Kathleen Hoeger MD MPH Professor of Obstetrics and Gynecology University of Rochester, Rochester NY Director, Strong Fertility Center

 Hormonal changes in the normal cycle  LAM and the menstrual cycle  Options for fertility control  Pregnancy in LAM  Natural fertility and age  Options for fertility to reduce estrogen exposure

 The normal cycle is a carefully orchestrated interplay of hormones that results in the release of a single follicle containing a single egg  Fertilization of that egg is only possible in a 24 hour window  Following ovulation the uterus is prepared for implantation  If there is no implantation, menstruation follows in a very prescribed window, usually about 14 days.

Ovary Hypothalamus Anterior pituitary Anterior pituitary ↑FSH Estradiol Inhibin Estradiol Inhibin

 LAM is known to present primarily in reproductive aged women  May improve postmenopausally  Rarely is seen prepubertally or in males  Laboratory study links pathology with the estrogen pathway  All of these suggesting a link between LAM and reproductive hormones

 As LAM is known to exhibit both estrogen and progesterone receptor positivity, it is possible there are variations across the menstrual cycle  There are no large studies that have analyzed the symptoms of LAM and menstrual cycle changes  Several case reports link worsening symptoms to the use of hormonal agents and pregnancy but even this is not consistent across all studies

 Case series of 2 young women with abdominal LAM presenting with abdominal cramping  Symptoms in these women were noted to worsen in the midcycle  Study of the retroperitoneal masses on day 1 of the cycle and day 14 of the cycle, each demonstrated a 4-6% increase in the size of the mass at the peak follicular estradiol levels  Sandrini et al Intern Med J 2011

 As many women are in the prime of their reproductive years when diagnosed with LAM, what is known about the effects of hormonal contraception?

 Used by about 1/3 of women as first choice in contraception  Combination oral contraceptives contain both an estrogen and progestin  Estrogen-mestronol, ethinyl estradiol and estradiol valerate, 17 β estradiol  Very potent estrogenic components (more than natural estradiol)  Progestins-more variable component  Majority derived from testosterone  Few newer agents derived from progesterone itself

 Because exogenous estrogens may promote disease progression, it is generally recommended that women diagnosed with LAM avoid combination oral contraceptives and hormone replacement therapy post menopausally  European Respiratory Guidelines; Johnson et al Eur Respir J 2010  There is an uncertain impact of progestin

 Survey of 91 women diagnosed with LAM  83 responded to survey and 87% were premenopausal  About 27% were using oral contraceptives  The age of diagnosis for those using COC was 29.2 versus 32.1 years in those who did not use COC  Suggested that COC may cause earlier presentation of disease  Oberstein EM et al J Women’s Health 2003

 About 30-40% of Tuberous Sclerosis patients develop LAM  Survey of 39 German women with TS on their use of COC  65% of the women had used COC  Odd Ratio of ( ) of developing LAM in those taking COCs at some point  Sauter M et al Eur J Contracept Reprod Health Care 2014

 Women who have LAM and become pregnant have 11X increased risk of complications in pregnancy  Increased risk of pneumothorax  Increased risk of chylous effusion  Risk of bleeding from angiomyolipomas  Pregnancy may worsen disease progression  Guidelines suggest against recommending pregnancy but each patient should be individually counselled

 Case series from Japan  8 pregnancies assessed  Mean age of LAM diagnosis was 29-mean age of delivery was 33 yrs  All were sporadic LAM and most had mild disease (3 were severely impaired)  7 pneumothoraces  6 pregnancies had no progression of disease  One patient in fertility treatment had to abandon treatment due to exacerbation  One had progression post partum Seyama Am J Repsir Crit Care Med 2011

 Survey of 328 women with LAM in the US and UK  205 had been pregnant, the majority prior to the LAM diagnosis (mean 1.8 pregnancies)  15 diagnosed during pregnancy  Pneumothorax 67%  Miscarriage 7%  Premature birth 46%  Those diagnosed before or during pregnancy had lower pulmonary function compared to those diagnosed after pregnancy or never pregnant  23 women expressed the desire to have more children  12 women had children following the diagnosis of LAM Cohen et al Respiratory Medicine 2009

 Despite the increased concerns regarding hormonal therapy, pregnancy and LAM, women affected are in their reproductive prime  Not clear if LAM reduces fertility  Are there any options for fertility treatments that minimize risk?

 Fertility potential varies significantly across the reproductive lifespan  This is primarily dependent on the biology of the ovarian follicular pool

 Ovarian reserve testing:  Anti-mullerian hormone (AMH)  FSH and estradiol  Antral follicle count (AFC)

 Ovarian reserve testing:  Anti-mullerian hormone (AMH)  FSH and estradiol  Antral follicle count

 Ovarian reserve testing:  Anti-mullerian hormone (AMH)  FSH and estradiol  Antral follicle count AMH

 Some women may choose to become pregnant with LAM  That decision is best made individually with your LAM physician  If there are no fertility concerns, either related or unrelated to LAM, natural conception is possible and therefore in that case women do not seek hormonal therapy to become pregnant  However some women may have fertility problems themselves or wish to delay pregnancy until later or wish to minimize the risks of pregnancy but still have biologic children

 In situations where the decision to proceed with pregnancy must be deferred there are options for fertility preservation to allow for family building on a more acceptable timeline  Increasingly women are turning to gestational surrogacy for family building when pregnancy itself is a significant health risk  This involves the use of a individuals OWN eggs and partner’s sperm to create embryos that are transferred into a surrogate uterus

 In normal stimulation for IVF there is a requirement for high doses of FSH to recruit a large number of eggs  This results in estradiol levels that are 5-20x higher than a normal menstrual cycle  If a condition is estrogen sensitive this can cause significant concern as these levels remain elevated for several weeks resulting in increased risk

 There are options for stimulating the ovaries to reduce the estrogen exposure during the stimulation  This is very helpful for those wishing to preserve their fertility for the future or who wish to use a gestational carrier for their pregnancy

 Eggs Embryos Ovarian tissue

Indications: Advanced breast cancer not responding to tamoxifen therapy; exemestrane is also used to prevent prostate cancer, Anastrozole adjunct for breast cancer inhibitors of the enzyme “aromatase” that is responsible for the conversion of Androgens to Estrogen Letrozole and Anastrozole are reversible competitive inhibitors Exemestrane is an irreversible inhibitor Aromatase Inhibitors

NEJM 348:2432.

Menses Cycle Day 2-3 FSH IU ~7 ~12 hCG or GnRH agonist Oocyte Retrieval 14 GnRH antagonist Letrozole 5 mg

Menses Cycle Day 2-3 FSH IU ~7 ~12 hCG or GnRH agonist Oocyte Retrieval 14 GnRH antagonist Letrozole 5 mg

 Peak estradiol levels are significantly lower, generally similar to follicular phase estradiol levels  Egg recoveries are similar to other protocols for fertility preservation (but somewhat less than standard IVF protocols

Cobo A et al. Hum Reprod 2010;25:  Frozen thawed embryos: ~ 45% live birth rate/transfer  Frozen thawed oocytes  embryos  No difference in fertilization or pregnancy rates  No apparent increase in birth defects Grifo JA et al. Fertil Steril 2010;93: SART 2012

Ovarian tissue

Mayerhofer K et al. Euro J Obstet Gyeco 2010:152:68-72

 Does not require any hormonal stimulation  Does require surgery to remove the ovary  Technology is still very experimental  Babies currently only from re-implantation of the tissue back into the woman and maturation in vivo

Hum Reprod Update Jul-Aug; 16(4): 395–414.

 Oocytes or embryos  2-3 week delay  Medical clearance for stimulation and retrieval Ovarian tissue Minimal delay Medical clearance for surgery Experimental

 What about genetic testing for LAM  LAM is associated with tuberous sclerosis in about 40%  Tuberous sclerosis demonstrates an autosomal dominant inheritance with which there are mutations in 2 genes (TSC1 and TSC2) for which preimplantation genetics can be done.  This involves IVF with creation of embryos that undergo trophectoderm biopsy on the 5 th day of development.  Genetic tests are performed on the embryo biopsy to screen for disease

 Oocyte/Embryo banking ~ $10-20,000  Stimulation, retrieval, cryopreservation ~$4,000  Storage ~$100/year  Thaw, fertilization, embryo culture, transfer ~$2,500/tx  Ovarian tissue banking ~$20-35,000  Surgery, cryopreservation of strips ~ $10,000  Storage ~$100/year  Thaw, transplant, +/- IVF ~ $10,000 - $25,000

 Preimplantation genetic studies $6,000  Surrogacy IVF ~ embryo banking $15,000/tx+ costs of surrogate cycle $10,000+  Adoption ~$5-45,000

 Impact of normal menstrual cycle on symptoms of LAM is uncertain  Some concern exits regarding traditional hormonal contraception but LARC that involve progestin only untested  Overall there are options for pregnancy in LAM if IVF/fertility preservation therapy is desired that will reduce estrogen exposure  Gestational surrogacy can offer biologic children without increased risk of pregnancy in LAM