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Theodore C. Friedman, M.D., Ph.D. Associate Professor of Medicine-UCLA Chief, Division of Endocrinology, Molecular Medicine and Metabolism Charles R. Drew University Reproductive Health MAGIC Foundation Affected Adult Convention February 5, 2006 Hormonal Axes • Adrenal (corticotropes)=CRH-ACTH-Cortisol • Thyroid (thyrotropes)= TRH-TSH-T4/T3 • Gonads (gonadotropes)= GnRH-LH/FSHTestosterone/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 Menstrual Cycle- hormones, temperature, ovulation QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. 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 o • Measure basal body temperature, increases by 0.5 C 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 100200 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. Physiology of Testosterone Secretion in Women Adrenal Glands Ovaries Testosterone Precursors 50% = 150 mg/day DHEA DHEAS Androstenedione 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% Albuminbound 50-68% SHBGbound 30-45% MEN Bioavailable Testosterone Albuminbound 25% SHBGbound 70% 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, testosteronedeficient women on transdermal estrogen. Short-term study Hypotheses • 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 Patients A.P. C.B. C.O.W. D.G. E.S. J.R. K.T. M.R. M.V. M.Z. N.S. S.G. Mean SD Age BMI Ethnicity Disorder Surgery 24 41 43 29 28 38 48 31 26 44 50 37 36.6 8.8 28.6 30.5 25.8 34.9 34.6 34.6 22.8 28.1 28.1 21.1 30.2 24.0 28.6 3.6 H H H H H C C H H H C H Acromegaly Acromegaly Sheehan's Non-secreting Macroadenoma Craniopharygioma Acromegaly Cushings Prolactinoma Craniopharyn Sheehans Hypothalamic-Pituitary Dysfunction Non-secreting Macroadenoma Y Y* N Y Y Y* Y Y Y N N Y 12 patients completed most of the study Deficiencies Go, ADH Go Go, GH, TSH Go, TSH, ADH Go, GH, TSH, ACTH, ADH Go,TSH, ACTH, ADH Go, GH, TSH, ACTH Go, GH, TSH, ACTH Go, GH, TSH, ACTH, ADH Go, TSH Go, GH, TSH, ACTH Go, GH, ACTH GH status high nl nl on gh-now nl not tested on gh-now nl nl on gh-now nl on gh-now nl on gh-now nl not tested on gh-now nl not tested Demographic Characteristics of Normal Volunteers Volunteers A.H. E.M. G.R. G.S. J.B. K.A. L.W. L.Z. S.A. T.J. Y.R. Mean SD Age 30 23 32 33 23 49 43 20 24 23 26 29.6 9.2 BMI 22.0 20.3 31.1 22.1 20.3 26.1 27.5 30.9 28.6 20.5 25.6 25.0 4.2 C C H C C H C H H C H 11 patients completed most of the study BMI Body Mass Index 40.0 35.0 30.0 kg/m2 25.0 20.0 15.0 10.0 5.0 0.0 PT NV Testosterone Testosterone Levels in hypopituitary and Healthy Volunteers testosterone levels ng/dL 80.0 70.0 ** 60.0 50.0 40.0 30.0 20.0 10.0 0.0 NV PT ** P < 0.0001 Cholesterol Cholesterol 300 * 250 mg/dL 200 150 100 50 0 PT NV * P < 0.005 LDL Cholesterol LDL 250 200 * mg/dL 150 100 50 0 PT NV * P < 0.05 HDL Cholesterol P =NS HDL 120 100 mg/dL 80 60 40 20 0 PT NV Triglycerides Triglycerides 300 * 250 mg/dL 200 150 100 50 0 PT NV * P < 0.05 400 m walk 400m Walk 300 * 250 Seconds 200 150 100 50 0 PT NV * P < 0.05 Stair climb (lower score is worse) P=NS Stair Climb 14.0 12.0 Watts 10.0 8.0 6.0 4.0 2.0 0.0 PT NV Chest press * P < 0.05 Chest Press 50.0 45.0 * 40.0 35.0 kg 30.0 25.0 20.0 15.0 10.0 5.0 0.0 PT NV Leg press P=NS Leg Press 350 300 250 kg 200 150 100 50 0 PT NV Thigh muscle mass by MRI Thigh Muscle Mass 140.0 120.0 100.0 CC 80.0 60.0 40.0 20.0 0.0 PT NV P=NS 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 T Value 80 85 70 75 ** 60 % 65 50 40 55 30 45 20 35 10 250 PT PT NV NV ** P < 0.0001 Female Sexual Distress Scale 35 * score range 0 to 48 30 normal range: <15; abnormal range: 15+ 25 20 p < 0.0001 15 10 5 0 Healthy Patients Hypopituitary Patients FSFI-Desire 4.5 4 Levels of Desire 3.5 P<0.0001 3 2.5 * 2 1.5 1 0.5 0 Healthy Volunteers hypopituitarism FSFI-Orgasm 5 Levels of Orgasm 4.5 4 3.5 P<0.0001 3 * * * 2.5 2 1.5 1 0.5 0 Healthy Volunteers Hypopituitary Less Pain Experienced During Vaginal Penetration FSFI-Pain 5 4.5 4 P<0.001 3.5 3 * 2.5 2 1.5 1 0.5 0 Healthy Volunteers Hypopituitary FSFI-Lubrication 5 4.5 Level of Lubrication 4 P<0.001 3.5 3 2.5 * 2 * 1.5 1 0.5 0 Healthy Volunteers Hypopituitary FSFI-Arousal 4.5 4 Levels of Arousal 3.5 3 2.5 P<0.001 2 * 1.5 1 0.5 0 Healthy Volunteers hypopituitarism FSFI-Satisfaction 4.5 4 Levels of Satisfaction 3.5 3 P<0.0002 2.5 * 2 1.5 1 0.5 0 Healthy Volunteers Hypopituitary Warm Sensation-Vagina 50 P<0.05 units * 45 40 Volunteers Patients Elevated warm sensation threshold indicates impairment of C-fiber sensory nerve function Vibratory Threshold-Vagina p < 0.05 12 * 10 units 8 6 4 2 0 Volunteers Patients Elevated vibratory threshold indicates impairment of A-beta sensory nerve function Objective Sexual Function (Blood-flow) Labia-post-stimulation Blood Flow Labia -Post 100.0 90.0 80.0 cm/sec 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 PT 4 patients and 2 normals below the cut-off of 30 cm/sec NV Objective Sexual Function (Blood-flow) Clitoral-post-stimulation Blood Flow Clitoris-Post 100.0 90.0 80.0 cm/sec 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 PT 4 patients and 1 normal below the cut-off of 30 cm/sec NV Differences in Pre-Post Clitoral Blood Flow 40 35 P<0.05 cm/sec 30 * 25 20 15 10 5 0 Healthy Volunteers Hypopituitary Clitoral Vibratory Threshold PS = NS Vibratory Threshold-Clitoris 18.0 16.0 14.0 microns 12.0 10.0 8.0 6.0 4.0 2.0 0.0 PT NV Clitoral Warm Sensation P = NS Warm Sensation-Clitoris 49.0 47.0 Degrees C 45.0 43.0 41.0 39.0 37.0 35.0 PT NV Vagina Cold Sensation Cold Sensation-Vagina 33.0 31.0 29.0 Degrees C 27.0 25.0 23.0 21.0 19.0 17.0 15.0 PT NV Reduced cold sensation threshold indicates impairment of C-fiber sensory nerve function. P = NS Clitoral Cold Sensation P = NS Cold Sensation-Clitoris 40.0 Degrees C 35.0 30.0 25.0 20.0 15.0 PT NV Conclusions of short-term studies • • • • • • • Low free and total serum testosterone levels in patients. Impaired chest press strength and 400 m walk. High cholesterol, LDL and TG Very reduced psychological well-being Impaired vaginal, but not clitoral thresholds Slightly impaired genital blood flow Recruitment is ongoing. Current Study • 80 women (ages 18 to 55 years) with testosterone deficiency secondary to hypopituitarism will be randomized to receive either placebo or transdermal testosterone gel (we will start with 12 mg of testosterone/day, leading to a targeted serum testosterone in the upper range of normal) in a double-blind study of 6 months duration. • All patients will be on stable physiological replacement regimens for other hormones including growth hormone and transdermal estrogen replacement. Inclusion Criteria • A. Women age 18-55 • B. Hypopituitarism with central adrenal and/or gonadal deficiencies AND • C. Serum testosterone level on transdermal estrogen replacement of ≤ 20 ng/dL or free testosterone <1.5 pg/mL Inclusion Criteria (2) • C. No other significant medical condition • D. Able to provide informed consent • E. All races and ethnicities • F. All patients regardless of marital status and relationship status. Study perks for patients • Free growth hormone during all parts of the study. • Open label period in which all patients would get testosterone gel for one year following randomization period. • Free hormonal testing including GH testing • Climara patch and Provera supplied without charge. Conclusion • • • • Sexual dysfunction in women matters! Psychological dysfunction in women matters! We hope this study addresses these problems We expect this study will accurately assess the important benefits and deleterious effects of physiological testosterone replacement in women with hypopituitarism. • At the conclusion of this study, we expect to determine whether it is of benefit to add testosterone to the standard hormonal replacement for women with hypopituitarism. Testosterone-replacement study at Drew • Location: King/Drew Medical Center in Willowbrook and UCLA in West Los Angeles • Patient Compensation: up to $800, plus pituitary hormone medications provided by the study. • Recruitment ongoing-please call 323-563-9385 or email [email protected] For more information/to schedule an appointment • www.goodhormonehealth.com • [email protected] • My book on thyroid diseases “Everyone’s Guide to Thyroid Disorders” should be out in Fall 2006 Thanks • Magic Foundation for inviting me and doing great work!