Adrenal insufficiency after megestrol acetate for fertility-sparing treatment of endometrial cancer

Highlights

• •AI is a rare yet potentially life-threatening side effect of MA when used for fertility sparing for EC/AH.
• •The presentation of AI is highly variable and clinicians should employ a low threshold for investigations.
• •AI can occur while on MA therapy or after abrupt withdrawal; MA should be tapered upon discontinuation.
• •Patients on MA may require stress dosing at times of surgery/procedures or acute illness.
• •Consider progestin IUD as a first line therapy, especially in patients with metabolic comorbidities.

1. Background

Endometrial carcinoma (EC) is the most common gynecologic malignancy (Suzuki et al., 2024). Though standard therapy for Federation International Gynecology and Obstetrics (FIGO) grade 1 early-stage, EC or atypical hyperplasia (AH) with total hysterectomy and bilateral salpingo-oopherectomy confers excellent 5-year disease-specific survival, this results in permanent loss of fertility (Suzuki et al., 2024). While most endometrial cancer occurs in post-menopausal patients, the most significant rise in endometrial cancer incidence in recent decades has occurred among women under 30, likely driven by increasing obesity rates and trends in delayed childbearing (Suzuki et al., 2024). As such, fertility-sparing treatment with progestin therapy is an increasingly desired option in highly selected patients (Suzuki et al., 2024).

Megestrol acetate (MA) is an oral synthetic 17-hydroxyprogesterone derivative approved by the Food and Drug Administration for appetite stimulation in acquired immunodeficiency syndrome and various cancers (Li and Winkler, 2012, Bulchandani, 2008). As a progesterone receptor agonist, it is also commonly used off-label for non-surgical or fertility-sparing treatment of EC/AH, functioning to interrupt aberrant endometrial proliferation (Suzuki et al., 2024). Common oral progestin-related side effects include weight gain, headache, increased appetite, nausea/vomiting and mood changes (Ozguroglu, 2006, Dev et al., 2007).

Adrenal insufficiency (AI) is a potentially life-threatening disorder of low circulating glucocorticoid, classified by the level of dysfunction in the hypothalamus–pituitary–adrenal (HPA) axis as either primary (due to adrenal gland dysfunction) or central AI (due to dysfunction of the pituitary gland or hypothalamus) (Fig. A) (Husebye et al., 2021). In addition to its affinity for the progesterone receptor, MA binds strongly to the glucocorticoid receptor with almost twice the affinity of the primary naturally occurring ligand cortisol (Dev et al., 2007, Delitala, 2013). Similar to consumption of other exogenous glucocorticoids, patients can therefore present with paradoxical glucocorticoid excess (with MA acting as a peripheral receptor agonist) and/or AI (secondary to shut down of the HPA axis with MA acting as a central receptor agonist) (Fig. A) (Dev et al., 2007).

Fig. A.

(1) Normal functioning hypothalamic–pituitary–adrenal (HPA) axis whereby sufficient circulating cortisol inhibits the release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) through negative feedback (2) The role of megestrol acetate (MA) as a progesterone and glucocorticoid receptor agonist and its impact on the hypothalamic–pituitary–adrenal (HPA) axis. CRH = corticotropin-releasing hormone; ACTH = adrenocorticotropic hormone.

We describe the first two documented cases of AI secondary to MA when used for fertility-sparing treatment of EC or AH and present a review of all other documented cases of AI secondary to MA prescribed for other indications. It is imperative for gynecologists and gynecology oncologists prescribing MA to be aware of this rare yet potentially life-threatening side effect and to understand the presentation and clinical implications of this side effect in this young population.

2. Cases

2.1. Case 1 (Fig. B)

Fig. B.

Timeline of case 1 and 2. AH = atypical hyperplasia; AI = adrenal insufficiency; BID = twice daily; D&C = dilation and curettage; EC = endometrial cancer; ED = emergency department; GA = general anesthesia; IUD = intrauterine device; m = momth; MA = megestrol acetate; PO = per os; T2DM = type 2 diabetes mellitus.

A 39-year-old nulligravid patient was diagnosed with AH with a small area suggestive of FIGO grade 1 EC confined within a polyp, identified after a hysteroscopic polypectomy during fertility investigations. The patient’s past medical history was significant for euthyroid thyroid nodules, and hyperprolactinemia secondary to a pituitary tumor managed with cabergoline. She had a body mass index (BMI) of 23.3. She was started on fertility-sparing treatment with MA, titrated to 80 mg orally twice daily.

Five months after initiation of MA, she was diagnosed with type 2 diabetes. One month later, she was seen in routine follow up for her known endocrine comorbidities. The patient had new hypertension and Cushingoid features, despite no recent corticosteroid use and no symptoms of AI. Bloodwork revealed a low morning cortisol of <28 nmol/L (normal: 101–536 nmol/L) and an inappropriately low adrenocorticotropic hormone (ACTH) of <1 pmol/L (normal 2–11 pmol/L), which was consistent with central AI. Brain MRI and pituitary panel including thyroid function was normal.

MA was tapered over five months and finally discontinued 11 months after its initiation. At that point, bloodwork was repeated and her morning serum cortisol and ACTH normalized to 158 nmol/L and 4.7 pmol/L, respectively.

An endometrial biopsy at the time of discontinuation of MA was negative for EC/AH and she was approved to proceed with fertility treatment. However, one additional biopsy completed prior to fertility therapy revealed focal AH, for which a levonorgestrel intrauterine device (IUD) (52 mg) was inserted. Following two additional serial negative biopsies, she underwent two attempts of egg retrieval with the IUD in situ, resulting in zero viable embryos. An endometrial biopsy done at the time of IUD insertion and all subsequent biopsies in follow-up were negative for EC/AH. After twenty-seven months of unsuccessful fertility therapy she underwent definitive hysterectomy and salpingectomy as she had no further fertility options. Final pathology revealed no EC/AH in the hysterectomy specimen.

2.2. Case 2 (Fig. B)

A 26-year-old nulligravid patient was diagnosed with FIGO grade 1 EC following hysteroscopy conducted for a two-year history of heavy menstrual bleeding. Her past medical history was significant for primary hypothyroidism and her BMI was 22.

She was started on fertility-sparing treatment with MA, titrated to 80 mg orally twice daily. She developed side effects including headache, nausea, and mood lability. Therefore, two attempts were made to insert a levonorgestrel IUD (52 mg) at 6 and 16 months after the initiation of MA but both were removed due to pelvic pain. The second IUD was inserted under general anesthesia.

Seventeen months after MA initiation and one month following IUD insertion and dilation and curettage (D&C) under general anesthesia, the patient presented to the emergency department with significant fatigue, syncope, weakness, and abdominal pain. Bloodwork demonstrated a low serum morning cortisol level of 6 nmol/L (normal 101–536 nmol/L) and ACTH < 1 pmol/L (normal 2–11 pmol/L), consistent with central AI. Brain MRI and additional pituitary hormone testing was normal. She was hemodynamically stable. She was evaluated by endocrinology who diagnosed AI secondary to MA suppressing the hypothalamic–pituitary–adrenal (HPA) axis. She was treated with one dose of IV hydrocortisone 25 mg, started on oral hydrocortisone 15 mg po in the morning and 5 mg po in the evening and MA taper was initiated.

Given her new diagnosis of central AI and complete response on recent D&C pathology, the patient was recommended to taper MA but was reluctant due to fear of recurrence. A slow taper of MA was eventually initiated, and MA was fully discontinued after 27 months (10 months after diagnosis of AI). She was stared on oral micronized progesterone for fertility-sparing treatment as she was previously unable to tolerate IUD treatment. Despite discontinuation of MA, she had ongoing adrenal suppression, requiring hydrocortisone replacement.

For personal reasons, the patient did not ultimately proceed with fertility treatment and underwent definitive hysterectomy 36 months after diagnosis of EC (9 months since discontinuation of MA and initiation of micronized progesterone). She required glucocorticoid stress dosing at the time of her surgery. The final hysterectomy specimen revealed recurrent FIGO grade 1 endometrioid EC, stage 1A without myoinvasion. The hydrocortisone replacement taper was initiated twelve months after the hysterectomy (31 months after the diagnosis of AI).

3. Discussion

To our knowledge, this is the first case report to describe AI secondary to MA used for fertility-sparing treatment in EC, highlighting a significant toxicity that physicians should be aware of when treating this young population.

The first case describes a patient who after 6 months of MA use developed features of glucocorticoid excess including type 2 diabetes, hypertension and Cushingoid features with paradoxical, biochemical, central AI. She was managed with MA taper and demonstrated biochemical resolution after 6 months. In the second case, the patient developed symptomatic central AI one month following a dilation and curettage under general anesthesia, after prolonged use of MA (17 months). Upon discontinuation, this patient had ongoing adrenal suppression, which required stress dosing for her definitive hysterectomy and ongoing steroid replacement until eventual discontinuation.

AI is a disorder of low circulating glucocorticoids, classified as primary (adrenal gland dysfunction) or central (pituitary or hypothalamic dysfunction) (Husebye et al., 2021) (Fig. A). Morning serum cortisol is a useful screening test: very low values (<50 nmol/L) are diagnostic of adrenal insufficiency, whereas levels > 300 nmol/L make the diagnosis unlikely (Husebye et al., 2021). Intermediate results (150–300 nmol/L) require dynamic testing, most commonly the ACTH (cosyntropin) stimulation test, which is the gold standard for confirming AI. Measurement of plasma ACTH helps distinguish primary from central causes, with inappropriately low levels supporting central AI (Husebye et al., 2021). Further investigations with pituitary imaging and hormonal workup should be considered to rule out other causes of central AI and hypopituitarism such as sella or hypothalamic mass or hypophysitis, especially if HPA axis does not recover as expected after weaning megestrol and/or glucocorticoid replacement. AI has a variable clinical presentation, ranging from biochemical/asymptomatic (asymptomatic suppression of the HPA axis identified on blood work) (Munshi, 2018, McKone et al., 2002); mild/moderate disease (vague anorexia, weakness, abdominal pain)(Dev et al., 2007, Delitala, 2013, Mehta et al., 2015), or adrenal crisis (a life-threatening state characterized by profound hypotension, acute abdominal findings, and marked laboratory abnormalities) (Bulchandani, 2008, Dev et al., 2007, Husebye, 2021, Delitala, 2013, Kwan, 2013, Leelalertlauw, 2018, Nanjappa, 2016). Management of AI secondary to MA may include either MA taper alone with consideration of glucocorticoid therapy as needed in the case of acute illness or surgery, as seen in the first case, or MA taper with prolonged glucocorticoid replacement, as seen in the second case.

The presumed pathophysiology of MA-induced AI is best understood by the dual binding capacity of the drug to both progesterone and glucocorticoid receptors (Fig. A). As a strong peripheral glucocorticoid receptor agonist with stronger affinity than the natural occurring cortisol ligand (Dev et al., 2007, Delitala, 2013), individuals on MA may develop side effects in keeping with peripheral glucocorticoid excess, including Cushingoid features, hypertension and new onset or worsening diabetes (Ozguroglu, 2006, Dev et al., 2007). However, by simultaneously binding to the central glucocorticoid receptors in the hypothalamus and pituitary, MA may suppress the HPA axis, resulting in adrenal insufficiency (Fig. B) (Ozguroglu, 2006, Dev et al., 2007, Kwan, 2013), resulting in adrenal insufficiency following abrupt discontinuation or adrenal insufficiency in the stressed state.

Upon reviewing the literature, we identified 10 case reports involving 15 patients who developed AI during treatment with MA (Li and Winkler, 2012, Bulchandani, 2008, Ozguroglu, 2006, Dev et al., 2007, Delitala, 2013, Munshi, 2018, McKone et al., 2002, Mehta et al., 2015, Kwan, 2013, Leelalertlauw, 2018, Nanjappa, 2016) and several case reports of patients who developed AI secondary to abrupt discontinuation of MA (Fried et al., 1997, Gonzalez Villarroel, 2008) (Table 1). AI occurred anywhere between 1 month and 6–7 years after initiation of therapy (Li and Winkler, 2012, Bulchandani, 2008, Ozguroglu, 2006, Dev et al., 2007, Delitala, 2013, Munshi, 2018, McKone et al., 2002, Mehta et al., 2015, Kwan, 2013, Leelalertlauw, 2018, Nanjappa, 2016) (Table 1), or several days to 1 month following abrupt discontinuation (Fried et al., 1997, Gonzalez Villarroel, 2008). AI is more likely to occur at higher doses of MA but has been reported to occur in patients on MA doses ranging between 160 mg (the highest dose typically used in the treatment of endometrial cancer) and 800 mg daily (Li and Winkler, 2012, Bulchandani, 2008, Ozguroglu, 2006, Dev et al., 2007, Delitala, 2013, Munshi, 2018, McKone et al., 2002, Mehta et al., 2015, Kwan, 2013, Leelalertlauw, 2018, Nanjappa, 2016). Interestingly, contrary to the typical phenotype seen in pre-menopausal patients with endometrial cancer, both patients presented in this report were noted to have normal BMI of 23 and 22, respectively. While no literature evaluates the relationship between BMI and adrenal insufficiency as a side effect of AI, one can infer that lower BMI patients (including those described here or individuals prescribed MA for weight gain) may be more susceptible to HPA suppression than patients with elevated BMI using the same dose. We identified three distinct presentations in the literature: (i) individuals who developed biochemical AI with clinical features of glucocorticoid excess including Cushingoid features (Ozguroglu, 2006, Leelalertlauw, 2018), (ii) individuals who developed symptomatic AI during a stress state (acute illness or surgery)(Bulchandani, 2008, Delitala, 2013, Nanjappa, 2016), and (iii) individuals who developed symptomatic AI secondary to abrupt discontinuation of MA (Fried et al., 1997, Gonzalez Villarroel, 2008). Where long-term outcomes were documented, all demonstrated biochemical resolution, implying that AI is a reversible side effect (Bulchandani, 2008, Dev et al., 2007, Delitala, 2013, McKone et al., 2002, Nanjappa, 2016).

Table 1.

Case reports describing adrenal insufficiency secondary to megestrol acetate therapy in the literature.

Author	Year	Age	Sex	Indication	Condition	Dose	Duration of use	Presentation	Investigations	Treatment
McKone et al. (McKone et al., 2002)	2002	47y	M	Appetite stimulation/weight gain	Cystic fibrosis	800 mg daily for 8 weeks, then 200 mg daily	16w	Impotence and decreased libido	AM cortisol; ACTH level; ACTH stimulation test; additional pituitary tests*; MRI brain	MA taper
Ozguroglu et al. (Ozguroglu, 2006)	2006	55y	F	Appetite stimulation/weight gain	Metastatic endometrial cancer	160 mg BID	8 m	New Cushingoid phenotype	AM cortisol; ACTH level; ACTH stimulation test	MA taper, steroid replacement
Dev et al. Patient 1 (Dev et al., 2007)	2007	20y	M	Appetite stimulation/weight gain	Metastatic osteosarcoma	600 mg daily	Not specified	During admission to hospital for pneumonia, was found to have hyponatremia, weakness, tachycardia	AM cortisol; ACTH level; ACTH stimulation test; additional pituitary tests*	MA taper, steroid replacement
Dev et al. Patient 2 (Dev et al., 2007)	2007	60y	M	Appetite stimulation/weight gain	Non-small cell lung cancer	400 mg daily	Not specified	Anorexia, fatigue, pre-syncope	AM cortisol; additional pituitary tests*	MA taper, steroid replacement
Dev et al. Patient 3 (Dev et al., 2007)	2007	71y	M	Appetite stimulation/weight gain	Metastatic carcinoma of unknown primary	800 mg daily	Not specified	Diaphoresis, nocturia, fatigue, dyspnea with exertion, drowsiness	AM cortisol; additional pituitary tests*	MA taper, steroid replacement
Bulchandani et al. (Bulchandani, 2008)	2008	80y	F	Appetite stimulation/weight gain	Failure to thrive	400 mg daily	1 m	During admission to intensive care unit for dyspnea developed hypotension	AM cortisol; ACTH level; ACTH stimulation test; MR brain	MA taper, steroid replacement
Li et al. (Li and Winkler, 2012)	2012	4y	M	Appetite stimulation/weight gain	Low appetite in otherwise healthy child	Not specified	2y	Hypotension (BP 90/44 mmHg), tachycardia, vomiting and diarrhea, persistent headache, malaise	Cortisol†	Steroid replacement‡
Delitala et al.Patient 1 (Delitala, 2013)	2013	81y	M	Not specified	Metastatic prostate cancer	160 mg daily	1y	During admission to hospital for pneumonia found to have hyponatremia (Na 129 mmol/L)	AM cortisol; ACTH level; additional pituitary tests*; MRI brain	MA taper, steroid replacement
Delitala et al. Patient 2 (Delitala, 2013)	2013	70y	F	Appetite stimulation/weight gain	Invasive ductal carcinoma	160 mg daily	2w	Severe asthenia and weight loss	AM cortisol; ACTH level; ACTH stimulation test; additional pituitary tests*; MRI brain	MA taper, steroid replacement
Delitala et al. Patient 3 (Delitala, 2013)	2013	70y	F	Appetite stimulation/weight gain	Ductal carcinoma	320 mg daily	5 m	Profound fatigue, anorexia, pre-syncope, nausea, hypotension, hyponatremia (Na 130 mmol/L). During admission, developed worsening fatigue, nausea, hypotension	AM cortisol; ACTH level; ACTH stimulation test; MRI brain	MA taper, steroid replacement
Kwan et al. (Kwan, 2013)	2013	80y	F	Appetite stimulation/weight gain	Diabetic nephropathy on dialysis	80 mg BID	5 m	Malaise, anorexia, hypotension (BP 90/60 mmHg), hypoglycemia	AM cortisol; ACTH level; ACTH stimulation test	MA taper, steroid replacement
Mehta et al. (Mehta et al., 2015)	2015	60y	F	Appetite stimulation/weight gain	HIV	800 mg daily	3 m	Nausea, constipation, significant fatigue, weakness, weight loss > 20 lbs	AM cortisol; ACTH level; additional pituitary tests*	MA taper, steroid replacement
Nanjappa et al. (Nanjappa, 2016)	2016	65y	M	Appetite stimulation/weight gain	Metastatic clear cell renal cell carcinoma	625 mg daily	1 m	During admission for a fall developed hypotension (BP 71/49 mmHg) and altered mental status	AM cortisol; ACTH level; ACTH stimulation test; MRI brain	MA taper, steroid replacement
Leelalertlauw et al. (Leelalertlauw, 2018)	2017	19y	M	Appetite stimulation/weight gain	Metastatic epithelioid sarcoma of the lumbar vertebrae	160 mg daily	6-7y	Cushingoid phenotype, low grade fever, hypotension (BP 80/50 mmHg), tachycardia (124 bpm)§	Cortisol†; ACTH stimulation test; additional pituitary tests*	MA discontinuation¶, steroid replacement
Munshi et al. (Munshi, 2018)	2018	48y	M	Appetite stimulation/weight gain	HIV	800 mg daily	Not specified	Impotence, decreased libido	AM cortisol	MA taper

^*Additional pituitary tests may include: growth hormone (GH) and insulin-like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone (TSH) and thyroid hormones (T3/T4), luteinizing hormone (LH) and testosterone or estrogen, and follicle-stimulating hormone (FSH).

^†Time at which serum cortisol drawn not specified.

^‡Discontinuation not specified.

^§Patient had three previous episodes of shock unspecified over the preceding 18 months.

^¶MA taper not specified.

The levonorgestrel IUD (52 mg) is an alternative, fertility sparing treatment of endometrial cancer with a higher rate of complete response (86 % (95 % CI, 69–95) vs. 66 % (95 % CI, 55–76)), similar pooled pregnancy rates (44 % (95 % CI, 6–90) vs. 58 % (95 % CI, 37–76), improved compliance and improved systematic toxicity when compared with oral progestin (Suzuki et al., 2024). As such, IUD should be considered a first line agent for fertility-sparing treatment in this population.

Clinicians using MA for fertility-sparing management of EC/AH need to be aware of AI as a rare, yet potentially serious side effect. Clinical considerations should include:

• (i)Low threshold for workup of AI with referral to endocrinology for patients on MA who develop symptoms of glucocorticoid excess (new hypertension, new or worsening diabetes, Cushingoid features) or AI (abdominal pain, anorexia, weakness or hemodynamic compromise).
• (ii)Gradual taper of MA for all patients upon discontinuation.
• (iii)Levonorgestrel IUD (52 mg) should be considered as first choice of treatment compared with oral progestin given similar oncologic and fertility outcomes with improved compliance and side effect profile.
• (iv)Consider stress-dose glucocorticoids before surgery or acute illness in individuals receiving high-dose MA (>160 mg daily) for > 3–4 weeks, consistent with guideline definitions of exposure associated with HPA axis suppression (Beuschlein et al., 2024).

4. Conclusion

We present the first reported cases of AI secondary to MA when used for fertility-sparing treatment for patients with AH/EC. Clinicians caring for these patients should be aware of this rare, but potentially life-threatening side effect and understand when workup or referral may be necessary. Given significant comorbidities of obesity and metabolic syndrome among younger patients with EC, clinicians should consider the progestin IUD as first-line for this population.

5. Author contributions.

All authors offered substantial contributions to the work as follows: project proposal (SF/SK), manuscript development (LC/LD), manuscript review (LC/LD, SK, NT, SE, SD, ED, SF), project supervision (SF).

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

CRediT authorship contribution statement

Lauren Clarfield: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Laura Diamond: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Soyoun Rachel Kim: Writing – review & editing, Supervision, Methodology. Shima Deljoomanesh: Writing – review & editing, Project administration. Nashwah Taha: Writing – review & editing, Writing – original draft, Supervision. Shereen Ezzat: Writing – review & editing, Writing – original draft, Supervision. Eleni Dimaraki: Writing – review & editing, Writing – original draft, Supervision. Sarah E. Ferguson: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.