auto-immune cause of thyroid hormone excess are well known as is the sluggish, tiredness and increased weight of myxoedema (thyroid hormone deficiency). In both sexes, the main endocrine glands are the pituitary, pineal, thymus, thyroid, adrenal glands and pancreas. Men additionally produce hormones in their testes and women produce them in their ovaries and these are discussed in another section.

The Pituitary Gland and the Hypothalamus This small pea shaped gland can cause or be affected by the following conditions: acromegaly, Cushing’s Syndrome, diabetes insipidus, hypopituitarism and prolactinoma. It is attached to the base of the brain by a thin stalk. The pituitary gland is itself controlled by the hypothalamus but has often been called the master gland since it controls several other hormone glands in the body with the thyroid, the adrenals, the ovaries and the testicles being just four important examples2. If the pituitary and Hypothalamus are regarded as an axis working together, it should be noted that the means of communication between the two is by both nervous tissue and hormones. Our temperature regulation, food intake, thirst and water intake, wake and sleep patterns, memory and emotional behaviour are all influenced by the hypothalamus.

The Pineal Gland – Let There Be Light This gland, by producing its single hormone, Melatonin, helps maintain circadian rhythm and regulates the hormones of reproduction. It sits in the middle of the head (actually outside the substance of the brain and near the entrance of the aqueduct of Sylvius) and is often easily identified on X-rays because it has calcifications (‘Brain sand3’). The philosopher Descartes (‘I think therefore I am’) waxed lyrically in a whole book about the pineal that, sadly, was scientifically wrong4. Light stops melatonin secretion, such that melatonin levels are low during daylight hours and high during the dark. Sleeping and waking are characteristics of a 24-hour biological cycle known as our circadian rhythm and, as we all know, this is affected by daylight and darkness and causes problems for shift workers. The length of day versus the length of night (photoperiod) varies around the world and throughout the year. We know from the above comments that the pituitary affects the ovary and the testes but melatonin from the pineal also affects the pituitary and, thus, all the organs of reproduction. Melatonin blocks the secretion of gonadotrophins from the anterior pituitary gland (Luteinising hormone – LH and Follicle stimulating Hormone – FSH). Those who travel across time zones are aware of ‘jet lag’ and some researchers feel that carefully dosed and monitored artificial melatonin can help them (caution is required for animal acquired melatonin since there is at least a theoretical risk of variant Creutzfeldt Jakob disease).

Summary

Excesses and deficiencies of hormones have predictable effects such as illustrated by the gigantism of acromegaly (in growth hormone excess) versus the dwarfism of a lack of growth hormone

The pituitary, the pineal and the hypothalamus are parts of an amazingly efficient regulatory system, which reveals itself in those who have dysfunction at any point in the system. The three communicate with each other by both neural messengers and hormones. Although the philosopher Descartes was wrong about the functions of the pineal gland, we can paraphrase him to say “I message via my hormones and therefore I am’ because without them we would not function.

References: 1

http://www.medicinenet.com/script/main/art.asp?articlekey=3783 Accessed 3/6/17

https://www.pituitary.org.uk/information/what-is-the-pituitary-gland/ Accessed 5/6/17

https://plato.stanford.edu/entries/pineal-gland/ Accessed 5/6/17

https://plato.stanford.edu/entries/pineal-gland/ Accessed 11/6/17

WWW.PRIMARYCAREREPORTS.CO.UK | 11

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Glands and Hormones Part 2 – The Thymus, Thyroid, and Pancreas Testes Dr Charles Easmon, Editor

The Thymus

The severe and fluctuating weakness of myasthenia gravis is an example in some people of a thymus dysfunction disorder

With the pineal and the pituitary, we have been focused around the head and now we move down towards the chest, but stop just behind the sternum between the lungs. Little in life is larger in childhood than in adults but the Thymus gland is one of those things. After puberty, it starts to slowly shrink and becomes replaced by fatty tissue. Its hormone, thymosin, stimulates the development of disease-fighting T cells (which are all formed for life by puberty1). The thymus is thought to be important in preventing autoimmune diseases as a general might prevent troops engaging in civil war rather than attacking the enemy. It can be regarded as a vital part of both the lymphatic system as well as the endocrine system, reconfirming the inter-connectedness of the various body systems and organs. The analogy of the thymus as a general who trains and deploys troops can be taken further since its function is to receive immature T Cells (raw recruits) that have been produced by the red bone marrow and it then ‘trains’ them into functional, mature T cells (‘crack troops’). Those correctly ‘trained’ T cells that respond to foreign antigens are selected to survive and mature (a process of positive selection2) but those that cannot or do not do this face cell destruction and phagocytosis by macrophages. Negative selection is the process by which ‘wrongly trained’ T cells that attack the body’s own antigens are destroyed. If the thymus is dysfunctional then these wrongly trained ‘autoimmune’ T cells can proliferate rather than being destroyed leading to the wide range of auto-immune diseases. Thymus hormones, like a general’s messenger, promote the maturation of T cells, their pathogen killing activity, their stimulation of B cells to produce antibodies and the T-cell memory that recalls previous antigens/pathogens and allows a faster and more powerful subsequent response

to exposure (we exploit this in the process of vaccination with modified antigens or modified live viruses, bacteria or parasites). The severe and fluctuating weakness of myasthenia gravis is an example in some people of a thymus dysfunction disorder as is the propagation of disease after Yellow Fever vaccine in those with thymus dysfunction3 (hence the contraindication for the vaccine). If a person’s myasthenia gravis is caused by antibodies blocking acetylcholine or the muscle-specific receptor tyrosine kinase, thymus dysfunction is most likely to be at the root of the problem.

The Thyroid A butterfly landing on your windpipe just below the Adam’s apple would look like the thyroid gland. The wings would be the two side lobes and the body would represent the connecting isthmus (bridge). The hormone thyroxine (T4) is just one of several thyroid hormones in which a number by a letter indicates how many iodine atoms the hormone has. T3 is the biologically active hormone and T4 is converted to it, but T3 is also directly secreted by the thyroid gland5. The now offensive term ‘cretin6’ is derived from the consequences of inadequate thyroid hormone in childhood7 on brain development and this was known to be common in mountainous regions where there was a lack of iodised salt. In adults, the problem led to the enlargement of the thyroid – endemic goitre8). Thyroid hormones are active in all parts of the body and influence metabolism, body temperature, growth and development9. C-cells of the thyroid gland also affect bone in terms of its calcium content, bone metabolism and blood calcium levels10. The hormone for this is calcitonin, which inhibits the activity of osteoclasts11 (the cells that break down bone).

About 15 per cent of people with myasthenia gravis have a tumour in their thymus, a gland under the breastbone that is involved with the immune system. Most of these tumours, called thymomas, aren’t cancerous (malignant)4.

12 | WWW.PRIMARYCAREREPORTS.CO.UK

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

The Adrenal Glands

The Pancreas

We often think of fight and flight reactions but how often do we think of the two small masses on the top of each kidney, which are the key components of this evolutionary process? The outer (cortical) part of the adrenal glands produces cortisol and aldosterone. Cortisol helps the body respond to stress and regulates metabolism12. The effects of aldosterone in controlling blood pressure have been exploited for their beneficial effects in hypertension therapy. It is from the middle part of the adrenal gland (the medulla) that adrenaline, the hormone that is synonymous with it, comes. Your patients with Addison’s Disease, Cushing’s Syndrome, Conn Syndrome and those suffering from systemic steroid side effects are your textbooks for some of the many functions of the adrenal glands13 (inner and outer).

This organ, that is part gland, produces key hormones and also produces digestive enzymes (these help in the break down and absorption of food). Your diabetic patients are well aware of its functions14 since its B Langerhans’s cells normally produce the effective insulin that they either lack or cannot produce enough of. The pancreas also produces glucagon (which acts in concert with insulin) and somatostatin (the hormone as a body builder).

Summary The thymus, the thyroid, the adrenals and the pancreas between their endocrine (hormone producing) and exocrine functions ensure growth, development and the maintenance of our bodily functions. When they fail to work properly we need to replace their hormones as with insulin and thyroxine but, alternatively, if they are over productive as in thyrotoxicosis, we need to reduce or switch off their function (in the latter case we then replace their actions with medication).

If a person’s myasthenia gravis is caused by antibodies blocking acetylcholine or the muscle-specific receptor tyrosine kinase, Thymus dysfunction is most likely to be at the root of the problem

References:

https://www.endocrineweb.com/endocrinology/overview-thymus Accessed 5/6/17

http://www.innerbody.com/image_endoov/lymp04-new.html Accessed 5/6/17

http://www.vaccinesafety.edu/yf-thymus.htm Accessed 11/6/17

http://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/symptoms-causes/dxc-20200262 Accessed 5/6/17

http://btf-thyroid.org/information/your-thyroid-gland Accessed 5/6/17

http://medical-dictionary.thefreedictionary.com/cretinism Accessed 11/6/17

6 7

http://www.nytimes.com/1985/04/02/science/iodine-deficiency-in-himalayas-is-believed-to-disable-millions.html

http://www.hormones.gr/pdf/The%20role%20of%20iodine%20in%20the%20evolution.pdf Accessed 11/6/17

Accessed 11/6/17 http://www.webmd.com/women/picture-of-the-thyroid#1 Accessed 5/6/17

9 10

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072572/ Accessed 5/6/17

http://www.hormone.org/hormones-and-health/what-do-hormones-do/calcitonin Accessed 5/6/17

https://www.endocrineweb.com/endocrinology/overview-adrenal-glands Accessed 5/6/17

12 13

https://medlineplus.gov/ency/article/002219.htm Accessed 5/6/17

http://www.news-medical.net/health/What-Does-The-Pancreas-Do.aspx Accessed 5/6/17 WWW.PRIMARYCAREREPORTS.CO.UK | 13

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Glands and Hormones Part 3 – The Testes and Ovaries Joanna Fischer, Medical Correspondent

The Testes

One thing we do know is that a person with no egg producing apparatus by definition will not experience the menopause

Human life would end without testes (also true of course for the ovaries). There would be no sperm and no testosterone1. Testosterone is required for the proper physical development of boys and it is involved in the growth of facial and body hair, the lowering of the voice, increases in height and muscle mass as well as the growth of the Adam’s apple. In adults the hormone maintains muscle strength, bone density and libido2. Interestingly men produce both oestrogen3 and progesterone4 but both in lower amounts than women. High levels of oestrogen are thought to correlate with prostatic enlargement. Debate about the existence or not of a ’male menopause’ will swing back and forth for many more years. However, it is clear that abnormally low levels of progesterone in men leads to symptoms that include mood swings, depression, insomnia, appetite changes, weight gain, irritability, migraines, anxiety, fatigue, and low sex drive but this is not as frequent or as inevitable as the cliff-hanger that women face when their egg production stops.

The Ovaries The ovaries produce the female sex hormones that control reproduction and their nonendocrine function is to produce the substrate (gametes) for the embryo. Oestrogen during puberty controls the development of the mammary glands and during the menstrual cycle stimulates the development of the uterine lining. Progesterone during pregnancy acts on the uterus to develop the womb5 and allow the implantation of the embryo. The pre-menopausal, post-pubertal monthly cycle of women is brought about by ovarian changes over a typical 28-day cycle (range 21-35) affected by hormones from the anterior pituitary. The follicle stimulating Hhrmone (FSH) is self-explanatory; whereas the Luteinising Hormone (LH) stimulates ovarian follicles to produce oestrogen in the first half of the cycle and then, after the egg is released, 14 | WWW.PRIMARYCAREREPORTS.CO.UK

stimulates the remaining corpus luteum to produce progesterone6.

What Makes a Man a Man and a Woman a Woman – Transgender and Non-‘Binary’ For many years, we might have assumed that genitalia define us. However, an estimated 5% of children born every year are not clearly male or female (intersex7,8,9). Transgender issues have become more prominent with the successful Amazon series ‘Transparent10’ and Olympic athlete Bruce Jenner’s transformation to Caitlyn11, honoured with the front cover of Vanity Fair in 2015. Another Amazon series “Orange is the New Black12” has made a star out of a person, Asia Kate Dhillon13 who was born female but now identifies as neither gender (non-binary14). Australia now allows a passport entry that is neither male or female15. The actress Emma Watson recently won the first non-gendered award16. There are challenges ahead for us and our children to understand and explain all this. Sexual identity can be regarded as an external set of values and behaviours, many of these culturally instituted (pink for girls and blue for boys). Genitalia are affected by hormones and can be manipulated alongside gender re-assignment surgery to give a new phenotype. Our clichéd images of what makes a man a man and a woman are being challenged but the developmental general and life experiences of a transgender person prior to gender re-assignment make this a complex subject with no easy answers. One thing we do know is that a person with no egg producing apparatus by definition will not experience the menopause.

The Menopause “Every woman’s experience of the menopause is different,” says Norma Goldman, founder and director of The Menopause Exchange . Men age and women age but for women the effect of hormone imbalance is symptomatically far greater. The menopause leads to symptoms in women aged 45 or older that include; hot flushes,

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

“Every woman’s experience of the menopause is different,” says Norma Goldman, founder and director of The Menopause Exchange17. night sweats, none or infrequent periods, mood changes, memory or concentration loss, vaginal dryness, lack of interest in sex, joint and muscle stiffness and headaches18.

Summary Women have a menopause as a biological fact and it causes significant symptoms. These can be treated safely with HRT. The National Institute for Health and Care and Excellence (NICE) gives clear advice about the use of HRT, when not to use it and advises on safe HRT regular reviews as below:

A review 3 months after starting a treatment for menopausal symptoms ensures that changes to dosage or formulation can be made if there are persistent side effects such as bloating, nausea and breast discomfort. Once treatment is established, further review is needed to assess new or pre-existing health problems, to carry out basic health checks (for example, measuring weight and blood pressure), and

Men age and women age but for women the effect of hormone imbalance is symptomatically far greater

to inform and engage women in national screening programmes. Review should take place at least once a year, but may be needed more often if there are clinical indications for this. For most women, the symptoms of menopause respond well to treatment. However, for some whose symptoms do not improve or side effects are troublesome, review will identify if they need to be referred for help and support from a healthcare professional with specialist training and expertise19.

References:

http://www.healthline.com/human-body-maps/testis Accessed 7/6/17 https://www.endocrineweb.com/endocrinology/overview-testes Accessed 7/6/17. 3 http://www.ihealthdirectory.com/estrogen-men/ Accessed 11/6/17. 4 https://www.ncbi.nlm.nih.gov/pubmed/15669543 Accessed 11/6/17. 5 http://www.innerbody.com/image_endoov/repo07-new2.html#full-description Accessed 7/6/17 6 http://emedicine.medscape.com/article/1949171-overview Accessed 7/6/17 7 http://www.isna.org/faq/what_is_intersex Accessed 11/6/17. 8 https://medlineplus.gov/ency/article/001669.htm Accessed 11/6/17. 9 http://www.isna.org/faq/frequency Accessed 11/6/17. 10 http://www.imdb.com/title/tt3502262/ Accessed 11/6/17. 11 http://www.vanityfair.com/hollywood/2015/06/caitlyn-jenner-bruce-cover-annie-leibovitz Accessed 11/6/17. 12 http://www.imdb.com/title/tt2372162/ Accessed 11/6/17. 13 http://www.imdb.com/name/nm3545872/ Accessed 11/6/17. 14 http://www.tht.org.uk/sexual-health/Sex,-reproduction-and-gender/Trans-women/Nonbinary Accessed 11/6/17. 15 http://www.bbc.co.uk/news/world-asia-pacific-14926598 Accessed 11/6/17. 16 http://www.bbc.co.uk/newsbeat/article/39841483/emma-watson-wins-first-gender-neutral-mtv-tv--movie-award-for-beauty--the-beast Accessed 11/6/17. 17 http://www.menopause-exchange.co.uk/downloads/health-and-lifestyle-tips-for-the-menopause.pdf Accessed 7/6/17 18 https://www.nice.org.uk/guidance/qs143/chapter/Quality-statement-1-Diagnosing-perimenopause-and-menopause Accessed 11/6/17. 19 https://www.nice.org.uk/guidance/qs143/chapter/Quality-statement-4-Reviewing-treatments-for-menopausal-symptoms Accessed 11/6/17 1

WWW.PRIMARYCAREREPORTS.CO.UK | 15

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

The Skin as a Mechanism to Deliver Hormone Replacement Therapy (HRT) and as a Beneficiary Dr Charles Easmon, Editor

Women over 45 years presenting with menopausal symptoms are diagnosed with perimenopause or menopause based on their symptoms alone, without confirmatory laboratory tests1.

The skin is an excellent way for women to acquire their HRT on a daily basis. It is lower risk than oral HRT and has a higher chance of continued adherence

HE SKIN is the largest organ of the body2. In adults, it has a surface area (depending on size) of at least 2 square metres and, if fully laid out, might fill the space of one tiger skin and a polar bear combined. It has layers including the outer epidermis, the dermis and the subcutaneous layer. It protects and nourishes and, of course, it needs to be protected and nourished. Archaeological digs of human and pre-human habitation seem to indicate that the use of balms, poultices and salves goes back far into history3. From the earliest days, it has been known that therapy can be given through the skin4. In more recent times great excitement and investment was put into a failed technological promise â&#x20AC;&#x201C; vaccines via the skin. The company was called Powderject5 and the idea was that through a series of pins on a patch attached to a gun applicator, the vaccine would be delivered

16 | WWW.PRIMARYCAREREPORTS.CO.UK

into the skin and hence prevent the need for a subcutaneous or intramuscular injection. Sadly, this gave rise to some controversy and the company got bought out. However, the skin as a delivery mechanism for substances other than vaccines is a well-studied and proven model of therapeutic drug delivery.

The Skin as a Safe Vehicle for HRT Adherence has been the buzzword in medicine over compliance for some years now. As a general practitioner, you need your patients to use your recommended therapies willingly for their own benefit rather than feeling compelled to do so. For a woman to apply a medication to her skin, as part of her daily routine is easy and studies show a higher uptake than the requirement for daily oral tablets. Skin based HRT can also use lower doses of oestrogen and a

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

special formulation of non-synthetic progesterone (micronised6). The combined innovations in skin HRT have been shown to reduce the risk of side effects and complications from HRT such as venous thromboembolism7 (VTE) and cardiovascular complications.8 The National Institute for Health and Care Excellence (NICE) provides clear guidance on avoiding any harm from HRT.

1. Do not offer hormone replacement therapy (HRT) (including oestrogen/ progestogen combination) routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to women with severe menopausal symptoms and with whom the associated risks have been discussed9. 2. D o not offer systemic hormone replacement therapy for the treatment of urinary incontinence10.

Most women want to look good and their skin looking good and healthy is part of that. Skin that reddens13 easily or oozes sweat (vasomotor effects) in social situations is obviously not helpful to confidence or sexual attraction. In most Western societies, hair in the right place adds to attractiveness and hair in the wrong place detracts. The menopausal woman not on HRT has a double whammy of thinning head hair and facial hirsutism (“even a single hair casts a shadow14,”), both of which, fortunately, are relieved by HRT. We all recognise the facial features of someone who feels sad (we still have one over computers in this area). A chronically sad, anxious or depressed person has this ‘etched’ on their face in the form of lines or skin affected by poor lifestyle choices in terms of smoking, eating and drinking. The depressed woman is likely to take less care of her personal appearance and, hence, compounds a cycle of feeling unattractive. The role of HRT in mood alleviation should not be ignored, especially since the World Health Organisation (WHO) now recognises depression as the leading cause of disability15 worldwide.

Perfect Skin

Summary

Hard leathery or dry skin11 is aesthetically unpleasant and can be uncomfortable. The vagina is normally well lubricated for sexual activity but it can become dry and atrophic12 in the menopause and this, in addition to the lack of sexual desire, can lead to uncomfortable and infrequent sex. This can have an impact on relationships.

The skin is an excellent way for women to acquire their HRT on a daily basis. It is lower risk than oral HRT and has a higher chance of continued adherence. The skin directly benefits from the HRT with a reduction in dryness, hot flushes, hirsutism and alopecia. More happiness and more confidence can be rubbed into the skin in an acceptable therapeutic solution.

As a General Practitioner you need your patients to willingly use your recommended therapies for their own benefit rather than feeling compelled to do so

HRT ‘may be beneficial in improving mood in early postmenopausal women with depressive and/or anxiety symptoms16.’

References: https://www.nice.org.uk/guidance/qs143/chapter/Quality-statement-1-Diagnosing-perimenopause-and-menopause

Accessed 11/6/17 2

http://www.nationalgeographic.com/science/health-and-human-body/human-body/skin/ Accessed 11/6/17

http://www.medicalnewstoday.com/info/medicine/prehistoric-medicine.php Accessed 11/6/17

http://www.bible-history.com/isbe/B/BALM/ Accessed 11/6/17

http://powerbase.info/index.php/PowderJect Accessed 11/6/17

https://www.sharecare.com/health/endocrine-system/what-is-micronized-natural-progesterone Accessed 11/6/17

7 8

http://www.bmj.com/content/336/7655/1227?tab=responses Accessed 11/6/17 http://bit.ly/2to2pZt Accessed 11/6/17

http://bit.ly/2rNFrsz Accessed 11/6/17

http://bit.ly/2svZpd6 Accessed 11/6/17

http://www.webmd.com/beauty/features/menopause-dry-skin-hormone-connection#1 Accessed 11/6/17

http://www.imsociety.org/manage/images/pdf/d0ad344b44faf5462478553de7000647.pdf Accessed 11/6/17

http://www.dermnetnz.org/topics/menopause-and-the-skin/ Accessed 11/6/17

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/hirsutism/

Accessed 11/6/17

http://www.who.int/mediacentre/factsheets/fs369/en/ Accessed 11/6/17

http://www.imsociety.org/manage/images/pdf/ba6379e868044bec13015ac2b84f2753.pdf Accessed 11/6/17 WWW.PRIMARYCAREREPORTS.CO.UK | 17

MANAGING MENOPAUSAL SYMPTOMS AND THE ROLE OF HORMONE REPLACEMENT THERAPY

Notes:

18 | WWW.PRIMARYCAREREPORTS.CO.UK

Primary Care Professionals Make More Effective Evidence Based Decisions With Primary Care Reports

For the past decade, Primary Care Reports has been helping GPs, and other primary care professionals to improve patient outcomes. Our Special Reports provide readers with an unparalleled depth of information on specialist subjects, which receive limited coverage in the mainstream medical media. Each report is designed to help primary care professionals to make more effective treatment decisions, by providing a unique mix of: • Subject specific clinical information • Insight and knowledge from internationally recognised key opinion leaders • Clinical guidelines • Independent data and analysis • Unbiased editorial content

subscriptions@globalbusinessmedia.org www.globalbusinessmedia.org