MENOPAUSAL DISORDERS IN ELDERLY FEMALE

A. Menopause: Menopause is defined as absence of menstrual periods for a period of 12 months.

B. Premature menopause: Premature menopause (premature ovarian failure) is the permanent end of menstrual periods before age 40 because the ovaries become unable to produce hormones and ovulation stops.

C. Peri-menopause means "around the time” of menopause i.e. from irregular cycles to absence of menstrual cycle.

D. Post-menopause is the entire period of time that comes after the last menstrual period.

A. MENOPAUSE

Introduction: Menopause is the time in a woman's life when the function of the ovaries ceases to produce estrogens and progesterone. This occurs either naturally or due to surgical removal.

Age of the Menopause: The average age of menopause is 51 years. Most women reach menopause between the age of 45 to 55, but menopause may occur as earlier as the 30s or 40s or may not occur until a woman reaches 60.

Reasons of Menopause:

  • Part of normal Physiology.
  • Certain medical and surgical conditions as surgical removal of the ovaries along with removal of the uterus (Pan Hysterectomy), Cancer chemotherapy and radiation therapy.
  • Premature ovarian failure i.e. occurrence of menopause before the age of 40. This condition occurs in about 1% of all women.

Symptoms of Menopause

  • Irregular vaginal bleeding
  • Hot flushes, night sweats and/or cold flashes, clammy feeling.
  • Loss of libido / Loss of Hairs.
  • Difficulty in sexual intercourse (dyspareunia) due to Dry vagina.
  • Vaginal /Urinary infections due to dryness, thinning, and less elasticity of vagina due to declining estrogen levels.
  • Breast tenderness.
  • Dizziness, light-headedness, episodes of loss of balance
  • Emotional and cognitive symptoms: As Irritability / Mood swings, sudden tears / Depression / Crashing fatigue with or without night sweats. Women often report a variety of cognitive (thinking) and/or emotional symptoms.
  • Other physical changes: Many women report some degree of weight gain along with menopause. The distribution of body fat may change, with body fat being deposited more in the waist and abdominal area than in the hips and thighs. Changes in skin texture, including wrinkles.
  • Since the body continues to produce small levels of the male hormone testosterone, some women may experience some hair growth on the chin, upper lip, chest, or abdomen.

Climacteric or Menopausal complaints:

These can be categorized as following:

1.    PSYCHOSOMATIC COMPLAINTS: Some vague complaints of functional disturbances like Insomnia, depression, Irritability and Headache.

2.    VASOMOTOR COMPLAINTS: Hot flushes, Night sweat, Leg cramps, Fomication (Burning or insect crawling type sensation in legs & skin), fatigue and weakness.

3.    METABOLISM RELATED COMPLAINTS: Hypertension, palpitation, Demineralisation of bones (Osteoporosis) causing Backache, increased fall and fracture rate. Lowered skin immunity and health leading to wrinkling, breast flabbiness, hair loss and nail thinning.

Vaginal atrophy due to low estrogen levels result in vaginal wall thinning and vaginal dryness. All of these lead to lowered vaginal immunity and dyspareunia, itching & pruritis.

Low levels of Testosterone result into loss of libido, decrease bone & muscle strength leading to family problems between husband & wife.

COMPLICATIONS OF MENOPAUSE:

1. Osteoporosis:

Osteoporosis is the deterioration of the quality of bone that causes an increased risk of fracture. The density of the bone (bone mineral density) normally begins to decrease in women during the fourth decade of life. However, that normal decline in bone density is accelerated during the menopausal transition. As a consequence, both age and the hormonal changes due to the menopause transition act together to cause osteoporosis. The prevention of osteoporosis is as important as treatment. Osteoporosis treatment and prevention measures are:  Lifestyle changes including cessation of smoking, exercising regularly, and consuming a balanced diet with adequate calcium and vitamin D.

2. Cardiovascular disease:

Prior to menopause, women have a decreased risk of heart disease and stroke when compared with men. Around the time of menopause, however, a women’s risk of cardiovascular disease increases. Coronary heart disease rates in postmenopausal women are two to three times higher than in women of the same age who have not reached menopause; this increased risk for cardiovascular disease may be related to declining estrogen levels.

3. Others: Depression, Anxiety, Hypertension, Urinary/Vaginal infections etc. 

TREATMENT APPROACH OF MENOPAUSE

Menopause itself is a normal part of life and not a disease that requires treatment. However, treatment is possible if the symptoms of menopause become substantial or severe. These treatment options are:

A. Hormonal Therapy

Estrogen and progesterone when taken together is called as Hormone Replacement Therapy (HRT).

§         Estrogen replacement therapy:

Estrogen replacement is used for symptoms associated with menopause: Hot flashes (feelings of warmth in the face, neck, and chest), sweating, sleep disturbance, vaginal discomfort (dryness and itchiness), poor concentration, and irritability. However, Estrogen therapy alone relieves menopausal symptoms by 76% but has potential to increase the risk of stroke, clot formation, endometrial proliferation and endometrial cancer. Besides estrogen also cause nausea & vomiting and heavy vaginal bleeding on therapy withdrawal.

 

 

§         Estrogen and progesterone therapy:

Hormone therapy (HT), also referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy (PHT), consists of estrogens or a combination of estrogens and progesterone (progestin). Hormone therapy has been used to control the symptoms of menopause related to declining estrogen levels such as hot flashes and vaginal dryness, and moreover this combination therapy lowers the risk of endometrial cancer Vs ERT.

HT is still the most effective way to treat these symptoms but long-term studies of women receiving combined hormone therapy still had an INCREASED RISK FOR HEART ATTACK, STROKE, and AND BREAST CANCER when compared with women who did not receive HRT.

§         Androgen -Estrogen therapy:

Combination of estrogen and testosterone (1:20) is one of the most effective treatment for menopause associated symptoms and complications at all stages of severity as it brings result in 85% of the menopausal females. And perhaps is the best therapy to avoid estrogenic bleeding as well as nausea and vomiting. Menopausal women can sense the complete sense of well being from troubling symptoms and can enjoy her sexual life to better extent. It works better when combined with short & long acting hormones of estrogen and testosterones. 

Role of Estrogen and testosterone in acute menopausal Stress:

Estrogens are produced by the body in greater amounts in females. They are necessary for normal sexual development of the female and for regulation of the menstrual cycle during the childbearing years. Androgens are produced mainly in males in greater however, androgens are also present in females in small amounts. Menopausal women are deficient in estrogen, progesterone, testosterone and DHEA. Hormone replacement therapy (HRT) generally consisted of one or two agents, typically estrogen and   progesterone, with increased risk of heart attack, stroke, dementia, and breast cancer. Female sexual dysfunction is a complex problem seen in menopausal state with multiple overlapping etiologies. Androgens play an important role in healthy female sexual function, especially in stimulating sexual interest and in maintaining desire. Symptoms of androgen insufficiency include absent or greatly diminished sexual motivation and/or desire, that is, libido, persistent unexplainable fatigue or lack of energy, and a lack of sense of well being. Numerous studies support that combination of testosterone AND estrogen is effective for treatment of menopausal symptoms, such as flushing, sweating, and sleep disturbance. Furthermore, testosterone therapy has been shown to improve psychosexual function, e.g., arousal, desire, satisfaction, and well-being in postmenopausal women.

Modest 45 is a combination of estrogen with testosterone and is an effective combination for treatment of acute menopausal symptoms. The exact duration of treatment is dependent on severity of the symptoms which generally varies from 3-6 mths or even more. This medication is given by injection into a muscle every 3 to 4 weeks depending on condition and response.

 

B. Alternative therapies

Plant estrogens (Phytoestrogens, Isoflavones etc.) are very useful in relieving menopausal symptoms and its complications like Osteoporosis and atherosclerosis etc. without causing any serious side effects. These are not very helpful in reliving the acute symptoms of menopause due to low efficacy but can be given for prolonged period.

 

As soon as the severity of the symptoms is controlled the injection should be withdrawn and be replaced with oral treatment with phytoestrogens /Oral isoflavonoids as Cap. OSTA-Eve which can be given for 1 to >2 yrs depending upon the menopausal symptoms.

Inj. Modest-45

COMPOSITION

Each ampoule of 1 ml contains:

Estradiol benzoate                        1 mg

Estradiol phenylpropionate             4 mg

Testosterone propionate                         20 mg

Testosterone phenylpropionate                40 mg

Testosterone isocaproate              40 mg      in Ethyl oleate base

PHARMACOLOGICAL CLASSIFICATION

Androgen-Estrogen combinations

PHARMACOLOGICAL ACTION & RATIONALE OF COMBINATION

§         Estradiol or Oestradiol is a form of estrogen. Estrogen is a female sex hormone necessary for many processes in the body. Estradiol is used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to treat lack of estrogen caused by ovarian failure or a condition called hypogonadism.

§         Testosterone is though considered as male hormone but in the females also it is secreted by the ovaries and adrenal cortex (1/7th of Male’s quantity) for bodily requirements like sexual desire, libido, muscle and bone strength and lack of energy.

Moreover, the combination of Estrogen and Androgen antagonize the side effects of each other that are seen when given alone.

INDICATIONS

§         Estrogen deficiency symptoms associated with the natural or surgical menopause (Ovariectomy).

§         Loss of libido or decreased energy levels following menopause.

§         Postpartum cessation of lactation in case of infant death.

 PHARMACOKINETICS:

Estrogens are rapidly absorbed after administration. They are also absorbed when applied to the skin and mucous membranes and can produce systemic effects. After absorp­tion, they are highly plasma protein bound (about 90%). They are metabolized mainly in the liver and excreted in urine. Modest 45 is combination of various salts of Estradiol on basis of duration of action as Estradiol benzoate (Short-acting) and Estradiol Phenyl-Propionate (Long-acting).

Testosterone: Well absorbed by all routes of administration. It has a very short biological half life (5 to 10 minutes). When administered IM in oily solution it is slowly absorbed and produces prolonged action. These are hydrolyzed into the natural hormone testosterone as soon as they enter the general circulation. A single dose of Modest 45 leads to an increase of total plasma testosterone with peak levels of approximately 70nmol/L (Cmax), which are reached approximately 24-48h (Tmax) after administration. Testosterone is metabolized via the normal pathways. Excretion mainly takes place via the urine. Modest 45 is combination of various salts of testosterone on basis of duration of action as Testosterone Propionate (Short acting), Testosterone Phenyl-Propionate (Long-Acting).

CONTRA-INDICATIONS

Pregnancy, Cardiovascular or Cerebro-vascular disorders, e.g. thrombophlebitis, thrombo-embolic processes or a history of these conditions, Hypertension, Severe migraine, Liver disorders; Cholestatic jaundice; a history of jaundice of pregnancy or jaundice due to estrogen/androgen use.

 

DOSAGE AND DIRECTIONS FOR USE

1.    Climacteric symptoms: 1 injection of 1 mL every 3 to 4 weeks un till the symptoms are controlled. Afterwards, one ampoule IM once per month.

2.    For cessation of lactation: Two ampoule stat after delivery.

3.    Following Salpingo-oophorectomy / Pan Hysterectomy: One ampoule IM stat and to be repeated as desired.  Modest 45 should be administered by deep intramuscular injection.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS

The following adverse reactions have been associated with either estrogen or androgen therapy alone or in combination:

Ø       Genito-urinary tract: Excessive production of cervical mucous, aggravation of endometriosis, enlarged clitoris, Breast tenderness & pain.

Ø       Gastro-intestinal tract: nausea, vomiting, cholelithiasis, cholestatic jaundice.

Ø       Cardiovascular system: Thrombosis, rise of blood pressure.

Ø       Central nervous system: headache, migraine, mood changes.

Ø       Others: water and salt retention, reduced glucose tolerance, change in body mass, hoarseness or deepening of the voice.

BENEFITS OF MODEST 45 Injection

Modest 45 is a balanced combination of Oestradiol esters and Testosterone esters of some short and long acting hormones.

·         Unlike alone estrogen therapy, Modest 45 provides all the essential hormones to correct the internal hormonal changes occurring during and after menopause and also helps her in maintaining the essence of life eg. Psychosomatic, vaso-motor and metabolic well being without compromising her sexual desires hence helps her in improving the quality of life.

·         Moreover. Modest 45 is prepared in Ethyl oleate base so it is less viscous, more mobile and painless injection, hence ensure better patient compliance.

·         Unlike others we are providing DISPOPACK i.e. Ampoule with a syringe.

PRESENTATION & PRICE:  DISPOPACK i.e. 1 ml ampoules with syringe.    MRP. Rs. 126.00

STORAGE INSTRUCTIONS

The ampoules should be protected from light and kept at temperatures below 30°C. Keep out of reach of children.

Reference support

J Clin Endocrinol Metab. 2007 Jun;92(6):2169-75. Epub 2007 Mar 6.

Effects of testosterone treatment on endometrial proliferation in postmenopausal women.

Zang H, Sahlin L, Masironi B, Eriksson E, Lindén Hirschberg A. Department of Woman and Child Health, Division of Obstetrics and Gynecology, Karolinska Institutet, SE-171 76 Stockholm, Sweden. hong.zang@ki.se

CONTEXT: Available data concerning effects of testosterone on endometrium of postmenopausal women are seriously limited. OBJECTIVE: Our aim was to compare the influence of treatment with testosterone and/or estrogen on endometrial proliferation in healthy postmenopausal women. DESIGN: This was an open, randomized clinical study with parallel comparison of the groups. SETTING: The study was conducted at a women's health clinical research unit and a research laboratory at a university hospital. PARTICIPANTS: Sixty-three women who had experienced natural menopause participated in this study. INTERVENTIONS: After random assignment, the participants were administered orally testosterone undecanoate (40 mg every second day), estradiol valerate (2 mg daily), or both for 3 months. MAIN OUTCOME MEASURES: Endometrial thickness was measured, and endometrial proliferation evaluated on the basis of histopathology and expression of Ki-67, a proliferation marker. RESULTS: Endometrial thickness was significantly increased by treatment with estrogen alone or in combination with testosterone but was unaltered by testosterone alone. Among the women receiving estrogen alone, the proportion exhibiting histopathology indicative of proliferation increased significantly to 50% (P < 0.05), there was a nonsignificant increase to 28% with the combined treatment, whereas testosterone alone had no effect at all. Expression of Ki-67 was up-regulated significantly in both glands and stroma (P < 0.05, respectively) in both estrogen treatment groups. However, the expression was significantly higher in stroma by estrogen treatment alone than after combined treatment (P < 0.05). CONCLUSIONS: The short-term treatment with testosterone of postmenopausal women does not stimulate endometrial proliferation. In addition, testosterone appears to counteract endometrial proliferation induced by estrogen to a certain extent.

 Eur J Endocrinol. 2009 Apr;160(4):681-7. Epub 2009 Jan 27.

Measures of bioavailable serum testosterone and estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study.

van Geel TA, Geusens PP, Winkens B, Sels JP, Dinant GJ.

Department of General Practice, Maastricht University, Maastricht, The Netherlands. t.vangeel@hag.unimaas.nl

OBJECTIVE: The physiologic role of circulating endogenous testosterone and estrogen concentrations in relation to lean body mass (LBM) and muscle strength is not as well documented in postmenopausal women as in elderly men. DESIGN: Three hundred and twenty-nine healthy postmenopausal women were randomly selected from a general practice population-based sample aged between 55 and 85 years. METHODS: Total testosterone and estrogen (TT and TE) and sex hormone-binding globulin (SHBG) were determined and estimates of bioavailable testosterone (free androgen index (TT/SHBG, FAI), calculated free testosterone (cFT), and estrogen (TE/SHBG, ESR) were calculated. Examinations included bone mineral density (BMD) of the spine and femoral neck (FN), LBM, maximum quadriceps extension strength (MES) and maximum handgrip strength (MGS), timed up-and-go test (TUGT), osteocalcin (OC), and urinary deoxy-pyridinoline/creatinine (DPyr). Correlations were assessed using Pearson's correlation coefficient (r). RESULTS: With advancing age, LBM, MES, MGS, BMD, and ESR significantly declined (range r: -0.356 to -0.141) and TUGT, and DPyr significantly increased (range r: 0.135 to 0.282 (P<0.05)). After age-adjustment, LBM, MES, and BMD in spine and FN were significantly related to bioavailable testosterone (range r: 0.146 to 0.193, for cFT, and 0.157 to 0.224, for FAI) and to ESR (range r: 0.162 to 0.273). OC and DPyr were significantly inversely related to ESR (r: -0.154 and -0.144 respectively). CONCLUSIONS: Age-related loss of LBM, MES and BMD in postmenopausal women is partly dependent on the presence of testosterone and estrogen.

J Endocrinol. 2010 Aug;206(2):217-24. Epub 2010 May 18.

Sex hormone modulation of proinflammatory cytokine and C-reactive protein expression in macrophages from older men and postmenopausal women.

Corcoran MP, Meydani M, Lichtenstein AH, Schaefer EJ, Dillard A, Lamon-Fava S.

Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, Massachusetts 02111, USA.

Inflammation plays a central role in the development and progression of coronary heart disease (CHD). The sex hormones estrogen and testosterone have been shown to modify the inflammatory response by influencing cytokine expression in human macrophages obtained from younger individuals. The effect of these hormones on the expression of proinflammatory markers in macrophages obtained from a CHD age-relevant population has not been studied. Human monocyte-derived macrophages (HMDMs) were obtained from healthy normolipidemic men and postmenopausal women (age 50-70 years), and cultured in autologous serum along with both physiological and supraphysiological concentrations of estrogen or testosterone. HMDMs were stimulated with oxidized low-density lipoproteins, and the expression of the cytokines tumor necrosis factor alpha (TNF-alpha or TNF), interleukin (IL)6, and IL-1 beta (IL1B) and of the acute-phase protein C-reactive protein (CRP) was measured. Both physiological and supraphysiological concentrations of testosterone reduced the expression and secretion of TNF-alpha and reduced the expression of IL-1 beta, but did not affect the expression of IL6 or CRP. Estrogen did not modify the expression of TNF-alpha, IL6, and IL-1 beta. Estrogen caused a variable response in CRP expression that was positively associated with the plasma small dense LDL-cholesterol concentration of the donors. There were no gender differences in any of the observed effects. Our results indicate that testosterone may exert anti-inflammatory effects by reducing macrophage TNF-alpha expression, while the effects of estrogen on macrophage CRP expression may depend upon the extracellular lipid environment.

Obesity (Silver Spring). 2010 Mar;18(3):604-10. Epub 2009 Aug 20.

Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study.

Janssen I, Powell LH, Kazlauskaite R, Dugan SA.

Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois, USA. Imke_Janssen@rush.edu

Visceral fat (VF) increases with the menopause and is an independent predictor of the metabolic syndrome, diabetes, and cardiovascular disease (CVD) in women. Little is known about how hormonal changes during the menopausal transition are related to the increase in VF. We aimed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors. The Study of Women's Health Across the Nation (SWAN) is a longitudinal, community-based study. This report uses baseline data from a population-based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)-assessed VF in women at different stages of the menopausal transition. Included are 359 women (47.2% black), aged 42-60 years, who were randomly selected from a complete community census in which a 72% participation rate was achieved. In multivariate models, bioavailable testosterone was associated with VF independent of age, race, percent total body fat, and other cardiovascular risk factors. Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone-binding globulin (SHBG). As bioavailable testosterone was associated with VF even after adjusting for insulin resistance, this suggests that it plays an important role in regional fat distribution. Our findings may have direct implications in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk.

Gynecol Endocrinol. 2008 Dec;24(12):691-5.

Effect of androgens combined with hormone therapy on quality of life in post-menopausal women with sexual dysfunction.

Blümel JE, Del Pino M, Aprikian D, Vallejo S, Sarrá S, Castelo-Branco C. Facultad Medicina, Departamento Medicina Sur, Universidad de Chile, Santiago de Chile, Chile.

AIM: To evaluate with validated instruments changes in quality of life and sexuality in women receiving hormonal replacement therapy (AHT). DESIGN: Randomised, double-blind, double-dummy study with two parallel treatment arms. PATIENTS AND METHODS: Forty-seven healthy post-menopausal women, aged 45-64 years, were evaluated using the Female Sexual Function Index (FSFI) and the menopause-specific quality of life questionnaire (MENQOL). Of them, 40 diagnosed with sexual dysfunction were randomised (1:1) to receive daily 0.625 mg of conjugated estrogens plus 1.25 mg of methyl-testosterone and 100 mg of micronised progesterone or placebo. After 3 months follow-up, FSFI and MENQOL questionnaires were administered for a second time. RESULTS: Quality of life was unchanged in the placebo group whereas AHT significantly improved scores of vasomotor, psychological, physical and sexual symptoms. As expected, FSFI was not modified in the placebo group while in AHT group the FSFI score improved significantly. In addition, at the end of the study, 68.7% of subjects of the AHT group did not fit did not fit the criteria for sexual dysfunction as per the FSFI (p < 0.0001). CONCLUSIONS: Adding methyl-testosterone to hormone therapy improves quality of life and sexuality in post-menopausal women with sexual dysfunction.

Climacteric. 2008 Jun;11(3):181-91.

Testosterone therapy for sexual dysfunction in postmenopausal women.

Hubayter Z, Simon JA. Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

BACKGROUND: After menopause, both surgical and natural, increases occur in the number of women experiencing sexual dysfunction. Although a direct link between sexual dysfunction and endogenous testosterone levels has not been clearly established, testosterone therapy is known to improve the signs and symptoms related to hypoactive sexual desire. However, testosterone supplementation is not approved in the United States for these clinical indications, primarily because of a lack of data evaluating the possible side-effects of these drugs. METHOD: A MEDLINE search was performed, with a priority for well-designed studies (randomized, controlled trials, meta-analysis), for published data related to the efficacy and safety of testosterone therapy in postmenopausal women. RESULTS: Randomized trials have demonstrated an improvement in sexual function with testosterone in postmenopausal women with hypoactive sexual desire disorder, particularly after oophorectomies. Side-effects have been well tolerated and reversible upon discontinuation. CONCLUSION: Exogenous testosterone treatment provides a rational therapeutic alternative to consider in women whose hypoactive sexual desire disorder negatively affects their quality of life and who have no biologic or psychosocial causes not related to decreased androgen levels for their sexual disorder. Women receiving testosterone should be monitored for clinical improvement and for adverse reactions. Transdermal patches and topical gels avoid the hepatic first-pass metabolism and are the preferred formulations. Testosterone therapy is usually administered concomitantly with estrogen therapy due to a lack of adequate safety and efficacy data on testosterone alone.

Gynecol Endocrinol. 2009;25(12):823-7.

Testosterone addition to estrogen therapy - effects on inflammatory markers for cardiovascular disease.

Kocoska-Maras L, Hirschberg AL, Byström B, Schoultz BV, Rådestad AF. Department of Woman and Child Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. ljiljana.kocoska-maras@karolinska.se

OBJECTIVE: To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women. METHODS: Fifty surgically postmenopausal women were included in this double-blind, placebo-controlled and randomized study to receive daily oral treatment with estradiol valerate 2 mg + placebo (E/P) or estradiol valerate 2 mg + testosterone undecanoate 40 mg (E/T) for 24 weeks and then switched to the other regimen for another 24 weeks. Sex hormones, High sensitivity CRP (hsCRP), Interleukin-6 (IL-6), Tissue necrosis factor (TNF)-alpha, Insulin-like growth factor binding globulin (IGFBP-1), vascular cell adhesion molecule (VCAM)- 1, and homocysteine were analyzed at baseline and after 6 and 12 months. RESULTS: Estradiol and androgens increased as expected during the treatments. After 6 months of E/P, increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded, whereas IL-6, TNF-alpha, and homocysteine were unchanged. When testosterone was added to estrogen, the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone. However, testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6, TNF-alpha, and homocysteine. CONCLUSION: Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects. On the contrary, the estrogen-induced increase in hsCRP was suppressed.

Fertil Steril. 2006 Jul;86(1):136-44. Epub 2006 Jun 5.

Effects of treatment with testosterone alone or in combination with estrogen on insulin sensitivity in postmenopausal women.

Zang H, Carlström K, Arner P, Hirschberg AL. Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden. hzang@hotmail.com

OBJECTIVE: Little is known about metabolic effects of testosterone treatment in postmenopausal women. The aim of the study was to compare the treatment effects of testosterone, estrogen, and testosterone plus estrogen on insulin sensitivities, body compositions, and lipid profiles in healthy postmenopausal women. DESIGN: An open, randomized clinical study with parallel group comparison. SETTING: Women's health clinical research unit at a university hospital. PATIENT(S): Sixty-three naturally postmenopausal women participated in the study. INTERVENTION(S): The participants were randomly assigned to 3 months of treatment with testosterone undecanoate (40 mg every second day), estradiol valerate (2 mg daily), or the combination of both. MAIN OUTCOME MEASURE(S): Insulin sensitivity assessed by euglycemic hyperinsulinemic clamp, body composition, and serum lipids. RESULT(S): Insulin-induced glucose disposal was reduced by approximately 20% after treatment with testosterone alone, and after the combined treatment, but not by estrogen alone. Body weight, but not total body fat, increased significantly by about 1 kg in all groups. Lean body mass was significantly increased in the group of combined treatment and tended to be increased by testosterone alone. High-density lipoprotein (HDL)-cholesterol decreased significantly by testosterone treatment. In contrast, HDL-cholesterol increased, whereas low-density lipoprotein (LDL)-cholesterol and lipoprotein-(a) [Lp(a)] decreased with estradiol treatment.

CONCLUSION(S): We conclude that 3 months of treatment with testosterone undecanoate in postmenopausal women induces insulin resistance and an adverse serum lipid profile but may increase lean body mass.

Tumour Biol. 2009;30(1):37-42. Epub 2009 Feb 5.

Estradiol and testosterone levels are lower after oophorectomy than after natural menopause.

Korse CM, Bonfrer JM, van Beurden M, Verheijen RH, Rookus MA. Department of Clinical Chemistry, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. t.korse@nki.nl

OBJECTIVE: The aim of this study was to compare hormone levels between women who became postmenopausal after a prophylactic bilateral salpingo-oophorectomy, and women who became postmenopausal in a natural way. METHODS: In this cross-sectional study, we investigated estradiol, testosterone, SHBG, IGF-1 and IGFBP-3 levels in 35 surgically and 40 naturally postmenopausal women. RESULTS: Serum samples were drawn at a mean age of 45.9 years for women with surgical menopause and at 56.5 years for women with natural menopause. Mean estradiol levels declined 1.4 pmol/l per year in both menopausal groups, however, at an 11.1 pmol/l lower level for women with surgical menopause. Testosterone levels of naturally postmenopausal women remained stable at a level of 0.89 nmol/l, while testosterone levels of the surgically postmenopausal women declined 0.04 nmol/l per year. CONCLUSIONS: For IGF-1, IGFBP-3 and SHBG, no differences were found between surgically and naturally postmenopausal women. Lower estradiol levels of surgically as compared to naturally postmenopausal women seem to be fully explained by the earlier onset of menopause in combination with the same age-related decrease. However, a decrease in testosterone levels seems to occur in oophorectomized women only, suggesting postmenopausal activity of ovaries in situ. 2009 S. Karger AG, Basel.