Womens / HRT

Androgenisation in women

Although androgens such as testosterone are considered to be male hormones, women also produce some androgen but in much smaller amounts.  However, some women produce too much testosterone and this condition is known as androgenisation.  The symptoms of androgenisation include hirsutism, which is unwanted hair in the male pattern, and includes the face, chest and back and is usually thickened and pigmented.  This condition is also associated with acne and/or seborrhoea (greasy skin from too much sebum) and androgen-dependent alopecia (hair loss).  

Anti-Androgens

Treatment of overproduction of androgens is based on blocking the androgen receptor, which prevents testosterone binding to its receptor to reduce the effectiveness of the hormone.  

Types of breast cancers

The majority of breast cancers are estrogen receptor positive (ER) and grow in response to estrogen, although a large number of these tumours are also progesterone receptor positive (ER/PR) and grow in response to progesterone.  Breast tumours that are only estrogen dependent respond well to anti-estrogen treatment which is usually started after surgery and chemotherapy/ radiotherapy.

Another form of breast cancer is responsive to Human Epidermal Growth Factor a protein that stimulates cell growth through a specific receptor (HER-2).  These tumours have more than usual numbers of receptors for HER-2 receptors and tend to be more aggressive and fast growing.  They do not respond to anti-estrogen therapy, although they do respond to another form of therapy that makes use of monoclonal antibodies to target and kill the cancer cells.  

Anti-estogen therapy

Anti-estrogen therapy is used to treat estrogen-dependent breast cancers to prevent their growth and recurrence.  There are two types of anti-estrogen therapy available and they work by different modes of action to reduce the stimulation of the cancer cells by estrogen.

• Selective oestrogen receptor modulator (SERM):  These drugs, such as tamoxifen, block the oestrogen receptor on tumour cells by binding to the receptor but do not mimic the action of estrogen on these cells.  This action prevents the binding of estrogen to its receptor and prevents the growth of early and advanced stage tumours and also helps prevent their recurrence. SERMS do however mimic the action of estrogens on other cells, such as bone cells and can be used to help prevent osteoporosis in post-menopausal women.
• Aromatase inhibitor:  These drugs, such as anastrozole and letrozole, block biosynthesis of oestrogen by inhibiting the action of the enzyme aromatase, which is a critical enzyme in the biosynthesis of estrogen from its precursors, particularly androstenedione, in peripheral tissues such as adipose and breast.¹  Estrone produced by the action of aromatase is then converted to estadiol, which is the more active form of estrogen and binds to the estrogen receptor in breast tumours.  These drugs and can only be used in post-menopausal women, who have stops producing estrogen naturally. 

References

1. Reed MJ.  The role of aromatase in breast tumors.  Breast Cancer Research and Treatment. 1994: 30; 7-17. 

Role of estrogen

Estrogen is the main female sex hormone produced primarily by the ovaries but it is also synthesised in smaller amounts in the adrenal glands and adipose (fat) tissue from androgens in these cells.  Estrogen is responsible for the development of female secondary sexual characteristics, including breast development and body shape and also the regulation of the menstrual cycle, including ovulation, endometrial thickening, and vaginal thickening and secretions. 

Estrogen has actions in various other metabolic processes including maintaining bone density, which is why it protects against osteoporosis in post-menopausal women.  Estrogen also regulates lipid (fat) metabolism to maintain cholesterol levels within normal levels, by reducing LDL cholesterol and increasing HDL cholesterol, thereby offering some protection against cardiovascular disease in post-menopausal women.  

Estrogen is a steroid hormone and works by entering cells of the target tissues, such as ovary, breast and uterus, and binding to its receptor.  The hormone-receptor complex then binds to DNA within the nucleus of the cell to regulate expression of certain genes involved in the production of proteins required for estrogen-dependent processes. 

Different forms of estrogen

Estrogen is not a single hormone but is classed as a group of hormones that exists in various different forms and with different potencies.   They are all synthesised from androgens, particularly androsteinedione, by the enzyme aromatase.

• Estradiol, specifically 17-beta-estradiol or E2, is the major and most active form of natural estrogen in the body.  It is responsible for the main actions of estrogen.  The level of estradiol rises through the first half of the menstrual cycle, reaching a peak just before ovulation and then begins to fall, but reaches another peak during the luteal phase of the menstrual cycle, falling again during the follicular stage before menstruation.  At menopause the production of estradiol ceases and levels drop to a low but constant level.
• Estrone or E1 becomes the most prominent form of natural estrogen during menopause, as estradiol drops, and is produced primarily in the adrenal glands.  Estrone is readily converted into a long lasting form estrone sulphate which concentrates in breast tissue of post-menopausal women and is thought to be involved the development of breast cancer, by being converted to estradiol.  Estrone can also cause breast tenderness or pain, nausea, headache, hypertension, and leg cramps.¹
• Estriol or E3, which is the weakest of the three natural forms of oestrogen.  It is the prominent form of estogen during pregnancy and is produced by the placenta, but plays no significant role in non-pregnant women as it is mild, short acting and normally present in small amounts.
• Conjugated oestrogens are a mixture of several different forms of estrogen (at least 10) isolated from horse urine.  They contain mainly forms of estrogen that are in the sulphate form and can be easily absorbed and converted to the active form estradiol.²
• oestradiol valerate is a prodrug (or precursor) of natural human oestradiol and is converted to 17-beta-estradiol by esterase enzymes in the blood and liver.  It is an effective form of estrogen used for intramuscular administration as it is absorbed slowly and lasts longer that estradiol itself. 
• Ethinyloestradiol is a synthetic form of 17-beta-estradiol that is more resistant to metabolism in the liver than natural estradiol but has the same biological activity. 

Delivery methods of oestrogen for HRT

Estrogen hormone replacement therapy is available in several different preparations and routes of administration.  These include:

• Oral preparations which are subjected to metabolism by the liver and this can cause problems in women with liver problems.  Also the amount of estrogen remaining in the blood after first pass through the liver may not actually correlate with the amount taken due to problems with absorption in some women.  Oral estrogen is associated with side effects, such as painful swollen breasts, nausea, headache and vaginal discharge.   There are also risks associated with estrogen therapy, including risk of stroke, heart attack, blood clots and breast and endometrial cancer.  For these reasons oral estrogen therapy is usually combined with a progestagen.
• Skin patches allow oestrogen to diffuse through the skin and into the blood.  This form of administration allows for lower doses to be used, as estrogen bypasses liver and is therefore, not subject to first pass metabolism by the liver.  It also provides more constant blood levels as it diffuses into the blood at a steady rate.  Also since estrogen in skin patches bypasses the liver they can be used in women with liver problems.  Various forms of estrogen can be used including estradiol, the natural and most active form of estrogen, and estradiol valerate.
• Topical creams containing oestriol or conjugated estrogens are applied into the vagina and used for topical treatment of urogenital symptoms of menopause such as atrophic vaginitis, as it is released slowly and acts directly on the vaginal skin, with little absorption into the blood.
• Topical transdermal gel containing estradiol, which is rubbed into the skin so that the estrogen diffused through the skin directly into the blood circulation.
• Pessaries containing estradiol inserted into the vagina, where it dissolves slowly releasing estradiol to act locally on the vaginal skin.  

References

1. Bhavnani BR. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism.  Proc Soc Exp Biol Med 1998: 217; 6-16
2. Pasqualini JR, Chetrite G, Nguyen B-L, Maloche C et al.  Estrone sulfate-sulfatase and 17β-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence.  J Steroid biochem Mol Biol 1995: 53; 407-412.

Risks of estrogen only versus combination HRT

Hormone replacement therapy (HRT) is used to help relieve symptoms of menopause by replacing female hormones that the body has stopped making naturally.  Most widely used forms of HRT are estrogen only and can be used by women with or without a uterus.  However, postmenopausal women who have not had a hysterectomy may be at risk of endometrial cancer after long-term HRT, due to continued action of oestrogen on the endometrium.

Oestrogen stimulates growth and proliferation of the endometrium and without the normal hormonal balance provided by progesterone, this stimulation by oestrogen can lead to excessive proliferation of the endometrial cells or endometrial hyperplasia, which increases risk of endometrial carcinoma.  The addition of a progestogen (natural or synthesised progesterone) counteracts the stimulatory effect of oestrogen, acting in a similar way to natural progesterone.

However, there is some evidence that oestrogen plus progestin can increase risk of breast cancer and ovarian cancer.  With more published studies more evidence is available to assess the relative risks of various forms of HRT.^1-3 Opinion regarding  Oestrogen only HRT are also changing and it is now thought that Oestrogen only HRT does not increase risk of breast cancer or substantially interfere with breast cancer detection by mammography. ³

Types of combination HRT

Combination HRT is available as tablets comprising combination of various forms of Oestrogen and progestin, including:

• Conjugated Oestrogens and Medroxyprogesterone 
• Oestradiol and Norethisterone

References

1. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F.  Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.  J Steroid Biochem Mol Biol 2005: 96; 95-108.
2. Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, Lane DS, Johnson KC, Wactawski-Wende J, Chen C, Qi L, Yasmeen S,Newcomb PA, Prentice RL. Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study.  J Natl Cancer Inst. 2013: 105; 526-35.
3. Chlebowski RT andGarnet L. Anderson GL.  Changing Concepts: Menopausal Hormone Therapy and Breast Cancer. J Natl Cancer Inst. 2012: 104; 517-27. 

Stages of conception

For a pregnancy to be successful there are several stages of a process that must be achieved. These include:

• Ovulation, which is the release of the egg from the ovary.
• Passage of the egg through the fallopian tube into the uterus.
• Fertilisation of the egg by the sperm, which usually takes place as the sperm meets the egg on its way through the fallopian tube towards the uterus. 
• Embryo development from the fertilised egg (now the zygote), which remains in the fallopian tube for 2-3 days and begins to divide forming the embryo. 
• Implantation of the embryo at day 5-7 post fertilisation into the endometrial lining of the uterus to form the placenta. 

Causes of infertility

Infertility is defined by the World Health Organisation as the inability to become pregnant after one year of unprotected intercourse.  In about 30% of infertility cases the problem lies with the woman and this can be the result of several factors:

• Ovulation failure (anovulation) due to hormonal problems, such as overproduction of testosterone (usually associated with polycystic ovary syndrome), or over production of prolactin by the pituitary gland, which suppresses oestrogen production by the ovaries.
• Luteal phase defect, which is due to insufficient production of progesterone by the ovaries, and can result in failure of the endometrium to develop sufficiently for implantation. 
• Blocked or damaged fallopian tubes (salpingitis) which prevents the egg from becoming fertilised and reaching the uterus. This could be due to pelvic inflammatory disease (usually caused by a sexually transmitted disease) endometriosis, adhesions, or surgery for ectopic pregnancy.
• Endometriosis can be the cause of infertility and is the growth of endometrial tissue outside the uterus, which can affect the normal functioning of the female reproductive system.
• Problems with the uterus, which can be a defect in the shape or the growth of benign tumours called fibroids.
• Treatments for cancer, particularly if they affect the cervix, uterus, endometrium or other parts of the female reproductive system.
• Certain medical conditions that can affect the normal menstrual cycle, such as kidney disease, thyroid problems or diabetes.
• Early menopause related to early ovarian failure.

Ovulation

Ovulation is dependent on a series of hormonal interactions that result in the release of an egg from the ovary.

Oestrogen levels produced by the ovary are low during the first phase of the menstrual cycle; known as the follicular phase and when oestrogen levels drop this induces the release of FSH (follicle stimulating hormone) from the hypothalamus, which stimulates growth and maturation of the ovarian follicle that releases the egg.  As the ovarian follicles mature, oestrogen levels rise and this induces the release of LH (luteinizing hormone) from the pituitary gland. 

Both LH and FSH are under the control of regulating hormones produced by the hypothalamus called gonadotropin releasing hormones (GnRH).  An intricate feedback mechanism exists between the hormones involved in regulating the menstrual cycle and if any part of the interaction of hormones malfunctions, this can prevent ovulation a condition known as  anovulation

When LH reaches a peak, known as the LH surge, this stimulates rupture of the dominant follicle releasing a mature egg and this is ovulation.  The other follicles die down and the active ruptured follicle becomes the corpus luteum and starts producing progesterone, which induces the endometrium (lining of the uterus) to thicken and ripen ready for conception. 

Treatments to restore ovulation

One treatment for infertility due to anovulation is the use of clomiphene, a drug known as a selective oestrogen receptor modulator or SERM.  This binds to the oestrogen receptor in the hypothalamus and instead of stimulating the receptor it blocks its action, resulting in low levels of oestrogen.  When levels of oestrogen fall this triggers release of FSH from the anterior pituitary and this helps return the menstrual cycle back under normal hormonal control, which should result in ovulation.  

What is osteoporosis?

Osteoporosis is a systemic skeletal condition where bone density is reduced and bone tissue loses its intricate structure so that the bones become weak and brittle, which increases risk of fracture.  There are usually no symptoms until a bone is broken or fractured and the condition can develop gradually over many years.  Fractures occur most commonly in the spine, hip and wrist which are painful and vertebral fractures can also result in loss of height.

Although osteoporosis can affect anyone, post-menopausal women are the most susceptible, as reduced levels of oestrogen contribute to the deterioration of bone mass.  Surgical removal of the ovaries also results in low levels of oestrogen.  The incidence of osteoporosis continues to increase with increasing risk of fracture, which causes considerable pain and disability and imposes a considerable financial burden on health services.¹

The diagnosis and management of osteoporosis is guided by international guidelines and includes the use of measurements for bone density, assessment for risk of fracture as well as the use of biological markers of bone metabolism.^{2, 3, 4}

Risk factors for osteoporosis

Bone density is a measure of the amount of bone tissue in a given volume of bone.  Bones reach peak density at the age 30-35 then start to decline with increasing age. 

There are several risk factors for reduced bone density leading to osteoporosis and increased risk of fracture, including:

• long-term treatment with a corticosteroid, an anti-inflammatory steroid,
• family history of osteoporosis
• lifestyle factors such as, inactivity, smoking, high alcohol or caffeine consumption
• low levels of vitamin D, as can result if insufficient exposure to sunlight
• low dietary calcium intake

some medical conditions such as Cushing's syndrome, in which the adrenal glands produce too much cortisol a natural corticosteroid.

Bone turnover

Bone is a complex connective tissue comprised of living bone cells and a matrix in which the cells are suspended.  The matrix comprises a soft component of collagen, a fibrous protein that is found in all connective tissue and provides bone with flexibility to withstand stress; and a hard mineral component hydroxyapatite, which is made up of deposits of calcium and phosphate and provides bone with its strength and rigidity.

There are wo different types of bone cells:

• Osteoblasts that are responsible for bone formation and building the matrix by producing collagen and releasing calcium and phosphate ions in a process called mineralisation to form hydroxyapatite.
• Osteoclasts that are responsible for bone resorption, whereby they dissolve old bone and remove matrix, which releases calcium and phosphate to be reused by the body.

Bone is a dynamic tissue and is constantly undergoing remodelling, a process of bone turnover by which old bone is broken down and replaced with new bone so that bones can grow and repair throughout life.  This process is the result of opposite activities of the osteoblasts and the osteoclasts and is regulated by a range of growth factors, hormones and cytokines.

Maintenance of bone structure and strong bones is dependent on a balance of bone turnover with bone formation matching bone resorption as needed.  An imbalance in the regulation of bone remodelling results in metabolic bone disease such as osteoporosis, when more bone is broken down than new bone is formed; and this shift in balance of bone turnover increases with age, particularly post-menopause.  Also an overall increase in bone turnover is thought to be a major cause of osteoporosis.⁵

Role of calcium metabolism in bone density 

Calcium is an important mineral for many body functions, including blood clotting, nerve transmission and maintaining bone mass, and is found primarily in bone.  It is stored in bone and can be released from bone when needed. Calcium metabolism depends on three mechanisms: intestinal absorption, reabsorption in the kidneys, and bone turnover, and these mechanisms are in turn regulated by Parathyroid Hormone (PTH) and 1,25-dihydroxyvitamin D3, which is the active form of vitamin D. 

The majority of Vitamin D is obtained from synthesis in the skin by the action of natural sunlight and a small proportion is obtained from the diet.  It is then converted to its active form by the action of enzymes in the liver and the kidney.  Vitamin D promotes calcium absorption and also increases bone density by promoting osteoblast differentiation and bone mineralisation.  Conversely, PTH increases the levels of blood calcium by promoting its absorption from the intestines and reabsorption in the kidneys.  PTH also promotes calcium release from bone by triggering bone resorption through binding to osteoblasts which then produce signals activating osteoclast to begin bone resorption. 

Bisphosphonates for osteoporosis management

Bisphosphonates are synthetic chemicals similar to pyrophosphate, the naturally occurring mineral in bone.  Several bisphosphonates have been developed, with different potencies depending on their structure.  They are potent inhibitors of bone resorption and work by binding with high affinity to hydroxyapatite (the scaffolding of bone architecture), specifically at the site of bone resorption and inhibiting the action of osteoclasts.

When taken orally, bisphosphonates have low availability with only around 1% of an oral dose being absorbed and of that dose around 50% ends up binding to bone.

The dose given depends on the potency of the bisphosphonates, which include: alendronate, etidronate, and risedronate.  Alendronate 70 mg once weekly and risedronate 35 mg once weekly are the most commonly used bisphosphonates worldwide and have been shown to significantly reduce risk of fracture in postmenopausal women. ⁴

The bisphosphonates zoledronic has been developed for intravenous infusion and is taken once a year to treat osteoporosis and reduce risk of fracture.  

Other therapies for osteoporosis

The selective estrogen receptor modulators (SERM) raloxifene is used to treat and prevent osteoporosis.  It works by binding to the oestrogen receptor in various tissues and acts as an oestrogen agonist or antagonist, depending on the target tissue.  Raloxifene has beneficial effects on bone by decreasing bone resorption and increasing bone density and mineralisation, restoring the balance in bone turnover and reducing the overall rate of bone remodelling, which has been shown to reduce risk of fracture, particularly vertebral fracture.  However it has anti-oestrogenic effects on the endometrial and breast tissue, and therefore, does not increase risk of oestrogen dependent cancers. ⁶

Calcitriol is the active metabolite of vitamin D that regulates calcium metabolism and also regulates bone remodelling by reducing bone resorption and promoting bone mineralisation.  Calcitriol is also used to treat osteoporosis to reduce risk of vertebral and hip fractures. 

References

1. Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006;38 (2 Suppl 1):S4-9.
2. Garnero P. Bone. 2014;66:46-55.  New developments in biological markers of bone metabolism in osteoporosis.
3. Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther. 2008;12:157-70.
4. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli, R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int.2013: 24; 23–57.
5. Garnero P, Sornay-Rendu E, Chapuy  M-C, Delmas  PD.  Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Min Res 1996; 11: 337-349
6. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial.JAMA1999;282:637-45.

What is PCOS?

Polycystic Ovary Syndrome (PCOS) is a common condition found in Pre-menopausal women and is characterised by the appearance of many small cysts along the outer edge of the ovary.  The condition is thought to have a genetic component and is caused by an imbalance in the hormones that regulate ovulation (Follicle Stimulating Hormone, FSH and Leutinising Hormone, LH).  This prevents the normal development of the ovarian follicle, resulting in fluid filled sacs or cysts containing an immature egg. 

PCOS is also associated with other metabolic syndromes, which includes high blood cholesterol, obesity, high levels of insulin and Insulin resistance, all of which predispose to increased risk of type 2 diabetes and cardiovascular disease.

High insulin levels are thought to stimulate over production of androgens by the ovaries and this can disrupt the normal female hormone balance and cause several of the symptoms associated with PCOS. 

Symptoms of PCOS

Symptoms of PCOS inclue:

• irregular menstrual periods , which can be infrequent, prolonged or absent
• Hirsutism, excess unwanted hair growth on the face and body
• Acne
• Androgenic alopecia, hair loss
• Seborrhoea, greasy skin from overproduction of sebum
• Weight gain
• Infertility

Treatments for PCOS

Treatments for PCOS focus on the symptoms and can include use of diabetic medications to reduce insulin levels, oral contraceptive pills to regulate menstrual cycle and antiandrogens to reduce androgen production and prevent symptoms due to overproduction of androgens.

A combination medication is available containing ethinyloestradiol, a synthetic oestrogen and cyproterone acetate, an antiandrogen that work together to reverse the effects of too much androgen, like acne and hirsutism.

What are progestins?

Progestins are a synthetic version of natural progesterone, with similar bioactivity.  They were originally developed to for their contraceptive potential and to counteract the problems of administering natural progesterone.  When taken orally natural progesterone has low bioavailability because it is rapidly metabolised in the gastrointestinal tract by up to 90% on first pass through the liver and therefore can only be used in high doses or when administered by injection.  Other administrative forms of natural progesterone have been developed to protect from metabolism, including micronized progesterone, in which a plant source of progesterone is used and reduced to tiny particles and delivered in oil filled capsules so that it is more readily absorbed.^{1, 2}

Several generations of progestins have been developed for use in contraceptives, to suppress ovulation usually in combination with an oestrogen; also for hormone replacement therapy to counteract the effects of oestrogen to reduce risk of endometrial cancer.  Most progestins, like norethisterone a first generation progestin and desogestrel a third generation progestin, have weak androgenic activity, although some progestins like medroxyprogesterone do have more noticeable androgenic side effects.  Other porgestins like dydrogesterone do not exhibit androgenic side effects such as hirsutism, acne.

Note:  Progestogen is a term that includes natural progesterone such as micronized progesterone as well as progestins such as medroxyprogesterone. 

What progestins are available?

Several progestins are available and they can be delivered in various forms.  These include:

• Desogestrel tablets
• Dydrogesterone tablets
• Norethisterone tablets
• Medroxyprogesterone liquid for injection and tablets
• Micronized progesterone in a topical gel or capsules
• Natural Progesterone injection

Clinical uses for progestins

Progestins are used to treat several conditions, including the following:

• Endometriosis, which is growth of endometrial tissue outside the uterus causing pain and bleeding.  Progestins used include medroxyprogesterone injection and tablets, dydrogesterone tablets and norethisterone tablets.
• Menstrual disorders and uterine bleeding disorders.  Progestins used include dydrogesterone, norethisterone, and the natural progesterone injection.
• To assist with infertility treatments by providing luteal support for infertility treatment.  Progestins used include micronized progesterone gel.
• To prevent spontaneous abortion (miscarriage).  Natural progesterone injection is used for this purpose.
• To counteract the stimulating effect of oestrogen on the endometrium, in hormone replacement therapy (HRT) for menopausal symptoms, thereby reducing the risk of endometrial cancer.  Progestins used include Dydrogesterone tablets, micronized progesterone, and medroxyprogesterone tablets.
• Contraception.  Progestins used include desogestrel tablets
• To treat (but not cure) certain oestrogen-related cancers like breast, endometrial and renal carcinomas.   When used at high doses, progestins can inhibit the growth of these tumours.  Progestins used include medroxyprogesterone injection. 

References

1. Warren MP and Shantha S.  Uses of progesterone in clinical practice.  Int J Fertil Womens Med.  1999: 44; 96-103
2. Hargrove JT, Maxson WS, Wentz AC.  Absorption of oral progesterone is influenced by vehicle and particle size. Am J Obstet and Gynecol. 1989: 161; 948–951. 

What are hot flushes?

A hot flush or flash is a very common symptom of menopause.  It is described as a feeling of sudden intense internal heat often accompanied by sweating and redness in the face.  Hot flushes are caused by a rapid dissipation of heat from the body due to dilatation of peripheral blood vessels close to the skin.  Normally the body has a wide range of temperatures, called the thermoneutral zone (TNZ), in which body temperature can be maintained without any metabolic expenditure such as sweating or shivering. 

As oestogen levels fall at menopause this contributes to a reduced TNZ such that small increases in core body temperature can trigger responses like flushing and sweating to reduce body heat.  This response is thought to be mediated by activation of the central sympathetic nervous system and this in turn is regulated by alpha adrenergic receptors in the central nervous system.  The regulation of body temperature is controlled by neurotransmitters like noradrenaline, which causes dilation of peripheral blood vessels. 

Oestrogen influences the thermoregulation centres in the hypothalamus of the brain and a fall in oestrogen at menopause is thought to disrupt the regulation by noradrenaline of body temperature.  Treatment with an alpha blocking medication like clonidine inhibits release of noradrenaline in the central nervous system and this in turn reduces vasodilation of peripheral blood vessels which helps relieve symptoms of hot flashes¹.  

Synthetic hormones for HRT

The synthetic steroid hormone tibolone can be used for HRT to treat symptoms of menopause.  Although tibolone itself has no biological activity it is rapidly metabolised into metabolites that have estrogenic, androgenic and progestagenic properties.   The active metabolites of tibolone have estrogenic effects on bone and vaginal tissue and function as a progestagen In endometrial tissue, whereas in the brain and liver they have androgenic effects.  In breast tissue tibolone blocks the conversion of estrone sulfate to the more active oestrogen oestrodiol, which may reduce the risk of breast cancer².  

Sequential hormone therapy for HRT

The use of sequential hormone therapy is an alternative form of HRT compared with the more commonly used continuous HRT.  The regime for sequential hormone therapy begins with a phase of oestrogen only followed by a combination of oestrogen with progesterone, for the remainder of the cycle, returning to oestrogen only again at the start of the next cycle.  For sequential hormone therapy oestrodiol has been combined with cyproterone, a progesterone derivative with weak progestational activity as well as anti-androgen activity and has been found beneficial in relieving symptoms of menopause.  

References

1. Freedman RR.  Menopausal hot flashes: mechanisms, endocrinology, treatment.  J Steroid Biochem Mol Biol.2014;142:115-20.
2. Modelska K, Cummings S.  Tibolone for postmenopausal women: systematic review of randomized trials.  J Clin Endocrinol Metab. 2002; 87:16-23.