National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2015 Annual Report of the Division of Intramural Research

Investigation of Adrenal Gland Disorders and Disorders of Female Reproduction

Lynnette Nieman
  • Lynnette Nieman, MD, Head, Section on Reproductive Endocrinology
  • Susmeeta T. Sharma, MD, Clinical Fellow
  • Raven McGlotten, RN, Research Nurse

Over the past decade, we have made important contributions to the differential diagnosis of hypercortisolism. We established the corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPS) as major diagnostic tools for the identification of pituitary adenomas causing Cushing’s syndrome. However, the detection of Cushing’s syndrome remains difficult, as does the localization of ectopic ACTH–producing tumors. We also evaluate endometrial function and the pathophysiology and potential new treatments for fibroids in women. The reproductive disorder is common, poorly understood, and lacks optimal medical treatments. In addition, we study the effect of gonadal steroids on mood disorders, particularly those surrounding parturition and menopause.

Adrenal gland disorders

Identification of a pituitary corticotropinoma is essential for the cure of Cushing's disease. Inferior petrosal sinus sampling (IPSS) is considered the gold-standard test to distinguish Cushing's disease (CD) from ectopic ACTH syndrome (EAS). Anomalous venous drainage, abnormal venous anatomy, and lack of expertise can lead to false-negative IPSS results and thereby misclassification of patients with ACTH–dependent Cushing's syndrome. We participated in the development of guidelines for the treatment of Cushing's syndrome. The guidelines recommend surgical resection of the causative lesion. If that is not possible, secondary treatment options must be individualized to each person's unique characteristics.

We also examined the utility of measuring aldosterone during the Cortrosyn(™) stimulation test to distinguish primary from secondary adrenal insufficiency. A Cortrosyn(™)-stimulated aldosterone level of 5 ng/dl (0.14 nmol/l) had 88% sensitivity and positive predictive value and 89.7% specificity and negative predictive value for distinguishing primary adrenal insufficiency (PAI) from secondary adrenal insufficiency (SAI). Spot urine sodium levels showed a strong correlation with peak aldosterone levels (r = -0.55, P = 0.02, n = 18) in the SAI but not PAI or HV groups. Posture did not have a significant effect on results. Thus, measurement of aldosterone during this test can help identify the cause of adrenal insufficiency, but the influence of sodium intake must be taken into consideration.

Disorders of female reproduction

Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that 'withdrawal' from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD). We evaluated initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October, 2003, and July, 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30), matched for age, body mass index, and reproductive status, who served as controls. After three weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for three additional weeks under double-blind conditions. We obtained Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels at weekly clinic visits. None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean [SD] scores increasing significantly from estradiol (i.e., 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo. In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy.

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test the hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (i.e., symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (i.e., irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. The data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

Additional Funding

  • Some of these projects received external funding from two cooperative research and development agreements (CRADAs) executed with HRA-Pharma, Paris France, under ongoing CRADAs.

Publications

  1. Martinez PE, Rubinow DR, Nieman LK, Koziol DE, Morrow AL, Schiller CE, Cintron D, Thompson KD, Khine KK, Schmidt PJ. 5a-Reductase inhibition prevents the luteal phase increase in plasma allopregnanolone levels and mitigates symptoms in women with premenstrual dysphoric disorder. Neuropsychopharmacol 2016; 41(4):1093-102.
  2. Schmidt PJ, Ben Dor R, Martinez PE, Guerrieri GM, Harsh VL, Thompson K, Koziol DE, Nieman LK, Rubinow DR. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015; 72:714-726.
  3. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100:2807-2831.
  4. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet 2015; 386:913-927.
  5. Abraham SB, Abel BS, Sinaii N, Saverino E, Wade M, Nieman LK. Primary vs secondary adrenal insufficiency: ACTH-stimulated aldosterone diagnostic cut-off values by tandem mass spectrometry. Clin Endocrinol (Oxf) 2015; 83:308-314.

Collaborators

  • Smita Abraham, MD, FDA, Silver Spring, MD
  • Diana Blithe, PhD, Contraception Discovery and Development Branch, NICHD, Bethesda, MD
  • Prashant Chittiboina, MD, Surgical Neurology Branch, NINDS, Bethesda, MD
  • Alicia Christy, MD, Contraceptive Discovery and Development Branch, NICHD, Bethesda, MD
  • Richard Chang, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
  • Clara Chen, MD, Nuclear Medicine Department, NIH Clinical Center, Bethesda, MD
  • Ahmed Gharib, MD, Office of the Scientific Director, NHLBI, Bethesda, MD
  • Edward H. Oldfield, MD, University of Virginia, Charlottesville, VA
  • Nicholas Patronas, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
  • James C. Reynolds, MD, Nuclear Medicine Department, NIH Clinical Center, Bethesda, MD
  • Ninet Sinaii, MPH, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD
  • Bob Wesley, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD

Contact

For more information, email niemanl@mail.nih.gov or visit http://irp.nih.gov/pi/lynnette-nieman.

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