Theodore C. Friedman, M.D., Ph.D.Associate Professor of Medicine-UCLAChief, Division of Endocrinology, Molecular Medicine and MetabolismCharles R. Drew UniversityReproductive HealthMAGIC Foundation Affected Adult Convention February 5, 2006
Hormonal Axes • Adrenal (corticotropes)=CRH-ACTH-Cortisol • Thyroid (thyrotropes)= TRH-TSH-T4/T3 • Gonads (gonadotropes)=GnRH-LH/FSH-Testosterone/estrogen • GH (sommatotropes) =GHRH-GH-IGF1
Abnormalities of gonadotropes • Gonads= GnRH-LH/FSH-Testosterone/estrogen/progesterone • Lack of ovulation • Irregular of no periods • Infertility • Vaginal Dryness • Osteoporosis • Decreased libido • Possibly poor sense of well-being
What to do if you have gonadotropin dysfunction? • If trying to get pregnant: • Determine ovulation • See reproductive endocrinologist • If not trying to get pregnant • Replace estrogen • Testosterone • Possibly Progesterone
How to Determine Ovulation • If not having monthly periods, probably not ovulating • If regular periods, probably, but not necessarily ovulating • Measure basal body temperature, increases by 0.5oC in 2nd half of cycle if ovulating. • Ovulation kits (measures LH surge) • Check a progesterone level in the 2nd half of the cycle and look for a rise. • Intercourse at the time of ovulation and right after
How to Get Pregnant with Hypopituitarism • See a Reproductive Endocrinologist • Exclude other causes of infertility • Male • Endometriosis • Tubal Problems • PCOS • Insulin resistance • Start with Clomiphene (estrogen blocker at the pituitary, blocks negative feedback • Ovulation induction with FSH/LH analogues
Estrogen Replacement • Amenorrhea or oligomenorrhea indicates gonadotropin deficiency • Younger women who are hypogonadal are likely to benefit from estrogen replacement. • Less clear for older women • Replacement and decision to have periods or not is based on patient preference and age
Estrogen Replacement (2) • Choices include: • Premarin (pregnant mare urine, “conjugated estrogen”, multiple estrogenic compounds) • Oral estrogen compounds (estrace) • Birth control pills (contain high doses progesterone and low doses estrogen) • Estrogen patches (Climara, Vivelle) • Estrogen creams (Estrogel) • Vaginal estrogen (Fem-ring, Estring) • Compounded Estrogen (creams, sublingual drops, pills)
Oral Estrogen Replacement, but not other routes • First pass effect in the liver • Blocks the action of GH at the liver to raise IGF-1 • Leads to high GH and low IGF-1 (both bad) • Raises sex hormone binding globulin (SHBG) • Raises total testosterone, but decreases free testosterone • Low free testosterone may lead to decreased libido (and maybe low energy, decreased muscle mass) • Recent study showed that effects of oral estrogens (including birth control pills) decrease free testosterone levels even after discontinuing.
Oral Estrogen Replacement, but not other routes (2) • Raises thyroid-binding globulin (TBG) which can lead to an increase in thyroid hormone requirements. • Raises cortisol-binding globulin (CBG) and leads to high levels of total cortisol which makes testing for adrenal insufficiency difficult
Oral Estrogen Replacement • In women with hypopituitarism, probably avoid it!
What type of Estrogen is Best? • Ovaries make estrone (E1), estradiol (E2), estriol (E3) • Estradiol is most abundant (“bioidentical”) • Slight evidence that estrone is detrimental (breast cancer) and estriol is good. • Oral estrogens get converted to estrone. • I use mainly estradiol (Climara or Estrogel). • Some compounding pharmacies encourage bi-est (estradiol/ estriol) or tri-est (estrone estradiol/ estriol). • Should take estrogen daily.
Should you take estrogen/progesterone to induce a period? • Taking 5-10 mg of Provera (synthetic Progestin) or 100-200 mg of Prometrium (progesterone “bioidentical”) for 10 days, then stopping will usually induce a period. • Taking 2.5 mg of Provera or 100 mg of Prometrium daily will usually not induce a period. • I tend to have women less than 40-45 have a monthly period and older than that not to have a period.
Should you take estrogen/progesterone to induce a period? (2) • Estrogen without progesterone in a women with a uterus can lead to uterine cancer. • Probably enough to take progesterone for 10 days every 4 months. • Provera, more than estrogen, was responsible for increased breast cancer in WHI. • Progesterone may be associated with fluid retention and weight gain. • Progesterone, if given should be given during the 2nd half of the cycle when progesterone levels rise. • I tend to give as little progesterone possible, but in some patients, it helps. • Progesterone creams or vaginal progesterone are good options, besides prometrium.
Should you have estrogen levels monitored? • If not on estrogen and having periods, estradiol levels are probably suffice, if no periods, estradiol levels are probably low. • Often helpful to confirm (or with irregular periods) by measuring estradiol (day 3ish) if having periods. • A level less than 50 pg/mL (check units) is low for this time of the cycle. • If on treatment, aim for a estradiol level of 70-125 pg/mL. • Some doctors check a mid-cycle estradiol level, I think its hard because if you are off a day or so, you will have very different values.
Should you have progesterone levels monitored? • Can be done to see if ovulation (check day 22ish) and compare to luteal values. • If on replacement progesterone, can look for mid-normal luteal values.
Testosterone Precursors Androstenedione DHEA DHEAS Physiology of Testosterone Secretion in Women Adrenal Glands Ovaries 50% = 150 mg/day 50% = 150 mg/day Circulating Testosterone Daily Secretion Rate = 300 mg/day
The physiologic role of testosterone in women remains poorly understood • Previous studies of testosterone supplementation, largely in surgically or naturally menopausal women, have reported improvements in : • subjective measures of sexual function • sense of well being • variable changes in markers of bone formation and resorption.
Potential Benefits of Androgen Supplementation in Women • Improved sexual function • Improved bone mineral density • Improved muscle mass and function • Improved mood and sense of well being • Improved cognitive function • Amelioration of autoimmune disease • Amelioration of premenstrual syndrome • Improvement in dry eye syndrome
Plasma Binding Proteins and Concept of Free and Bioavailable Testosterone Unbound or Free 0.5 – 3.0% Albumin- bound 25% Albumin- bound 50-68% Bioavailable Testosterone SHBG- bound 70% SHBG- bound 30-45% MEN WOMEN Free T = unbound T Bioavailable = unbound + albumin bound
Defining Androgen Deficiency in Women • Statistical definition: • Serum total or free T less than the lower limit of normal for healthy young women (<15 ng/dL) • Relative Androgen Deficiency • Lower than the median (30 ng/dL) for young, menstruating women (Used in clinical trials (Shifren et al, 2000, Miller et al, 1998). • Definition Based on Clinical Threshold • Use a testosterone threshold below which high prevalence of “clinical disorder” (example: osteoporosis, hypercholesterolemia)
Female Androgen Deficiency Syndrome (FADS) From the Princeton Conference (June 2001): • Global loss of sexual desire (low libido) • Decreased sensitivity in the nipples and clitoris • Decreased arousability and capacity for orgasm • Loss of muscle tone • Diminished vital energy (fatigue) • Thinning and loss of pubic hair • Dry skin • Blunted motivation, lack of well-being Unresolved at Princeton Conference: • No agreed upon cut-off level for normal range of T
Problems in the Measurement of Testosterone Concentrations in Women • Suboptimal sensitivity to measure T levels in women • Lack of sufficient precision in the low range • Paucity of normative data • Cross-reactivity issues • Lack of consistency in reagents and assay methods Padero, Bhasin, Friedman, et al, JAGS 2002
Causes of Androgen Deficiency in Women • Age-related decline • Oophorectomy • Surgical • Radiation • Chemical • Adrenal insufficiency • Panhypopituitarism • Glucocorticoid treatment • Chronic illness such as HIV-infection • Premature ovarian failure • Turner’s syndrome
Testosterone in hypopituitarism • Acquired hypopituitarism in women is characterized by central hypogonadism and/or hypoadrenalism and therefore affects critical sources of androgen production in women. • Surprisingly, there have only been a few studies on testosterone levels in women with hypopituitarism and no large studies on testosterone replacement in women with hypopituitarism.
Testosterone in hypopituitarism (2) • A recent large study demonstrated that patients with hypopituitarism have increased mortality, which was mainly due to cardiovascular, respiratory, and cerebrovascular events. • Hypopituitarism in women is associated with a number of symptoms, including obesity, poor quality of life, decreased libido and osteopenia, that persist in spite of standard hormonal replacement.
Severe Androgen Deficiency in Women with Hypopituitarism • Women with hypopituitarism: • Have impairment of both the adrenal and ovarian sources of androgen production. • Have lower T and DHEAS levels than women with ovarian failure alone Miller et al, J Clin Endocrinol Metab 2001;86:561-7.
Potential adverse effects associated with testosterone supplementation • The potential risks of testosterone administration to women include the risk of • virilization • hirsutism • acne • effects on plasma lipids • effects on behavior
Testosterone delivery • Currently, the only FDA-approved drug for testosterone in women is Estratest, which contains methyl testosterone, a compound that when given orally is associated with liver toxicity in animals and humans. • DHEA is a considered a prohormone of testosterone, most of its actions are probably due to binding to the testosterone receptor • DHEA (25-50 mg)/day is a reasonable approach in women. • Other possibilities include • Patches (Procter & Gamble, no FDA approval, 2005) • Gels (compounded or investigational) • Injections • Sublingual
Tostrelle • Cellegy Pharmaceuticals • Excellent pharmacokinetic data in surgically-menopausal, testosterone-deficient women on transdermal estrogen.
Short-term studyHypotheses • Women with hypopituitarism will have decreased serum free and total testosterone levels. • They will have decreased muscle strength and physical performance, reduced sexual function, decreased lean mass and impaired psychological performance on the SCL-90R. • Pharmacokinetic studies giving Tostrelle will raise serum testosterone levels into the upper-normal range.
Demographic Characteristics of Women with Hypopituitarism (T < 20 ng/dL) Name Age BMI Ethnicity Disorder Surgery Deficiencies GH status Patients A.P. 24 28.6 H Acromegaly Y Go, ADH high nl C.B. 41 30.5 H Acromegaly Y* Go nl C.O.W. 43 25.8 H Sheehan's N Go, GH, TSH on gh-now nl D.G. 29 34.9 H Non-secreting Macroadenoma Y Go, TSH, ADH not tested E.S. 28 34.6 H Craniopharygioma Y Go, GH, TSH, ACTH, ADH on gh-now nl J.R. 38 34.6 C Acromegaly Y* Go,TSH, ACTH, ADH nl K.T. 48 22.8 C Cushings Y Go, GH, TSH, ACTH on gh-now nl M.R. 31 28.1 H Prolactinoma Y Go, GH, TSH, ACTH on gh-now nl M.V. 26 28.1 H Craniopharyn Y Go, GH, TSH, ACTH, ADH on gh-now nl M.Z. 44 21.1 H Sheehans N Go, TSH not tested N.S. 50 30.2 C Hypothalamic-Pituitary Dysfunction N Go, GH, TSH, ACTH on gh-now nl S.G. 37 24.0 H Non-secreting Macroadenoma Y Go, GH, ACTH not tested Mean 36.6 28.6 SD 8.8 3.6 12 patients completed most of the study
Demographic Characteristics of Normal Volunteers BMI Age Volunteers A.H. 30 22.0 C E.M. 23 20.3 C G.R. 32 31.1 H G.S. 33 22.1 C J.B. 23 20.3 C K.A. 49 26.1 H L.W. 43 27.5 C L.Z. 20 30.9 H S.A. 24 28.6 H T.J. 23 20.5 C Y.R. 26 25.6 H Mean 29.6 25.0 SD 9.2 4.2 11 patients completed most of the study
BMI Body Mass Index 40.0 35.0 30.0 25.0 kg/m2 20.0 15.0 10.0 5.0 0.0 PT NV
Testosterone ** P < 0.0001 Testosterone Levels in hypopituitary and Healthy Volunteers 80.0 70.0 ** 60.0 50.0 testosterone levels ng/dL 40.0 30.0 20.0 10.0 0.0 PT NV
Cholesterol * P < 0.005 Cholesterol * 300 250 200 mg/dL 150 100 50 0 NV PT
LDL Cholesterol * P < 0.05 LDL 250 * 200 150 mg/dL 100 50 0 NV PT
HDL Cholesterol P =NS HDL 120 100 80 mg/dL 60 40 20 0 NV PT
Triglycerides * P < 0.05 Triglycerides 300 * 250 200 150 mg/dL 100 50 0 PT NV
400 m walk * P < 0.05 400m Walk * 300 250 200 Seconds 150 100 50 0 NV PT
Stair climb (lower score is worse) P=NS Stair Climb 14.0 12.0 10.0 8.0 Watts 6.0 4.0 2.0 0.0 NV PT
Chest press * P < 0.05 Chest Press 50.0 * 45.0 40.0 35.0 30.0 kg 25.0 20.0 15.0 10.0 5.0 0.0 NV PT
Leg press P=NS Leg Press 350 300 250 200 kg 150 100 50 0 PT NV
Thigh muscle mass by MRI P=NS Thigh Muscle Mass 140.0 120.0 100.0 80.0 CC 60.0 40.0 20.0 0.0 PT NV
SCL - 90 (higher score worse) ** P < 0.0001 SCL-90R (GSI) 2.50 ** 2.00 1.50 1.00 0.50 0.00 PT NV
SCL - T Score ** P < 0.0001 T Value T Value 85 80 ** 70 75 60 65 50 % % 40 55 30 45 20 35 10 25 0 PT NV PT NV
Female Sexual Distress Scale 35 * 30 normal range: <15; abnormal range: 15+ 25 20 score range 0 to 48 p < 0.0001 15 10 5 0 Healthy Patients Hypopituitary Patients
FSFI-Desire 4.5 4 3.5 P<0.0001 3 2.5 Levels of Desire * 2 1.5 1 0.5 0 Healthy Volunteers hypopituitarism
FSFI-Orgasm 5 4.5 4 3.5 P<0.0001 3 ** Levels of Orgasm 2.5 2 * 1.5 1 0.5 0 Healthy Volunteers Hypopituitary