Archive for Investigations

Measurement of Testosterone in Women

Introduction

Recent studies from the Women’s Health Secrets research group have shown that there is no relationship between testosterone levels throughout the different decades and libido or responses to a sexual function questionnaire in a community-based sample of women. Whether testosterone levels are decreased in women specifically complaining of low libido has not been clearly documented. There is no established level of free testosterone below which a woman can be said to be deficient, nor any level to which a woman should be restored that determines that she is replete. However, the availability of normal ranges for testosterone in different age groups allows the clinician to determine whether an individual’s level is below the normal range. The diagnosis of diminished sexual function due to low testosterone remains a clinical diagnosis of exclusion. In the absence of a reliable free/total testosterone assay the limitations of the available assays should be understood, and the measurement of testosterone used to exclude use of testosterone in women in whom therapy might result in testosterone excess.

Measuring testosterone in women

Measuring testosterone in the blood of women is not straightforward. Most laboratories use assays that were set up to measure testosterone in men. These can be useful for the measurement of elevated testosterone in women who have conditions of androgen excess. However, these assays lack the sensitivity and specificity to accurately measure the much lower values in women who have normal or low testosterone.

Measuring total testosterone

Automated direct total testosterone immunoassays are limited by ‘noise’ from assay interference and by cross-reactivity with other steroids, which becomes worse at low testosterone concentrations and when women are taking steroids such as conjugated equine oestrogens.  The accuracy of an assay can be improved by the inclusion of steps to remove components that cross react, for example, by organic solvent extraction and then isolation of the testosterone by running each sample down a celite column and measuring testosterone in the eluate. This is clearly labour intensive and expensive. Manual testosterone assays may provide greater sensitivity and we have evaluated the accuracy of the Biosource total testosterone assay against other more rigorous methods. This assay was used by the Dorevitch laboratory in the past. The Biosource assay appeared to provide a reliable estimate of testosterone in the low female range and the result could be used to calculate free testosterone. It has been replaced by another assay which gives comparable results. It requires a specific request for ‘sensitive testosterone’, in conjuction with calculated free testosterone. If an accurate assay is not available it is simply not possible to distinguish low testosterone from normal using these assays.

Total testosterone levels alone are not sufficient to evaluate a woman’s androgen exposure. Testosterone circulates in women about 66 per cent bound to sex hormone binding globulin (SHBG) and 33 per cent bound to albumin with only about one per cent being free in the blood. Thus, free or non-SHBG-bound (sometimes called bioavailable) testosterone measures are believed to be the most reliable indicators of tissue testosterone exposure. The measurement of SHBG is not controversial and is relatively simple to perform with good reproducibility.

Measurement of free testosterone

All methods for measuring free testosterone are dependent on having a precise total testosterone assay.

The gold standard methodology for measurement of free testosterone is considered by many investigators to be equilibrium dialysis. In this method, a sample of serum with radiolabelled testosterone added is placed in a chamber and dialysed across a membrane that blocks the transfer of albumin and SHBG. The percentage of free testosterone that is dialysed across the membrane can then be calculated. Absolute free testosterone can be derived from this and total testosterone measurement. This method is influenced by dilution of the hormone to be measured and also relies on being able to measure total testosterone accurately. Furthermore, it is labour intensive and expensive, and not feasible for clinical practice.

Non-SHBG bound testosterone, which correlates highly with free testosterone quantified by equilibrium dialysis, can be measured by the ammonium sulfate precipitation technique. However, frequently encountered sources of error in this assay include incomplete precipitation of globulins, use of impure tritiated testosterone, and insufficient counting time of the relatively small amount of radiolabelled bioavailable testosterone in the assay. Like the equilibrium dialysis, the ammonium sulfate precipitation method generates a percentage of non-SHBG bound testosterone and this percentage is then multiplied by the concentration of total testosterone to determine the bioavailable testosterone concentration.

It is generally recognised that the Sodergard equation can be reliably used to calculate free testosterone if total testosterone, albumin and SHBG are know. Again, this requires a reliable determination of total testosterone, and SHBG and albumin are quantified by routine methodology. See calculated free testosterone above.

Measurement of free testosterone by analogue assays (direct assays) is widely available but notoriously unreliable, particularly at the lower end of the normal female range and is not recommended.

Salivary testosterone has been used reliably in studies of women with hyperandrogenism, but has never gained wide support because the normal range seems excessively large and also has questionable accuracy in the lower ranges. It is important to realise that salivary testosterone levels should not be equated to levels of free testosterone.

The free androgen index (FAI) [nmol/L total testosteronex100/nmol/L SHBG ] has been used as a surrogate for free testosterone, but it is unreliable when SHBG levels are low.

Timing of measurement to prevent misdiagnosis of low testosterone

Ideally blood should be drawn between 8:00am and 10:00am as testosterone levels are usually higher in the early morning and lower in the afternoon. In premenopausal women, testosterone levels are lowest during the first week of the menstrual cycle (i.e. during a woman’s period or the early follicular phase) with small but less significant variation across the rest of the cycle. Thus, blood should be drawn after day eight of the cycle, and preferably before day 20. A serum sample is preferred over plasma.

Measuring other androgens

The chief androgen precursor in the adrenal gland is DHEA. It is usually measured in the sulphated form, DHEAS, because the half-life is much longer, resulting in more stable levels. The immunoassay for DHEAS is relatively stable, gives consistent results, and is simple to perform. Several companies provide kits for this clinical assay, and their performance is generally considered to be acceptable. There is a consensus that DHEAS does not vary in concentration within the various phases of the menstrual cycle, and that it is not bound to SHBG. It also does not seem to be affected by oestrogen therapy at standard doses. A number of authors have shown normal, age-related decline curves for DHEAS, which are all quite compatible. If very low levels are found, a morning cortisol level should be drawn to rule out adrenal insufficiency. This hormone is primarily measured to detect androgen excess in women with polycystic ovarian syndrome. There is no evidence that low DHEAS levels should be supplemented and indeed recent research suggests no benefit on a range of health outcomes with two years of DHEAS therapy in men and women.

Summary of androgen measures

  1. Testosterone levels are of limited usefulness in the assessment of libido or sexual dysfunction in women. Low levels do not necessarily correlate with symptoms. Therefore levels should be performed if suspecting androgen excess, or if a clinician is considering androgen therapy based on clinical assessment and has made a diagnosis of exclusion of as yet poorly defined female androgen insufficiency, to exclude high levels prior to considering any testosterone therapy. Free testosterone and/or non-SHBG bound testosterone are felt to be most reflective of the hormone available to tissues. Free testosterone should be measured by equilibrium dialysis or calculated using the Sodergard equation from total testosterone, SHBG, and albumin. Since total testosterone levels play an important role in determining free testosterone concentrations in those methods, a reliable and sensitive total testosterone assay is essential.
  2. SHBG should always be measured so that the testosterone profile can be accurately interpreted and as a guide to therapy (see 4).
  3. The majority of the direct commercial immunoassays cannot be recommended for reliably determining low total testosterone in women.
  4. SHBG provides additional information regarding overall androgen exposure, as it is sensitive to total body androgen status. Low SHBG levels indicate a considerable increase in risk of androgen excess with testosterone therapy, whereas high levels indicate a reduced metabolic clearance of testosterone. SHBG provides additional information regarding overall androgen exposure, as it is sensitive to total body androgen status. Low SHBG levels indicate a considerable increase in risk of androgen excess with testosterone therapy, whereas high levels indicate a reduced metabolic clearance of testosterone.
  5. For either research or diagnostic purposes, serum for testosterone measurement should be drawn between 8:00am and 10:00am, and not during the early follicular phase in premenopausal women.
  6. In the absence of a reliable free/total testosterone assay, the limitations of the available assays should be understood, and the measurement of testosterone used to exclude women in whom testosterone therapy might be dangerous. Other factors must be used as guides such as a low SHBG indicating increased treatment risk and clinical presentation.
  7. DHEAS measurements are primarily useful in diagnosing androgen excess. Evidence that the use of DHEA in women with even low normal levels is beneficial or safe is lacking and current literature suggests that two years therapy has little benefit but also causes little harm. Further research is needed in this area. DHEAS is not approved for use in Australia and indeed is a banned substance and cannot be imported.

Top Steroid Products Sales

Proviroxyl

Proviroxyl from Legal Supplier
Substance: Mesterolone
Manufacturer: Kalpa Pharmaceuticals
Unit: 30 tabs (25 mg/tab)

Clenbuterol 40

Buy Clenbuterol 40 on Sale
Substance: Clenbuterol Hydrochloride
Manufacturer: Balkan Pharmaceuticals
Unit: 60 tabs (40 mcg/tab)

DNP

Purchase DNP from Legit Supplier
Substance: Dinitrophenol
Manufacturer: Gen-Shi Laboratories
Unit: 30 caps (100 mg/cap)

Assessment

The assessment of the menopausal woman is primarily the assessment of the well woman, who may be symptomatic or coincidentally, with the menopausal transition may have risks or medical disorders impacting on her wellbeing.

Indications for consultation

The reasons the woman consults a medical practitioner must be carefully listened to.

The woman may be seeking:

1. Symptom relief
2. Information
3. A preventative health care plan
4. Update of her medication
5. Therapeutic management for side effects from previously prescribed medicines
6. Support or counselling during a major life stress

Sensitivity to issues

In taking a history and performing an examination, the doctor must be aware and sensitive to many issues including:

1. The age of the woman.

2. Her cultural background including which country she was born in, how long she has been in Australia, and her language expertise.

3. The status of her menopause, e.g. premature menopause at 32.

4. Previous experiences with other doctors, either positive or negative (the dissatisfied woman will be keen to find a sympathetic doctor who will listen to her).

5. The amount of time the doctor has available – if inadequate explain to the woman and, if possible, make a further appointment for a long consultation.

6. How comfortable the doctor feels about managing patients of menopausal age, and the doctor’s education and socio cultural beliefs about the menopausal experience.

7. Specific fears the woman may have about the menopause and treatments including HRT, such as a fear of breast cancer and weight gain.

History taking

In taking a medical history, it is important to elicit the appropriate information:

1. Current Situation

  • Presenting symptoms; vasomotor, urogenital, psychological, social, musculoskeletal, sexual
  • Menstrual status
  • Patterns of vaginal bleeding
  • Urinary or bowel symptoms including incontinence
  • Contraceptive practice
  • Lifestyle behaviour e.g. dietary patterns, exercise routines
  • Cardiovascular risks e.g. obesity, smoking
  • Osteoporosis risks e.g. 2º amenorrhoea, smoking, corticosteroid use
  • Time of previous pap smear, mammogram, lipid profile or bone density

2. Past medical and surgical history, particularly:

  • Menstrual cycle history
  • Obstetric and gynaecological history
  • Cancer history particularly breast, uterine, ovarian or bowel
  • Diabetes and/or thyroid disease
  • Previous fracture
  • Irritable bowel syndrome and other GIT disorders
  • Contraceptive problems
  • Thrombo-embolic events
  • Hepatic and renal disease

3. Family history, in particular:

  • Any familial disorders
  • Cancers, especially breast, uterine, ovarian and bowel
  • Cardiovascular disease, IHD, MI, HT, thrombo-embolic events
  • Osteoporosis and/or fracture
  • Diabetes mellitus

4. Medications being taken including prescriptives such as H2 antagonists and all non-prescriptive medicines including vitamins and herbal products

5. Midlife issues including:

  • Attitudes towards ageing
  • Partnership status
  • Partners/husbands midlife health and wellbeing
  • ‘Empty nest’ or ‘full nest’ household
  • Elderly parents or relatives
  • Employment status/financial position

Physical examination

The examination of the woman should include the:

  • Cardiovascular system examination
  • Breasts examination
  • Gynaecological examination, including a Pap smear if greater than two years has lapsed, if there is abnormal vaginal bleeding or a previous abnormal smear. A bimanual examination should be performed to exclude pelvic pathology such as ovarian cysts or fibroids, especially following hysterectomy where the ovaries have been conserved
  • Evaluation of thyroid status
  • Specific system examination, depending on the symptom presentation

Investigations

Some investigations may be necessary to perform for diagnosis or to help in formulating a treatment plan.

Here are the most commonly used investigations and their indications.

The Pap smear and mammography should be mandatory routine screening investigations for all women over forty:

1. Pap smear
  • Every two years
  • If had previous abnormal smear (dysplasia or HPV changes) within the last two years
  • A vault smear every 2 years following hysterectomy if the woman has ever had an abnormal pap smear or cancer of the cervix or uterus
  • If presents with abnormal vaginal bleeding

2. Mammogram ± breast ultrasound

  • Every two years over the age of 50 years and probably between 40-50 years particularly if post menopausal
  • If any breast abnormality is found on examination

The following investigations are not mandatory and should be chosen judiciously depending on the woman’s history and examination.

3. Hormone levels

FSH/Oestradiol levels:

  • Have limited use because of the variability day to day in the perimenopause (best taken in early follicular phase i.e. day three of cycle to assess reduced ovarian reserve. E2<150pmol/l with FSH>10IU/l).
  • On oral therapy are inaccurate and should not be used as a guideline for determining dosages.
  • Where there is doubt in diagnosis e.g. after hysterectomy with no subsequent menstrual marker.
  • FSH may be helpful in determining between premature menopause and secondary amenorrhoea in the under – 40 age group.
  • To track absorption where implant therapy is used, also with implant tachyphylaxis and where absorption with patch or gel use is concerned.

Testosterone levels:

May be appropriate when symptoms of loss of energy and sexual function.

  • Measure in the morning and after day seven of the cycle; include total sensitive testosterone,  and  Sex Hormone Binding Globulin (SHBG) and free testosterone to evaluate non – SHBG bound level. A “sensitive” testosterone level may reflect the androgen status more accurately.

Thyroid Stimulating Hormone:

  • Indicated where there are symptoms of thyroid dysfunction or palpable thyroid, which may manifest around the time of the menopause.

4. Lipid profile & fasting glucose

 

  • Especially if risk factors or family history

5. Coagulation studies

 

  • Where past history of thrombo-embolism, particularly if spontaneous and/or less than 40 years.
  • Where family history or known familial disorder.

6. Full blood examination, iron studies

 

  • Where abnormal bleeding, especially menorrhagia.

7. Vaginal ultrasound

 

  • To assess endometrial thickness where there is abnormal vaginal bleeding:
    >4mm thickness in the post menopausal woman requires endometrial sampling either by endometrial biopsy or hysteroscopy and curettage.
  • To exclude endometrial pathology such as polyps or submucous fibroids.
  • To exclude pelvic pathology such as ovarian cysts or fibroids.

Referral to a gynaecologist is appropriate for further investigations such as hysteroscopy and endometrial biopsy, where the ultrasound shows an increased endometrial thickening greater than 4mm in the post menopause, pelvic pathology or with any postmenopausal bleeding.

8. Bone assessment

Bone density:

There are different techniques for establishing bone density. The most reproducible form is the DEXA (dual energy X-ray absorptiometry), which scans both the lumbar spine and the femoral neck. The test is indicated:

Where there are major risk factors for osteoporosis:

  • E.g. strong family history, previous fracture, history of oral corticosteroid or   thyroxine for the treatment of other illnesses.
  • Further biochemistry including calcium and 25 hydroxy vitamin D when   osteopenia or osteoporosis is detected on bone density.
  • Urinary or serum bone turnover markers are still controversial, mainly used for experimental trials and are not recommended routinely. Henry noted that this dot point could be worded a little better.

9. Urodynamic Assessment

Where there is a history of stress and or urge incontinence, to determine the severity of the incontinence. The result will aid in planning and managing the symptom.

Diagnostic categories

The woman being assessed will fall into a number of diagnostic categories from which a management plan may be developed.

1. Symptoms of the menopause
2. Abnormal vaginal bleeding
3. Contraceptive requirements
4. Breast abnormality, such as a specific lump, cystic breasts
5. Sexual dysfunction
6. High fracture risk
7. Cardiovascular risks
8. Incontinence – urine or faecal
9. Psychosocial problems.

The diagnostic category or categories reached after a thorough assessment of the menopausal woman will determine how to develop a management plan.

Management planning

In every case the woman should be advised about improving her lifestyle by having a healthy diet, maintaining a consistent and individually appropriate exercise program and managing stress. Smoking is particularly associated with postmenopausal morbidity and mortality. Alongside lifestyle improvements, a therapeutic regimen may be developed which may include non-prescriptive or complimentary therapies as well as prescriptive medicines. Specific therapies or programs will be covered in the other lectures.

Management plans may include:

  • Therapy for symptom relief, either hormonal or non-hormonal
  • Contraceptive advice
  • Preventative therapy e.g. for osteoporosis, including lifestyle, calcium, hormone therapy, vitamin D
  • Therapy for osteopenia or osteoporosis, either hormonal or non-hormonal, such as the bisphosphanates, SERMS
  • Therapy for present cardiovascular risk e.g. hypercholesterolaemia
  • Referral for surgery for either pelvic or breast pathology
  • Counselling, either psychosexual or psychotherapeutic
  • Assessment of incontinence, referral to pelvic floor rehabilitation physiotherapist
  • Lifestyle, dietary, exercise advice as well as giving information or providing educational resources

Regular follow-up, with two visits in the initial six months after commencing a treatment plan, provides an opportunity for both the woman and her practitioner to discuss her progress, side effects to medication or difficulties in management and treatment. Yearly assessments should then occur. If therapy is necessary long term, annual review should occur to re-examine risks and benefits and to discuss any new options.

Conclusion

A thorough assessment of the menopausal woman should culminate in a management and/or treatment plan, outlining to the woman her options so that she may decide on choices to improve or maintain her quality of life, at the same time developing an empathic, communicating and ongoing relationship for the woman with her doctor.

Top Steroid Products for Sale

Testo-C 1250 (5ml)

Purchase Testo-C 1250 (5ml) Online
Substance: Testosterone Cypionate
Manufacturer: Gen-Shi Laboratories
Unit: 5 mL vial (125 mg/mL)

Primoxyl 100

Best Primoxyl 100 for Sale
Substance: Methenolone Enanthate
Manufacturer: Kalpa Pharmaceuticals
Unit: 10 mL vial (100 mg/mL)

Aromaxyl

Order Aromaxyl for Sale
Substance: Exemestane Administration: Oral
Manufacturer: Kalpa Pharmaceuticals
Unit: 30 pills (25 mg/pill)

Investigations

Some investigations may be necessary to perform for diagnosis or to help in formulating a treatment plan.

Here are the most commonly used investigations and their indications.

The Pap smear and mammography should be mandatory routine screening investigations for all women over forty.

1. Pap smear

  • Every two years
  • If had previous abnormal smear (dysplasia or HPV changes) within the last two years
  • A vault smear every 2 years following hysterectomy if the woman has ever had an abnormal pap smear
  • If presents with abnormal vaginal bleeding.

2. Mammogram ± breast ultrasound

  • Every two years over the age of 50 years and probably between 40-50 years particularly if post menopausal
  • If any breast abnormality is found on examination.

The following investigations are not mandatory and should be chosen judiciously depending on the woman’s history and examination.

3. Hormone levels

FSH/Oestradiol levels:
  • Have limited use because of the variability day to day in the perimenopause (best taken in early follicular phase i.e. day three of cycle to assess reduced ovarian reserve. E2<150pmol/l with FSH>10IU/l).
  • On oral therapy are inaccurate and should not be used as a guideline for determining dosages.
  • Where there is doubt in diagnosis eg after hysterectomy with no subsequent menstrual marker.
  • FSH may be helpful in determining between premature menopause and secondary amenorrhoea in the under – 40 age group.
  • To track absorption where implant therapy is used, also with implant tachyphylaxis and where absorption with patch or gel use is concerned.
Testosterone levels:

May be appropriate when symptoms of loss of energy and sexual function.

 

  • Measure in the morning and after day seven of the cycle; include total sensitive testosterone, and Sex Horomone Binding Globulin (SHBG) and free testosterone to evaluate non – SHBG bound level. A “sensitive” testosterone level may reflect the androgen status more accurately.
Thyroid Stimulating Hormone :
  • Indicated where there are symptoms of thyroid dysfunction or palpable thyroid, which may manifest around the time of the menopause.

4. Lipid profile & fasting glucose

  • Especially if risk factors or family history

5. Coagulation studies

  • Where past history of thrombo-embolism, particularly if spontaneous and/or less than 40 years.
  • Where family history or known familial disorder.

6. Full blood examination, iron studies

  • Where abnormal bleeding, especially menorrhagia.

7. Vaginal ultrasound

  • To assess endometrial thickness where there is abnormal vaginal bleeding: >4-5mm thickness in the post menopausal woman requires endometrial sampling either by endometrial biopsy or hysteroscopy and curettage.
  • To exclude endometrial pathology such as polyps or submucous fibroids.
  • To exclude pelvic pathology such as ovarian cysts or fibroids.

Referral to a gynaecologist is appropriate for further investigations such as hysteroscopy and endometrial biopsy, where the ultrasound shows an increased endometrial thickening greater than 5mm in the post menopause, pelvic pathology or with any postmenopausal bleeding.

8. Bone Assessment

Bone Density:

There are different techniques for establishing bone density. The most reproducible form is the DEXA (dual energy X-ray absorptiometry), which scans both the lumbar spine and the femoral neck. The test is indicated:

Where there are major risk factors for osteoporosis:

  • eg strong family history, previous fracture, history of oral corticosteroid or thyroxine for the treatment of other illnesses.
  • Further biochemistry including calcium and 25 hydroxy vitamin D when osteopenia or osteoporosis is detected on bone density.
  • Urinary or serum bone turnover markers are still controversial, mainly used for experimental trials and are not recommended routinely.

9. Urodynamic Assessment

Where there is a history of stress and or urge incontinence, to determine the severity of the incontinence. The result will aid in planning and managing the symptom.

Best Steroid Products for Sale

Enantat 250

Buy Enantat 250
Substance: Testosterone Enanthate
Manufacturer: Dragon Pharma
Unit: 10 mL vial (250 mg/mL)

Cutaxyl 150

Best Cutaxyl 150 from Legal Supplier
Substance: Drostanolone Propionate, Trenbolone Acetate, Testosterone Propionate
Manufacturer: Kalpa Pharmaceuticals
Unit: 10 mL vial (150 mg/mL)

Cutaxyl 150

Buy Cutaxyl 150 for Sale
Substance: Drostanolone Propionate, Trenbolone Acetate, Testosterone Propionate
Manufacturer: Kalpa Pharmaceuticals
Unit: 10 mL vial (150 mg/mL)