Dr. John Carmichael and Leslie Edwin

Dr. John Carmichael, Co-Director of the USC Pituitary Center at the Keck School of Medicine, gave a presentation on hypopituitarism and pregnancy at the 2019 American Association of Clinical Endocrinologists conference in April.  We hear from patients who are concerned about their chances of becoming pregnant after treatment for Cushing’s Disease, so we hope that the information shared in the following summary of that presentation will be a good starting point for anyone in this position.

Causes and Categories of Infertility

Related to pituitary disease and surgery, there are several potential causes of pituitary failure that can lead to problems with fertility.  Structurally, adenomas and other masses cause dysfunction.  Functionally, diseases like obesity and chronic illness, hormonal excess or deficit, and certain medications can contribute to this as well. 

Infertility can also be caused by a broad range of culprits outside of a pituitary source including intense exercise, eating disorders, stress, polycystic ovarian syndrome (PCOS), hypothyroidism, adrenal adenomas, and renal/liver impairment.  While it is daunting to face these types of challenges, knowing what they are is a first step to a patient’s best possible outcomes when the goal is a healthy mom and baby.

The World Health Organization (WHO) sorts ovulation disorders into three categories.  Women with pituitary damage or dysfunction due to Cushing’s Disease will usually find themselves in Class 1.  Infertility treatment depends on the cause of the disorder:

• Class 1 – Hypogonadotropic hypogonadal

-approximately 5-10% of cases fall under this category

-problems in hypothalamus and pituitary

• Class 2 – Normogonadotropic normoestrogenic

-approximately 70-85% of cases

-problems in hypothalamus, pituitary, and ovaries

• Class 3 – Hypergonadotropic hypoestrogenic

-approximately 10-30% of cases

-problems in ovaries

While a classification system is helpful, at this time there are still relatively few published studies to guide successful infertility treatment in women with hypopituitarism.  Because the hormones required to become pregnant can be affected by having or treating pituitary Cushing’s, most women will be affected by this, at least for a little while.  Although women have been receiving hormonal infertility treatments since 1961, there isn’t much data specifically about women who have chosen it due to pituitary deficiencies.

Two Studies in the Literature

In his presentation, Dr. Carmichael referenced a couple of studies.  The first was done in England in 2002 looking at high-risk pregnancies in a group of nine women with hypopituitarism(1).  Compared to the general population, these women experienced a high rate of miscarriage and maternal mortality.  Amongst the nine there were 18 pregnancies with a live birth rate of 61%, a miscarriage rate of 28%, fetal death rate of 11%, and a 100% rate of C-section births.  Half of the live births were at or below the 10^th percentile for weight and the majority of the women were unable to breastfeed.

The next study came out four years later and had a total of 19 women with hypopituitarism including the nine from the earlier study.  This study looked at pregnancies but also the fertility of the women(2).  This group saw a 42% live birth rate, and seven out of 18 pregnancies ended in miscarriage.

Hormone Replacement During Pregnancy

Optimization of existing hormone replacement therapy should be discussed before a woman with hypopituitarism becomes pregnant so that she has time to adjust to changes or additions to her dosing.  Both mother and developing child must be monitored carefully throughout the pregnancy to ensure that dosing remains correct or is adjusted as necessary.  Dr. Carmichael referenced the Endocrine Society Clinical Practice Guideline on hormone replacement in hypopituitarism in adults (3) that gives information on the interactions between replacement hormones and management during pregnancy:

• Glucocorticoids + Growth Hormone = increased conversion of cortisol to cortisone, patient should have HPA axis tested before and after starting growth hormone in patients who do not take glucocorticoids
• Glucocorticoids + Thyroid Hormone = increased clearance of cortisol, patient should be evaluated for adrenal insufficiency (AI) prior to initiating treatment for hypothyroidism
• Glucocorticoids + Diabetes Insipidus (DI) = AI might mask DI, patient should be monitored for DI after initiating treatment for AI
• Estrogen + Growth Hormone = estrogen increases growth hormone resistance, women taking oral estrogen need higher doses of growth hormone for adequate IGF-1 production
• Estrogen + Thyroid Hormone = increased production of thyroid-binding globulin, patient needs to be reassessed for increased need for levothyroxine to stay in the normal range

Further, each type of hormone replacement has specific recommendations during pregnancy:

ADRENAL

• hydrocortisone is preferred, with adjustments made as needed
• hydrocortisone is deactivated in the placenta
• patient must be monitored for over- and under-replacement
• stress dosing recommended for delivery

THYROID

• levothyroxine is preferred with adjustments made as needed
• increased dose during first trimester, through delivery

GONADAL (estradiol and progesterone)

• discontinued during first trimester
• requires collaboration with OB/GYN

GROWTH

• discontinuation during pregnancy is standard

DIABETES INSIPIDUS (DI)

• pregnancy can bring out DI when previously it was not a problem for the patient
• patient should be treated with DDAVP (desmopressin) at bedtime with dosing adjusted as needed
• caution must be used to avoid overtreating

ENDO Hypopituitarism Guidelines

It is clear that fertility is impaired in patients with hypopituitarism.  It’s also an unfortunate reality that women who experience fertility challenges due to pituitary problems have poorer outcomes compared to women with other types of infertility.  Making sure replacement hormones are at their best possible levels before conception seems to give the greatest chance to both mother and baby, and the patient needs to have her levels monitored throughout the pregnancy so deficits or excesses can be quickly adjusted.

It is encouraging to know that pituitary damage does not necessarily bar a person from becoming pregnant in the future.  Knowing the challenges and the guidelines for best case scenarios could make a huge difference for a patient who might not be working with doctors who are very familiar with optimal conditions for patients with hypopituitarism trying to conceive.  We had a few more questions for Dr. Carmichael:

Q – Do men with hypopituitarism experience fertility problems?  If so, what can they do about it other than optimizing existing hormone replacement therapy?

A: Yes, quite commonly. In addition to optimizing other hormones, in most cases, there needs to be a transition from standard gonadal replacement with testosterone to hormones that directly stimulate testosterone and sperm production in the testes. As the goal of gonadal replacement shifts toward optimizing fertility, medications change from replacing testosterone to human chorionic gonadotropin (hCG) injections. HCG stimulates testicular production of both sperm and testosterone. In some cases, additional hormonal therapy is required to increase sperm production with human menopausal gonadotropin (hMG) or recombinant human follicle-stimulating hormone (rhFSH).

Q – Are there any current studies underway to look at fertility and pregnancy issues for patients with hypopituitarism?

A: While pregnancy is tracked during many studies, including those with patients with hypopituitarism, searching clinicaltrials.gov for hypopituitarism and pregnancy yields no studies directly investigating the influence of hypopituitarism on pregnancy or fertility outcomes. There may be studies conducted locally that may not be listed, but these would usually not include anything interventional or prospective.

Q – What kind of impact would too much or too little hormone replacement therapy have on a developing fetus?

A: There are several concerns here. Firstly, too much glucocorticoid therapy can result in macrosomia, where the fetus becomes larger than normal, potentially causing issues with delivery. Over-treatment also may impact the mother with weight gain, gestational diabetes, and hypertension, among other systemic problems. Significant morbidity and mortality risk for the mother and fetus comes with adrenal insufficiency, especially at the time of delivery, most notably issues with hypotension. Effects on the fetus are rare though, due to placental regulation of maternal glucocorticoids and placental corticotrophin releasing hormone (pCRH) increasing fetal cortisol. The effects of hypothyroidism during pregnancy vary and may depend  on the degree of hypothyroidism but include loss of the pregnancy, preeclampsia, low birth weight, cesarean delivery, postpartum hemorrhage, and neuropsychological and cognitive impairment in the child.

Q – I can find some research that points to maternal high cortisol and stress during pregnancy causing developmental delays in the young child.  I also read that hydrocortisone does not cross the placenta.  Is cortisol not needed for fetal development?  Might there be some benefit then, if there is no or low natural cortisol and the replacement does not cross the placenta?

A: The research in this area shows correlation between these findings but does not distinguish between the association and the cause. Hydrocortisone is altered by the placenta, deactivating it to varying degrees, but some does cross, and fetal cortisol is driven by placental stimulating hormones as well, so cortisol is very crucial to the development of the fetus, and is equally as vital for the health of the mother.

Q – Do or would you recommend therapy or other mental health support for a patient with hypopituitarism who wishes to become pregnant?  It seems like a very emotional, stressful experience to try to stay healthy and have a healthy pregnancy with hypopituitarism.

A: Absolutely, I think that there is not enough emphasis placed on the stress and challenge, both mentally and physically there is in going through this process. Most reproductive endocrinologists are aware of how their patients can benefit from a support system, which may include counseling from a mental health specialist.

References:

1. Overton, Caroline & J Davis, Colin & West, Christine & C Davies, Melanie & S Conway, Gerard. (2002). High risk pregnancies in hypopituitary women. Human reproduction (Oxford, England). 17. 1464-7. 10.1093/humrep/17.6.1464.
2. Hall, R, Manski-Nankervis, J, Goni, N, Davies, MC, Conway, GS.  (2006). Fertility outcomes in women with hypopituitarism.  Clinical Endocrinology.  65. 71-74.  https://doi.org/10.1111/j.1365-2265.2006.02550.x
3. Maria Fleseriu, Ibrahim A. Hashim, Niki Karavitaki, Shlomo Melmed, M. Hassan Murad, Roberto Salvatori, Mary H. Samuels, Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 11, 1 November 2016, Pages 3888–3921, https://doi.org/10.1210/jc.2016-2118