Fertility Blaze
Fertility Blaze 2018 › Fertility Blaze Vol-5, No-1, 2018

Oestrogen Menarche to Menopause

INTRODUCTION

Hormones like oestrogen, progesterone, testosterone, cortisol and thyroid are the chemical messengers for every cell in the body.1Schroeder E. From menarche to menopause. Available from: https://women inbalance. org/2014/05/14/from-menarche-to-menopause/ [Accessed on 14th October 2017]   Oestrogen plays an important role in the normal sexual and reproductive development in women. The woman’s ovaries make most oestrogen hormones, although the adrenal glands and fat cells also make small amounts of oestrogen.2Estrogen’s effects on the female body. Available from: https://www. urmc.rochester. edu/encyclopedia/content.aspx? ContentTypeID= 85& Content ID= P00559 [Accessed on 16th October 2017]    The primary function of oestrogen is development of female sexual characteristics this includes the growth of breast tissue, increase in endometrium, regulation of the menstrual cycle, growth of ovarian follicles, lubrication of the vagina and thickening of vaginal wall by increasing blood vessels to the skin. It helps decelerate height increase in females during puberty, accelerates burning of body fat and reduces muscle bulk.3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]  In addition to regulating the menstrual cycle, oestrogen affects the reproductive tract, the urinary tract, the heart and blood vessels, bones, breast tissue, skin, hair, mucous membranes, pelvic muscles and the brain. Secondary sexual characteristics also begin to grow when oestrogen level rises, such as pubic and armpit hair. Many organ systems, including the musculoskeletal and cardiovascular systems (CVS) and the brain are affected by oestrogen.2Estrogen’s effects on the female body. Available from: https://www. urmc.rochester.edu/encyclopedia/content.aspx? ContentTypeID= 85& Content ID= P00559[Accessed on 16th October 2017]   It also helps to decelerate height increase in females during puberty, accelerates burning of body fat and reduces muscle bulk. It also contributes to brain health, mood stability and vaginal secretions.4Travis RC, Key TJ. Oestrogen exposure and breast cancer risk. Breast Cancer Res.2003, 5:239-247. doi 10.1186/bcr628

 

 

Oestrogen is present in significant amount in both men and women. However it is significantly higher amount in girls after menarche (onset of menstrual periods at puberty) until menopause (cessation of menstrual periods after completion of reproductive age).3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]    The stages from menarche to menopause are as follows:1Schroeder E. From menarche to menopause. Available from: https://women inbalance.org/2014/05/14/from-menarche-to-menopause/ [Accessed on 14th October 2017]

  • Menarche: The mean age at menarche among Indian women is 13.76 years and is the start of puberty. During this time, the hormone dehydroepiandrosterone (DHEA), which is a precursor to oestrogen and testosterone, is produced in increasingly large amounts. This triggers the beginning of puberty.
  • The Menstrual Cycle: Day one is the first day of bleeding. On this day all hormones are very low (start of follicular phase). Oestrogen begins to rise the first week and then peaks at ovulation, generally day 14. After ovulation (luteal phase), progesterone begins to rise, which prepares the endometrium for implantation. If the egg is not fertilised within that week, both progesterone and oestrogen will start to fall and a week later (day 28) bleeding will resume. If this hormone cycle is out-of-balance in young women, symptoms can occur such as: Moodiness, acne, polycystic ovary syndrome (PCOS), irregular periods, heavy bleeding, and endometriosis.
  • Perimenopause: Perimenopause can begin as early as the mid-thirties, as first progesterone and then oestrogen produced by the ovaries starts to decline. This decline will interrupt ovulation which can cause irregular periods and many menopausal symptoms and this is known as perimenopause. Symptoms include; lack of sleep, night sweats, bloating, depression or anxiety, weight gain, hair loss, skin and vaginal dryness.
  • Menopause: Menstrual cycles may get closer together or more spread apart until they go away completely. After 12 consecutive months without a cycle a woman is officially in menopause. The average age of menopause onset is 48-52 years. There is no way to predict how long symptoms will last.

MENOPAUSE AND HORMONE REPLACMENT THERAPY (HRT)

May be natural or due to oophorectomy, chemotherapy or radiotherapy to abdomen during the menopausal transition or menopause, a reduction in ovarian function results in a number of symptoms. Symptoms secondary to changes in ovarian hormones can be difficult to distinguish from those due to general aging and/or other life changes. Symptoms often attributed to oestrogen deficiency are many and vary in intensity among women. Symptoms most commonly reported during the menopausal transition include; vasomotor symptoms, such as hot flashes and night sweats, vaginal and vulvar dryness and sleep disturbances. The prevalence of vasomotor symptoms is 14-51% in premenopausal women, 35-50% in perimenopausal women and 30-80% in postmenopausal women. Most women have hot flashes for 6 months to 2 years. However, one study group reported that 26% of women had hot flashes for 6-10 years and that 10% had them for more than 10 years. According to the Study of Women’s Health Across the Nation (SWAN), the prevalence of vasomotor symptoms is highest among African-American women (46%), followed by Hispanic (34%), Caucasian (31%), Chinese (21%), and Japanese (18%) women.5Szymanski LM. Estrogen therapy. Available from: https://emedicine.medscape.com/article/276107-overview?pa=tZuOfNPdjs4KZ%2BkUFx3aYdhW9JY8FA3qrnCEiI%2BulEiH4xadzNZZ5K1ue3xRamHy56MI7dGTgNawPfsOtJla9Q%3D%3D#showall [Accessed on 14th October 2017]  Hormone replacement therapy (HRT) means taking menopausal hormone therapy (MHT) i.e. oestrogen or progesterone or both. It helps in relieving the symptoms of perimenopause and menopause.6Hormone therapy. ACOG. 2015. Available from: https://www.acog.org/Patients/FAQs/Hormone-Therapy [Accessed on 14th October 2017]  Traditionally, oestrogen alone or in combination with progesterone was used as the standard treatment for symptomatic relief of vasomotor and genito-urinary symptoms.7Malik S, Pannu D, Prateek S, et al. Comparison of the symptomatic response in Indian menopausal women with different estrogen preparations for the treatment of menopausal symptoms: A randomized controlled trial. Arch Gynecol Obstet. 2016.doi 10.1007/s00404-016-4034-9

The Women Health Initiative (WHI), a large-scale randomised control trial comprising of a set of clinical trials and an observational study, was conducted by the National Institutes of Health (NIH) in 1991 on 161,808 healthy post-menopausal women. The clinical trials was designed to test the effects of post-menopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer. The hormone trial had two random studies: The oestrogen-plus-progestin (E+P) study of women with a uterus and the oestrogen-alone study of women without a uterus. A number of limitations with the WHI E+P trial were noted as follows8Women’s Health Initiative. Available from: https://www.nhlbi.nih.gov/whi/ [Accessed on 17th August 2017] :

  • Effect of other doses, formulations or routes of administration.
  • Effect of progestin separate from oestrogen.
  • Longer term assessment of risks and benefits.

After 2002, a drop in the use of HRT was noticed as WHI trial was halted early due to some serious side-effects like increased risk of stroke, heart disease and breast cancer.7Malik S, Pannu D, Prateek S, et al. Comparison of the symptomatic response in Indian menopausal women with different estrogen preparations for the treatment of menopausal symptoms: A randomized controlled trial. Arch Gynecol Obstet. 2016.doi 10.1007/s00404-016-4034-9   The conflicting results led to the “timing hypothesis”; the idea that the differences in cardiovascular outcome can be accounted for by time since menopause until the start of HRT.9Schierbeck LL, Rejnmark L, Landbo C, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial.BMJ. 2012;345:e6409. doi: 10.1136/bmj.e6409[Accessed on 4th November 2017].   The development of “timing hypothesis” was based on differing effects of oestrogen on younger (approximately 50 years of age), healthy, recently postmenopausal (typically within 2 years) women compared with older (mean age in the 60s, typically >10 years past menopause) women. It put forward the effects of HRT on atherosclerosis and coronary heart disease depend on the timing of the initiation of HRT relative to menopause, age, or both, which are in turn related to the health of the underlying vascular tissue or to other factors, such as reduction in or down-regulation of oestrogen receptors.10. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221-31. doi: 10.1056/NEJMoa1505241

The results of the two sister trials — the Estrogen in Prevention of Atherosclerosis Trial (EPAT) and the Women’s Estrogen Lipid- Lowering Hormone Atherosclerosis Regression Trial (WELL-HART), were with regard to the effect of HRT on the progression of atherosclerosis, differed according to the health of the underlying vascular tissue. After completion of EPAT and WELL-HART, in early 2002, the NIH proposed the Early versus Late Intervention Trial with Estradiol (ELITE). ELITE trial was specifically designed to test the hormone-timing hypothesis in relation to atherosclerosis progression in postmenopausal women. The primary hypothesis was that postmenopausal hormone therapy would reduce the progression of subclinical atherosclerosis when therapy was initiated soon after menopause (<6 years) but not when therapy was initiated a long time after menopause (≥10 years).10. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221-31. doi: 10.1056/NEJMoa1505241

MHT is an effective treatment for the typical menopause-related symptoms. The benefits of MHT i.e. systemic oestrogen therapy (with or without progestin) include relief from hot flashes, night sweats and vaginal dryness, protection against the bone loss and helps in prevention of hip and spine fractures, reduction in the risk of colon cancer; reduction of distressing symptoms of menopause, osteoporotic fractures, dementia and colorectal cancer, improvement in well-being, quality of life, vaginal epithelium, sexual enjoyment and bladder capacity and increase in the longevity.10. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221-31. doi:10.1056/NEJMoa1505241   11Wren BG. The benefits of oestrogen following menopause: Why hormone replacement therapy should be offered to postmenopausal women. Med J Aust.2009;190 (6): 321-325   Side-effects of MHT includes; nausea, vomiting, abdominal cramps, bloating, breast tenderness, fluid retention, altered blood lipids. In patients with uterus and having other high risk factors for endometrial hyperplasia unopposed oestrogen replacement therapy can cause endometrial hyperplasia and in few cases it may progress to endometrial carcinoma. However the risk should be calculated on individual basis and most of these depend on the dose and duration of therapy. Local oestrogen therapy or lowest dose for shortest duration of time should be considered in these individuals with close monitoring. MHT may increase the risk of certain types of cancer and other conditions like uterine cancer, heart attack, stroke, deep vein thrombosis (DVT), breast cancer, gallbladder disease, etc.6Hormone therapy. ACOG. 2015. Available from: https://www.acog.org/Patients/FAQs/Hormone-Therapy [Accessed on 14th October 2017]   The side-effects of MHT include: Risk of thromboembolism, promotes growth of pre-existing breast cancer, cause vaginal spotting, heavy bleeding, fluid retention, breast soreness, etc.10. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221-31. doi:10.1056/NEJMoa1505241   11Wren BG. The benefits of oestrogen following menopause: Why hormone replacement therapy should be offered to postmenopausal women. Med J Aust.2009;190 (6): 321-325

Decision-making regarding MHT is based on the following criteria: Choosing candidates (indications for MHT), calculating the risks, starting oestrogen therapy (route, dose, adding a progestin, side-effects, factors affecting oral oestrogen metabolism, etc.), duration of therapy, monitoring the menopausal transition with mammography, stopping MHT (tapering, implications of stopping, extended use of MHT, etc.) and follow-up. 12Sood R, Faubion SS, Kuhle CL, et al. Prescribing menopausal hormone therapy: An evidence-based approach. International Journal of Women’s Health. 2014:6 47–57.http://dx.doi.org/10.2147/IJWH.S38342   Woman suffering from severe menopausal symptoms resistant to alternative treatments, MRT should be offered after counselling about risks and informed consent is given. This remains prime indication for MRT. Decision to take MRT should be based on a woman’s individual risk profile, personal and family medical history (cancer, heart disease, stroke and osteoporosis) after counselling and informed choice. In management of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause, topical vaginal oestrogen should be considered.

EFFECT OF HORMONE REPLACEMENT THERAPY (OESTROGEN) ON VARIOUS BIOCHEMICAL PARAMETERS (MUSCULOSKELETAL, CARDIOVASCULAR SYSTEM AND BRAIN)

Bone Health (Osteoporosis, Hip Fractures, etc.)

The rise in oestrogen levels at menarche in girls is associated with a large reduction in bone turnover markers. This reduction reflects the closure of the epiphyseal growth plates, the reduction in periosteal apposition and endosteal resorption within cortical bone, and in bone remodelling within cortical and cancellous bone. Oestrogen promotes these changes, in part, by promoting apoptosis of chondrocytes in the growth plate and osteoclasts within cortical and cancellous bone. The decrease in the levels of oestrogen at the time of the menopause results in an increase in the rate of bone remodelling and this plays a major role in the development of postmenopausal osteoporosis.13 Eastell R. Role of oestrogen in the regulation of bone turnover at the menarche. Journal of Endocrinology. 2005;185:223–234

In a meta-analysis of data from 22 trials involving a total of 8800 women, Grady and Cummings found a 27% reduction in risk of non-vertebral fractures in older women who received HRT. For hip and wrist fractures, the risk reduction was 40%, increasing to 55% in women younger than 60 years. The data from the WHI also demonstrated decreased bone fractures in women on HRT. Karim et al ., evaluated the impact of this cessation and found that women who discontinued HRT were at higher risk for hip fracture and lower bone mineral density (BMD) than women who continued HRT; they also found that the protective effect of HRT against hip fracture disappeared within 2 years of cessation.14Coney P. Menopause. Available from: https://emedicine.medscape.com/ article/264088-overview#showall [Accessed on 14th October 2017]   The stance adopted by the ACOG is that the use of HRT for osteoporosis prevention or treatment needs to be individualised and needs to include the woman’s need for treatment of vasomotor symptoms.9Schierbeck LL, Rejnmark L, Landbo C, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial.BMJ. 2012;345:e6409. doi: 10.1136/bmj.e6409[Accessed on 4th November 2017].   Thus, oestrogen reduces bone resorption and increase bone formation.3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]

Facial Appearance and Skin Aging

In a study Law Smith MJ et al ., observed a statistically significant associations between late follicular oestrogen levels and three perceptual ratings of facial appearance: femininity, attractiveness and health. Thus, the study provided evidence that the sexually dimorphic appearance of female faces is related to oestrogen levels.15. Law Smith MJ, Perret DI, Jones BC, et al., Facial appearance is a cue to oestrogen levels in women. Proc. R. Soc. B. 2006;273:135–140. doi:10.1098/rspb.2005.3296

Aging is associated with a decrease in skin thickness due to atrophy of the epidermis, dermis and subcutaneous fat. In humans, structural and functional changes attributable to aging are more visibly evident in the skin than in any other organ. Oestrogens have significant effects on skin physiology and modulate epidermal keratinocytes, dermal fibroblasts and melanocytes, in addition to skin appendages including the hair follicle and the sebaceous gland. Importantly, skin aging can be significantly delayed by the administration of oestrogen.16. Stevenson S, Thornton J. Effect of estrogens on skin aging and the potential role of SERMs. Clinical Interventions in Aging. 2007;2(3):283–297   For many years it has been recognised that oestrogens are important in the maintenance of human skin. They improve collagen content and quality, increase skin thickness and improve blood supply to the skin. Oestrogen act via oestrogen receptors on human skin.3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]   The menopause causes hypoestrogenism, accelerating age-related deterioration, which results in thinner skin, an increase in number and depth of wrinkles, increased skin dryness, and decreased skin firmness and elasticity. HRT has been shown to increase epidermal hydration, skin elasticity, skin thickness and also reduces skin wrinkles. It also enhances the content and quality of collagen and the level of vascularisation.17Rosano GM, Panina G. Oestrogens and the heart. Therapie. 1999;54(3):381-5

In a randomised, double-blind, placebo-controlled trial, Maheux et al., demonstrated that after 12 months of oral oestrogen therapy, dermal thickness was increased by 30%, resulting in increased skin thickness in postmenopausal nuns. Varila et al ., demonstrated an increase in collagen content following topical oestrogen administration. They also demonstrated an increase in collagen synthesis as shown by increased type I and type III pro-collagen levels. Thus, HRT has relevance in postmenopausal women and the potential value of selective oestrogen receptor modulators (SERMs) as a therapy for diminishing skin aging.18Masood D, Roach EC, Beauregard KG, et al. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010;11(8):693–714

Cardiovascular Disease Prevention

The menopausal age is characterised by an imbalance of the neurohormonal system i.e. sudden increases of plasma catecholamines. This abnormal release of catecholamines reduces coronary flow reserve and increase peripheral vascular resistance. Oestrogens effectively modulate the neurohormonal system by reducing of sympathetic tone. Large-scale epidemiological studies have demonstrated that oestrogen replacement therapy leads to approximately 50% reduction of cardiovascular disease in women taking hormones, compared with untreated women. Endothelium dependent mechanisms have been identified and imply that oestrogen act through the endothelial release, mainly, of nitric oxide, a potent vasodilating substance which has been identified with endothelium derived relaxing factor (EDRF). Oestrogens positively affect plasma lipids and exert a beneficial effect upon carbohydrate metabolism and the haemocoagulation profile.17Rosano GM, Panina G. Oestrogens and the heart. Therapie. 1999;54(3):381-5

Oral oestrogen may also cause an increase in circulating levels of coagulation factors II, VII, IX, X, plasminogen, and increased platelet adhesiveness, and decreased anti-thrombin levels.18Masood D, Roach EC, Beauregard KG, et al. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010;11(8):693–714   It also has anti-atherogenic properties. Angiographic studies conducted in humans have demonstrated that women on oestrogen have significantly less coronary disease and less severe occlusion scores compared with women not taking HRT.17Rosano GM, Panina G. Oestrogens and the heart. Therapie. 1999;54(3):381-5   In the Postmenopausal Oestrogen/Progestin Interventions (PEPI) trial, lipoprotein (a) [Lp(a)] concentrations, shown to be an independent predictor of the risk of coronary heart disease in women were reduced by 25% on average among women treated with CEE, with or without the addition of a progestogen.19Mikkolaa TS, Clarksona TB. Estrogen replacement therapy, atherosclerosis and vascular function. Cardiovascular Research.2002;53:605–619  Thus, cardioprotective effect is demonstrated by oestrogen.17Rosano GM, Panina G. Oestrogens and the heart. Therapie. 1999;54(3):381-5

Obesity

Oral oestrogen regimens have been shown to increase plasma triglycerides, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 (apoA1) levels, while decreasing low-density lipoprotein (LDL) cholesterol and Lp(a) levels. In the PEPI trial, 875 healthy postmenopausal women aged 45–65 years were studied for three years using a randomised, double-blind protocol. The group receiving oral conjugated equine oestrogen (CEE) (0.625 mg/day) had a 10–12% decrease in LDL cholesterol levels and a similar increase in HDL cholesterol levels during the study.19Mikkolaa TS, Clarksona TB. Estrogen replacement therapy, atherosclerosis and vascular function. Cardiovascular Research.2002;53:605–619

Female Sexual Function and Dysfunction (Libido)

In the study conducted by Santoro N et al ., demonstrated the improvement in well-being was achieved by relief of vasomotor and other symptoms like libido was also improved. Thus, oestrogen have significant role in female sexual function and dysfunction.20Santoro N, Worsley R, Miller KK, et al. Role of estrogens and estrogen-like compounds in female sexual function and dysfunction. J Sex Med. 2016;13(3):305-16. doi: 10.1016/j.jsxm.2015.11.015

Development of Foetus

Oestrogen helps in causing physical differentiation of the foetus to either male or female as per their genetic code.3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]

Breast Cancer and Colon Cancer

Combined oestrogen and progestin therapy slightly increases risk of breast carcinoma in woman with other risk factors or family history for cancer breast. It can cause a recurrence in a patient with pre-existing breast carcinoma undergoing lumpectomy and having oestrogen and progesterone receptor positivity. However the risk should be calculated on individual basis and most of these depend on the dose and duration of therapy.

Local oestrogen therapy or lowest dose for shortest duration of time should be considered in these individuals with close monitoring and counselling. Analysis of the effects of hormonal factors on breast tumour development, ER-positive/PR-positive tumours and ER-negative/PR-negative tumours should be considered separately from each other. Oestrogen-only HRT increases the risk of breast cancer in a small percentage of people, but only when used for more than 10 years. Women receiving HRT may be more likely to comply with breast cancer screening recommendations and thus may have increased rates of breast carcinoma detection relative to women who have never received HRT. Studies showed that there is 20% reduction in colon cancer and a 19% reduction in rectal cancer in women who had ever used MHT compared with never users. The observed decrease was greatest among current users, with 34% risk reduction. The duration of therapy had no effect on cancer risk.

Lung Function

Studies have shown that in asthma, estradiol shuttles adaptive immunity towards the T H 2 phenotype. In cystic fibrosis (CF), estradiol has been demonstrated to up-regulate MUC5B gene (mucus production) in human airway epithelial cells and inhibit chloride secretion in the airways. In chronic obstructive pulmonary disease (COPD), cigarette smoke is detoxified through Phase I and Phase II enzymes and oestrogen preferentially up-regulate Phase I enzymes, leading to accumulation of toxic metabolites through a process called bioactivation. Phase I is mediated largely by cytochrome P450 (CYP) enzymes that are responsible for de-toxifying cigarette smoke and other environmental irritants into intermediate metabolites, suggesting that female sex hormone plays a relevant role in inflammatory airway disease by amplifying airway inflammation.21Tam A, Morrish D,Wadsworth S, et al. The role of female hormones on lung function in chronic lung diseases. BMC Women’s Health. 2011;11:24. http://www.biomedcentral.com/1472-6874/11/24

Mood and Mental Health

The sudden appearance of higher levels of oestrogen in puberty alters the sensitivity of the neurotransmitter systems. Premenstrual syndromes may be the result of an altered activity or sensitivity of certain neurotransmitter systems. Pregnancy and delivery produce dramatic changes in oestrogen and progesterone levels as well as significant suppression along the hypothalamic–pituitary–adrenal axis (HPA axis), possibly increasing vulnerability to depression.22Steiner M, Dunn E, Born L. Hormones and mood: From menarche to menopause and beyond. Affect Disord. 2003;74(1):67-83   Sudden decrease in blood levels of oestrogen and periods of sustained oestrogen low levels correlate with significant mood lowering. After childbirth nearing menopause and after menopause low levels of oestrogen can predispose to depression.3Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14th October 2017]

At menopause, oestrogen levels decline while pituitary luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels increase. The loss of modulating effects of oestrogen and progesterone may underlie the development of perimenopausal mood disorders in vulnerable women. The pattern of neuroendocrine events related to female reproduction is vulnerable to change and is sensitive to psychosocial, environmental, and physiological factors. Thus, oestrogen has important role and potential relevance to psychiatric disorders specific to women from menarche to menopause.22Steiner M, Dunn E, Born L. Hormones and mood: From menarche to menopause and beyond. Affect Disord. 2003;74(1):67-83   Climacteric depression is more severe in the transitional phase which is 2 to 3 years before the cessation of periods rather than after the established menopause. MHT is to be offered to these women to help them tide over the phase. However, obvious clinical depression should be evaluated by a psychiatrist as close history may reveal its existence.

A randomised, single blind, parallel study was conducted by Malik S et al ., to compare symptomatic response in 200 post-menopausal Indian women using placebo, estradiol valerate (E2V), conjugated equine oestrogen (CEE) and isoflavones (phytoestrogens) for 24-weeks. It was found that; both E2V and CEE groups were effective in reducing severity and frequency of hot flashes (Figure 1). A decrease was observed in mean hot flash score i.e. 91.9% in the E2V group, 89.2% in the CEE group, 60.42% in the isoflavones group and 47.9% in placebo. After 24-weeks of therapy there was significant increase in vaginal health index in the E2V, CEE and isoflavones group and no serious side-effects were reported in any of the groups. Thus, low doses of CEE and E2V were equally effective for management of vasomotor/vaginal symptoms when administered over 24-weeks.7Malik S, Pannu D, Prateek S, et al. Comparison of the symptomatic response in Indian menopausal women with different estrogen preparations for the treatment of menopausal symptoms: A randomized controlled trial. Arch Gynecol Obstet. 2016.doi 10.1007/s00404-016-4034-9

BENEFITS OF MICRONISATION

Micronisation is defined as the oral bioavailability of drugs presented in a solid dosage form. It mainly depends on size, size distribution and morphology of particles.23Krishnaiah YSR. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. J Bioequiv Availab. 2010;2:28- 36. doi:10.4172/jbb.1000027   For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills like jar mills or fluid energy mills; are used to micronise powders. Micronisation improves digestive absorption, bioavailability and clinical efficacy of a drug.24Chaumeil JC. Micronization: A method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol. 1998;20(3):2115   Micronised estradiol valerate is structurally similar to endogenous oestrogen. It naturally replenishes the oestrogen level and is better accepted by physiological systems of the body. It is micronised which enhances its dissolution and thereby absorption. Also it is esterified which prevents the first pass metabolism.7Malik S, Pannu D, Prateek S, et al. Comparison of the symptomatic response in Indian menopausal women with different estrogen preparations for the treatment of menopausal symptoms: A randomized controlled trial. Arch Gynecol Obstet. 2016. doi 10.1007/s00404-016-4034-9

A randomised cross-over study conducted by Wiegratz I et al. , to compare a sequential 28-day HRT using micronised estradiol and a cyclic 21-day HRT using estradiol valerate with regard to the pharmacokinetics of estradiol in 50 post-menopausal women. The pharmacokinetic profile of the serum concentrations of estradiol was measured on day 1, 21 and 28 each immediately before and 1, 2, 4, 6, 8 and 10 hours after intake of a tablet, and the area under the curve (AUC) was calculated. The serum concentrations of estradiol on day 1, increased from a mean of 10 pg/ml up to 40 pg/ml with micronised estradiol and 30 pg/ml with estradiol valerate. On day 21, estradiol concentration increased to 80 pg/ml with micronised estradiol and 60 pg/ml with estradiol valerate. But on day 28 estradiol concentration decreased to 40 pg/ml with micronised estradiol and 10 pg/ml with estradiol valerate (Figure 2). The AUC as calculated from both treatment cycles was significantly higher on day 1, 21 and 28. During treatment with micronised estradiol (2 mg) the serum concentrations were significantly higher than with estradiol valerate (2 mg). On day 28 of treatment with estradiol valerate, the estradiol levels decline to baseline values, while using micronised estradiol they remain in the range of those measured on day 1.25Wiegratz I, Fink T, Rohr UD, et al. Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol. Zentralbl Gynakol. 2001;123(9):505-12

CONCLUSION

Menopause marks the end of the reproductive years. Most women enter a transitional phase in the years leading up to menopause called perimenopause. Oestrogen is the most effective treatment available for relief of menopausal symptoms, most importantly hot flashes. According to Brinton, “Oestrogen is a ‘Goldilocks’ molecule”. Out of all vasomotor symptoms, the hot flushes and the vaginal symptoms are the most closely associated with menopause. MHT i.e. oestrogen alone or combined with a progestin is currently indicated for management of menopausal symptoms. The goal of MHT is to relieve menopausal symptoms most importantly hot flashes (vasomotor symptoms). Other symptoms associated with perimenopause and menopause that respond to oestrogen therapy (ET) include mood lability/depression, vaginal atrophy, sleep disturbances (when related to hot flashes), and in some cases, joint aches and pains. Oestrogen also have action on multiple organs like; in musculoskeletal, CVS and brain – it reduces bone resorption and increase bone formation; helps in protein synthesis, increases coagulation proteins, decrease LDL and promote fat deposition, helps in the growth and maintenance of hormone-sensitive breast cancers, etc. Counselling women about the risks and benefits is very essential prior to MHT. Follow-up visits should be planned so women are under supervised therapy.

REFERENCES

  1. Schroeder E. From menarche to menopause. Available from: https://women inbalance.org/2014/05/14/from-menarche-to-menopause/ [Accessed on 14 th October 2017]
  2. Estrogen’s effects on the female body. Available from: https://www. urmc.rochester.edu/encyclopedia/content.aspx? ContentTypeID= 85& Content ID= P00559 [Accessed on 16 th October 2017]
  3. Mandal A. Estrogen function. Available from: https://www.news-medical.net/health/What-Does-Estrogen-Do.aspx [Accessed on 14 th October 2017]
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