MENSTRUAL CYCLE CONTROL IN
FEMALE ASTRONAUTS & THE
ASSOCIATED RISK OF VENOUS
THROMBOEMBOLISM
Varsha Jain
NIHR Academic Clinical Fellow
School of Biomedicine
Centre of Human and Aerospace Physiological Sciences
Disclosure Slide
No financial relationships to disclose
Off-label uses of the oral contraceptive pill will be discussed,
although these are common practice amongst clinicians
Overview
•Physiology of the normal reproductive cycle
•Introduction to menstrual suppression
•Mechanism of action of current regimes
•Advantages and disadvantages of current methods
•Pathophysiology of venous thromboembolism (VTE)
•Risk factors for VTE
•Spaceflight related risks for VTE
•Quantifying the risk for female astronauts of VTE
•Ideal menstrual suppression agent for female astronauts
•Future work
Demographics (*2014 publication)
Total number of humans in space
534
Total females in space
57
Total US astronauts in space
330
Total US female astronauts in space
48
Age range at US selection
26-47 yrs
Mean age US ASCAN* finalist
32 yrs
Mean age US female astronaut at first
flight
38 yrs
2013 selected female ASCANs*
*ASCAN – astronaut candidate
50%
Physiology of the Normal Menstrual Cycle
Normal Menstrual Cycle
Introduction to Menstrual Suppression
The adoption of a therapeutic device (e.g. the levonorgestrel
intrauterine system) or treatment (e.g. hormonal preparations
such as the oral contraceptive pill) to prevent menstrual flow.
Clinical advantages:
• Gynecological: menorrhagia, endometriosis, dysmenorrhea
• Neurological: menstrual migraines
• Hematological: inherited bleeding disorders
Cultural:
• During exams, special holidays
• Following tubal ligation in a pre-menopausal woman
Menstrual Suppression vs 21/7 day regime
160 versus 450 cycles per lifetime
Thomas SL et al 2000
Similar contraceptive efficacy and safety profiles to cyclic use
No difference in compliance or discontinuation due to bleeding
Fewer hormonal side effects
Bleeding patterns improved with continuous use
Edelman et al, Cochrane, 2014
Menstrual Suppression for Astronauts
Pregnancy delays selection process
Pregnancy contraindicated for certain training activities
Contraindicated for spaceflight
Waste management systems on board station
Microgravity environment
Requirement: minimal breakthrough bleeding, effective
contraception
Personal choice
Education required
(Powell-Dunford et al 2011)
Options for Menstrual Suppression
Combined Oral
Contraceptive Pills
(COCs)
Hormone based intra-uterine
devices (IUD) e.g. Mirena or Skyla
Hormone based subdermal
implants e.g. Nexplanon
Hormone Profiles with the COC
COC
Hormone Profiles with the COC
LH FSH
Progesterone
1. Inhibition of FSH
2. Follicle maturation does not
occur
3. Estrogen levels do not rise
4. No LH surge
5. No ovulation
6. No corpus luteum
7. No rise in progesterone
8. Endometrium thin and sheds
with 7 days of placebo pills
The Combined Oral Contraceptive Pill
•1950s - 21/7 cycle due to cultural and social pressures
•Combined estrogen and progesterone – multiple preparations
•Inhibits ovulation and changes cervical mucus
•Failure rate – approximately 1%
•Contra-indications: thromboembolic disease, cerebrovascular
disease, migraine, diabetes, liver disease, breast cancer,
hypertension
•Interactions with other medications due to liver metabolism
•Interference with blood lab tests
•VTE risk doubled
Intra-Uterine Devices (IUDs)
•1909 – first intra-uterine ring
•1970s - Dalkon Shield had high rates of pelvic inflammatory
disease
•Safe, effective, long acting, reversible
•Non-hormonal IUDs – Copper  heavier bleeding
•Hormonal IUDs – Levonorgestrel (progestin)
•Mirena - 52mg levonorgestrel; Skyla – 13.5mg levonorgestrel
•Inserted with ultrasound guidance in clinic
•Failure rate – 0.7% at 5 yrs (Mirena)
Mechanism of Action - Levonorgestrel IUD
•Localized effects
•Down-regulates endometrial estrogen and progesterone
•Endometrium insensitive to circulating estradiol
•Strong anti-proliferative effect
•Systemic concentration of levonorgestrel much lower compared
to COC usage.
Levonorgestrel IUD: benefits for astronauts
•Mirena (hormonal IUD) can suppress bleeding completely
•Does not affect BMD
•Can be used in conjunction with oral estrogen
•Licensed for 5 years (amenorrhea rate increases with continuous
use)
Wong et al, Aus NZ J Obs Gyn, 2010
•Very low rate of uterine perforation (0.26% - 0.9%)
Van Houdenhoven, K. et al 2006, Margarit,
L. M. et al 2004
• Predominantly occurs at insertion – operator dependant
•Expulsion (5.8% - most likely in first 3 months) – rare
• This is a likely reflection of operator skill
Heineman et al, Am J Obs Gyn, 2014
***WARNING***
The next two slides contain dissected
anatomy and blood
Levonorgestrel IUD “in situ”
Uterus removed at vaginal
hysterectomy with a
“Mirena” levonorgestrel IUD
in situ.
An epithelialised layer has
formed around the IUD,
which has been in situ for 2
yrs.
Levonorgestrel IUD removal
Epithelialised layer
DOES NOT impede
removal
Hormonal Implant
•Nexplanon – 68mg etonogesterel (progestin)
•Sub-dermal, 4cm rod, radio opaque contraceptive implant
•Long acting (3 yrs), reversible, safe, effective contraceptive
•Most effective contraceptive currently available
•Mechanism of action: inhibits ovulation
•Oestradiol levels above threshold for maintaining bone mass
et al, Human Reproduction, 2000
•Only 1 in 10 discontinue use due to irregular bleeding
•1 in 5 users have amenorrhea within 3 years
Beerthuizen
Recommendations for menstrual suppression
•COCs effective
– However compliance, upmass, trash & stability considerations
•Long acting reversible contraceptive (LARC) possible
•52mg Levonorgestrel – IUD suggested
•Hormonal implant has a higher potential for irregular bleeding
but due to normal BMI of astronauts, may not be a problem
•Start one year prior to flight at minimum
•Add back low dose estrogen (suggest 10 mcg) alongside LARC
•Estrogen effects on bone
•Introduce a transvaginal ultrasound probe on station
Venous Thromboembolism (VTE)
“Venous Thromboembolism is a disease that includes deep vein
thrombosis (DVT) and pulmonary embolism (PE)”
i.e. blood clots in the venous system of the legs or lungs
Sudden Death
Lethal
Underdiagnosed
Common
Preventable
Dangerous
Serious
Treatable
Economic burden
Public health problem
Silent killer
Dopesh 2009
Virchow’s Triad
Hypercoagulability
Hereditary Deficiencies:
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin gene mutation
Dysfibrinogenemia
Acquired:
Cancer
Pregnancy & Postpartum period
Oral contraceptives
Hormone replacement therapy
Polycythemia Vera
Smoking
Antiphospholipid Syndrome
Stasis:
Hypercoagulability
Venous
Thromboembolism
Stasis of blood
flow
Endothelial
Damage
Immobility/cast/travel
Advanced age
Acute medical illness
Major surgery
Spinal cord injury
Obesity
Endothelial Damage:
Major surgery
Trauma
Central venous
catheterisation
Age
Rheumatoid
Arthritis
Congestive
Cardiac Failure
Asthma
Demographic
Status
Smoking
Family
History
Sex
Hormone
Replacement
Therapy
Obesity
Risk Factors for
VTE
Contraceptive
Pill
Cancer
Thrombophilia
Varicose Veins
Immobility
Hospitalization
Pregnancy
Hip Fracture/Surgery
Hyperhomocysteinaemia
VTE and spaceflight
•No episodes pre-, during or post-flight documented
•Oral contraception doubles risk of VTE terrestrially
•Terrestrial risk calculators do not consider astronaut selection,
pre-flight training or space flight environment
•Pre-flight Training:
–
–
–
–
Long haul travel
Diving
Injury risk
Immobility – Soyuz training
Potential In flight Risk Factors
The following are terrestrial risk scores:
•Hemoglobin: <1st centile  OR of VTE is 3.4
•Mean Corpuscular Volume(MCV): <1st centile  OR for VTE is 1.95
(hematinics); >99th centile  OR for VTE is 2.65
•Hematocrit: upper 20% of normal range  1.5 times ↑ VTE risk
•Reticulocyte count: indication of blood turnover
•Platelet count: acute phase protein, high levels increase
coagulability of blood
•Prothrombin time: <11 secs  increased coagulability of blood
•Homocysteine: >15mcmol/L  RR of VTE is 1.5-2 (increases due to
Vit B12, folate deficiency)
Methods
•Retrospective cohort study
•LSAH database – medical and research data
•Post 2000, female short and long duration flights, not on HRT
•Repeat fliers counted as separate episodes
•Last pre-flight value and first post-flight value used to calculate:
1.Comparing post-flight data of dependent variables to normative high risk data
from the literature.
2.Characterizing descriptively the changes between pre vs post-flight data of
each dependent variable and determining if significant changes by using
repeated measures t-test.
HYPOTHESIS: Predict spaceflight does not increase risk of VTE
compared to terrestrial population
Results
• None of the post flight values crossed the at-risk threshold for
increased risk of VTE.
• We found no obvious trend towards abnormality or increased
risk of VTE with short or long duration spaceflight with
hormonal contraception
• Thus supporting our hypothesis: Spaceflight does not increase
the risk of VTE in female astronauts using hormonal
contraception.
Results
The Percent Increase of Known VTE Risk Factors after Short or Long Duration
Spaceflight in Female Astronauts Taking the Combined Oral Contraceptive Pill
Variables in green are
not increasing the risk of
VTE in the female
astronauts taking COCs
Variables in red are
moving in the direction
of potential increased
risk of VTE however, do
not cross the risk
threshold
Contraceptive Agents & their VTE risk
Lidegaard 2014
“Ideal” contraceptive agent to reduce VTE risk
•When combined with age >35 yrs, first choice contraceptive
agent would be progestin only contraceptive and second choice
would be a low risk combined product with norethisterone,
levonorgestrel, norgestimate.
•High risk products should not be taken – but some women might
be happy to take on the risk.
•When comparing LNG-IUD to COC with levonorgestrel (30-40mcg
EE) – then LNG-IUD has not got increased risk of VTE, in fact
potentially protective (adjusted rate ratio when adjusted for
length of use was 0.18 (95% CI at 0.12 – 0.26)
(Lidegaard 2014)
(Lidegaard 2014)
(Lidegaard et al 2012 ).
Future Work
Hypercoagulability
Venous
Thromboembolism
Stasis of blood
flow
Endothelial
Damage
Endothelial Damage:
Major surgery
Trauma
Central venous
catheterisation
Quantifying endothelial damage
•Muscle injury impacts VTE risk:
• sprain (adjusted OR 3.1 with 95% CI 2.1 – 4.6)
• minor injury in prior three months (adjusted OR 3.5 95% CI 2.8-4.3)
• muscle or ligament rupture (adjusted OR 10.9 CI 5.6 – 21.3)
•How great a risk is this for astronauts?
Food for thought
•Current menstrual suppression regimes could be adapted to LARC
use +/- estrogen add-back
•Additional risk factors for astronaut population could include:
– Lack of lower limb activity
– Levels of dehydration and red cell lysis
– Stress as an immunosuppressant
– Radiation impacts
• Exercise mitigation strategies
• Compression stockings post-flight
• Longer duration missions and their impact
Acknowledgements
This projects would not have been possible without:
•Funding & opportunity to travel for research: Bart’s Health NHS
Trust & National Institute of Health Research
•Baylor College of Medicine: support with visa paperwork 2015
•USRA: Virginia Wotring, Rob Ploutz-Snyder
•NASA: Serena Aunon, Mike Barratt, Jackie Charvat and LSAH team,
Janine Bolton
•Wyle: Pam Baskin
•Richard Jennings
•Ellen Baker
•Michele Blackwell
CONTACT DETAILS
DR VARSHA JAIN
NIHR ACADEMIC CLINICAL FELLOW (OB/GYN) – BART’S HEALTH NHS TRUST
HONORARY RESEARCH ASSOCIATE – KING’S COLLEGE LONDON
EMAIL: VARSHA.JAIN@KCL.AC.UK