Month-Long Hormone Assessment: What goes up must come down George Gillson MD PhD 1 Disclaimer The information presented in this Webinar is the opinion of Dr. Gillson based on his research and experience. Dr. Gillson s opinions do not necessarily reflect the opinions of any other individual or organization. 2 Aims and Objectives Review some physiology Introduce this test to practitioners who are unfamiliar with it Go over the rules for collecting the specimens Go over interesting profiles Discuss who should have this test 3 1
The Test 11 first morning saliva samples spaced out over 31 days First tube collected on first or second day of menses Measure E2 and Pg in each tube Calculate Pg/E2 for each point Make a pooled sample from all 11 tubes and measure Testosterone on the pooled sample 4 5 6 2
The Menstrual Cycle Complex interplay of multiple steroid and peptide hormones (LH, FSH, E2, Pg, Inhibins) Local feedback loops within ovaries and probably uterus Feedback loops between brain (hypothalamus/pituitary) and pelvic organs 7 Biphasic profile http://pcosjournal.com/horm ones-normal-menstrualcycle/ 8 Hypothalamic oscillator Oscillating GnRH Oscillating LH and FSH Pulses of ovarian hormones Spikes of electrical activity from hypothalamic neurons 9 3
FSH LH http://www.glowm.com/index.html?p=glowm.cml/section_view&articleid=299 10 http://pcosjournal.com/horm ones-normal-menstrualcycle/ 11 12 4
High FSH: Ovaries are failing to respond Front Biosci 2007;12:2782-96. Interaction and signal transduction between oocyte and somatic cells in the ovary. Liu YX. 13 Once E2 is high enough for long enough, the LH surge is triggered through ERβ Rising estrogen keeps LH suppressed through ERα 14 If estradiol isn t rising in the follicular phase, it is unlikely that follicles are developing 15 5
Bleeding is terminated by rising estradiol levels Bleeding is initiated by falling estradiol levels 16 Progesterone helps along the fall in E2 by downregulating E2 receptors and downregulating the production of E2 We tend to fixate on the rise and fall of Pg as the trigger for menses 17 If a CL doesn t form, you don t make progesterone Sometimes the CL can form even if the follicle doesn t rupture So you get an LH surge and a Pg surge, but no egg release This is called a Luteinized Unruptured Follicle 18 6
What is Progesterone Really For? Sperm use Pg as a homing signal, and Pg affects sperm motility Pg thickens the cervical mucus plug The primary role of progesterone is to promote the development of the endometrial glands which permeate the endometrium in the 2 nd half of the cycle. 19 What is Progesterone Really For? The glands secrete mucins, glycogen, growth factors and cytokines that foster implantation and help nourish the developing trophoblast Progesterone in the picture makes for a nicer bleed if no implantation takes place: usually lighter and shorter Progesterone is not for bleeding!!! 20 Silent Anovulation Only detected when there is a fertility issue Normal frequency and length of bleeding, but no ovulation 10 to 20% of women chosen at random will have at least one episode per year Common in teens and in perimenopause Jerilyn Prior has been researching this phenomenon (http://www.cemcor.ubc.ca/help_yourself/articles/ egglessly_cycling) 21 7
J Clin Endocrinol Metab. 1998 Dec;83(12):4220-32. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. De Souza MJ, Miller BE, Loucks AB et al. Runners trained at least 2 hours/16 km per week and the average mileage was 32 km/week Effects didn t correlate to the amount of exercise, but did correlate to energy intake, energy expenditure and energy balance Compared the runners to sedentary women 22 Sedentary Runners 23 Sedentary Runners 24 8
Approx 50% of 17 women aged 20 to 31 had anovulatory cycles with no luteal surge or truncated luteal surge They all had regular menses 25 How to do Month-Long Profiles Collect the first tube on the first day of bleeding, if starts before 10AM Otherwise do it in the first hour of waking on the second day Do all subsequent tubes in the first hour of waking Collect a sample every 3 rd day after that. Keep going even if you start bleeding! 26 How to do Month-Long Profiles We need 11 tubes!! The software crashes if it doesn t have 11 data points. I either have to interpolate, extrapolate, or fill with zeroes 27 9
HYPOTHETICAL EXAMPLE!!! BLEEDING HAPPENED TO START ON THE 1 st!!! 28 If bleeding starts here Just keep swimming, just keep swimming Dory the Fish 29 We need 11 tubes! Collect each tube in the morning! Just be thankful you re not my dentist 30 2/19/2011 30 10
31 32 Patient conceived during this collection 33 11
26 yrs old with regular menses Point is that the luteal E2 surge is higher than the ovulatory surge 34 35 Sometimes you wind up with a dominant follicle, but no LH surge, no ovulation and no CL 36 12
Textbook monophasic cycle. 42 yrs old with regular menses. On Mirena Next menses started here This was her 2 nd or 3 rd day of light spotting 37 25 yrs, regular menses, c/o breast tenderness 38 Pg/E2 never really makes it into the normal range Patient is slender and Testo is toward the high end of the range. Aromatization of testo? Subtle ovarian dysfunction: first follicle never became dominant 39 13
45 yrs, BMI 20.9 Irregular menses 40 39 yrs, irreg menses, BMI 47 We had to fill with a zero, because pt only sent 10 tubes! 41 25 years old. This is her first month off Alesse. Classic monophasic cycle 42 14
47 yrs old, BMI 21.8 Pooled testo 10! Bled for 49 days straight, several months prior to this collection 43 Mood swings Paranoid Impatient Intolerant Heavy mucus discharge First day of bleeding 44 Cessation of menses c/o hot flashes during this time -Sky high progesterone also measured two years prior at another lab -General complaints of fatigue and foggy thinking 45 15
Breast tenderness Water retention No bleeding 46 Estrogen dominant E2 fits with her BMI E2 is probably ectopic i.e. produced in visceral fat from androgen precursors 47 44 year old woman with irregular bleeding 48 16
44 year old woman with irregular bleeding Anovulatory cycles but bleeding for the first 2 weeks of the month Patient stopped bleeding when her E2 rose above 1 pg/ml! 49 Next menses started here 43 years old, BMI 23, regular menses, acne, oily skin, Testo high end of range 50 Last Pg use Patient uses progesterone cream 37.5 mg bid, 12 days/month 51 17
Last Pg applied 29 days before here 27 yrs old, normally using Pg cr 50 mg bid, days 16-32 Complains of bloating 52 3000+ This profile was taken in Feb 2011, and pt hadn t used Pg cream for 2 months. She has regular menses 53 Approximately 2 months later ( 4 months after stopping Pg cream) 54 18
Approximately 7 months after stopping Pg cream 55 5 months post Pg cream 47 years old with prior hx of menorrhagia and clots prior to starting Pg cream Pg cream used up until January 2011 This profile was taken April 2011 56 Pt began to menstruate here for the first time in 4 months???? This profile was taken in December 2011 57 19
Prior use of Pg cream It appears as though the ovaries store topically supplemented Pg and are able to release it in subsequent cycles, in more or less controlled fashion If this is true, a little bit goes a long way Better to start with a low dose, use cyclically, and be patient 58 Prior use of Pg cream It may take several months (or even longer) to clear things back to baseline Always inquire about prior Pg cream use before setting up this test for a patient 59 Other Explanations Pg stored elsewhere, but that storage depot is somehow synchronized to the ovaries We need to administer some radiolabelled Pg via the skin, and look to see where it winds up Any volunteers? 60 20
???? 25 yrs old, regular menses, uses Pg cream 10 mg bid every day Point here is that her E2 doesn t seem to do much. Why is she having regular menses? 61 28 yrs old, BMI 18.9 uses Pg in oil on skin every day (3 mg bid) Spotted throughout this collection Says she spots all the time unless she takes an OCP Testo 42 and c/o hirsutism, acne and oily skin 62 Month-Long Profiles No bleeding? Erratic bleeding: Too little E2? Too much E2? Luteal phase defect? Proper follicular phase with peaking E2? Silent anovulation? Demonstrate to patient what OCP, Mirena may be doing to her natural cycle 63 21
Month-Long Profiles Can yield insight into confusing presentations Occasionally can leave you more confused than ever Pg supplementation can lave long-lasting effects: use it wisely! 64 Month-Long Profiles Valuable test! Please collect the specimens properly! 65 22