Female Androgen Deficiency Syndrome

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Female Androgen Deficiency Syndrome

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Androgens the Major Circulating Steroids

• Androgens are the major circulating steroids in
  both women and men. In women, androgen
  concentrations in plasma are many times higher
  than the concentration of estrogen, even during
  reproductive life.
• Dehydroepiandrosterone (DHEA) and its sulphate
  (DHEA-S) are sources for testosterone and
  estrogens throughout life. They can be converted
  peripherally to estrogen and other biologically
  active androgens. The circulating concentration
  of DHEA-S in adults is higher than that of any
  other steroid except for cholesterol.

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The Role of Androgens in Women

• Circulating testosterone is also a prohormone,
  which can be converted to the biologically active
  hormone dihydrotestosterone (DHT), by 5
  alpha-reductase, or estradiol, by aromatase.
• Ovaries and adrenals produce androstenedione,
  testosterone, and DHEA adrenals also produce
  DHEA-S.
• After menopause, circulating androgens become the
  major source of estrogen for women.

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Current Research Status Androgens in Women

• Little research on androgens.
• Focus on androgen excess conditions
• Pronounced floor effect of testosterone assays

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No direct regulator of androgen production in
women

• Androgen production is increased by increased
  ovarian activity (such as increased LH secretion)
  or by increased adrenal activity ( increased ACTH
  secretion). Thus, Addison's disease,
  hypopituitary states, or removal of ovaries will
  lead to reduced levels of androgens.
• Circulating testosterone is bound to sex
  hormone-binding globulin (SHBG) and albumin.
  Increased levels of estradiol increase SHBG (and
  testosterone binding), decreasing biologically
  available testosterone.

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Androgen Levels in Women

• Age-related changes in Androgen Levels
• Phase-related changes in Androgen Levels

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Age-related Changes in Androgen Levels

• Testosterone is relatively high soon after birth,
  falls to low levels during childhood, increases
  again at the time of appearance of pubertal hair,
  reaches an apparent peak in the early
  reproductive years (third decade), and then
  declines with age so that women in their 40s have
  approximately half the level of circulating total
  testosterone as women do in their 20s.
• The rate of age-related decline in total
  testosterone is not specifically related to
  menopause. DHEA-S shows similar changes to those
  described for testosterone but has an even more
  pronounced age-related decline after the early
  reproductive years which continues through to
  later life.

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Phase-related Changes in Androgen Levels

• There are both diurnal- and menstrual
  cycle-linked changes in testosterone and
  androstenedione.
• Testosterone (and androstenedione) levels are
  highest in the morning before 1000 AM
• Testosterone (and androstenedione) levels are
  highest in the middle third of the menstrual cycle

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Androgen in Women (Summary)

• Androgens are produced in significant quantities
  in women throughout life.
• They are important precursors of estrogens.
• They vary with age and the reproductive life
  cycle, and testosterone and androstenedione vary
  with menstrual cycle phase and diurnally.
• In addition to their important roles as precursor
  hormones, androgens have specific effects in many
  tissues. Androgen target tissues include brain,
  bone, adipose tissue, skin, vascular endothelium,
  smooth muscle, and skeletal muscle.

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Reported Symptoms of Androgen Deficiency

• Global loss of sexual desire
• Decreased sensitivity to sexual stimulation in
  the nipples and in the clitoris
• Decreased arousability and capacity for orgasm
• Loss of muscle tone
• Diminished vital energy
• Thinning and loss of pubic hair
• Dry skin.

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The Features of Women Likely to Respond to
Androgen Therapy

• Low libido
• Blunted motivation
• Fatigue
• Lack of well-being in the presence of normal
  plasma estrogen levels but low levels of
  bioavailable testosterone

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Clinical Hazards in the Female Androgen
Deficiency Syndrome

• No cutoff level for a normal range of
  testosterone could be agreed.
• No current biochemical definition of androgen
  deficiency assay differences and difficulties
  with measuring low levels of testosterone.
• Clinical definition is the criterion that the
  symptoms cannot be attributed to low levels of
  estrogen.
• The same symptoms may reflect different
  etiologies, such as major depressive disorder or
  marital problems.

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Women at Risk for Androgen Deficiency

• Low levels of activity of pituitary, adrenal, or
  ovarian function such as hypopituitarism,
  adrenal insufficiency, anorexia nervosa,
  exercise-induced amenorrhea, and premature
  ovarian failure.
• Exogenous corticosteroids and chronic illness
• HIV-positive premenopausal women
• Estrogen in HRT

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Current Status of Androgen Replacement Therapy

• Androgens are not currently approved by the FDA
  for the treatment of mood and sexual complaints
• Testosterone has been investigated in clinical
  trials and is available in at least some
  countries in oral, injectable, and transdermal
  forms.
• The evidence thus far indicates that androgen
  administration may play a useful role as a
  component of therapy for women with lowered mood
  and sexual dysfunction which cannot be attributed
  primarily to psychiatric disorder, relationship
  problems, or estrogen deficiency.

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Effects of Androgen Replacement Therapy (1)

• Masculinization unwanted acne, facial and body
  hair, and even voice change
• Androgen administration in pregnancy or lactation
  could virilize a female infant
• Somatic effects fluid retention and bloating
• Other serious adverse effects hepatocellular,
  cardiovascular, and cancer risks.
• Androgen-dependent neoplasia is an absolute
  contraindication
• Methyl testosterone adversely affects
  high-density lipoprotein cholesterol (HDL)
• Androgens can precipitate sleep apnea, especially
  if the person is overweight.

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Effects of Androgen Replacement Therapy (2)

• Antimammogenic effects of hyperandrogenic states
  such as congenital adrenal hyperplasia. Although
  estrogen induces mammary epithelial
  proliferation, the risk is lowered by addition of
  testosterone.
• There is a significant additive effect on bone
  mineral density of combined androgen/estrogen
  administration over estrogen alone. In addition
  to increased bone mineralization, administration
  of androgens induces increased muscle strength
  and increased lean mass.

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Conclusions

• Normal ranges for the different androgens and for
  each ethnic group.
• Larger observational studies are needed.
• Validated measures of mood and sexuality
• Measure bioavailable or free testosterone at the
  lower levels of the range.
• Larger double-blind trials to delineate effects
  of administered androgens on a range of health
  outcomes.

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Female androgen insufficiency the princeton
consensus statement on definition,
classification, and assessment.

• A multinational conference in the United States.
  Evaluation of peer-review literature and
  consensus conference of international experts.
• The term "female androgen insufficiency" was
  defined as consisting of a pattern of clinical
  symptoms in the presence of decreased
  bioavailable T and normal estrogen status.
• Currently available assays were found to be
  lacking in sensitivity and reliability at the
  lower ranges, and the need for an equilibrium
  dialysis measure was strongly emphasized.
• Causes of androgen insufficiency in women were
  classified as ovarian, adrenal,
  hypothalamic-pituitary, drug-related, and
  idiopathic.