The impact of exercise, energy deficiency and stress on the adolescent menstrual function: what s a clinician to do? The Alvin Goldfarb Lectureship

Size: px

Start display at page:

Download "The impact of exercise, energy deficiency and stress on the adolescent menstrual function: what s a clinician to do? The Alvin Goldfarb Lectureship"

Isabel Jennings
6 years ago
Views:

The impact of exercise, energy deficiency and stress on the adolescent menstrual function: what s a clinician to do? The Alvin Goldfarb Lectureship Debra K.

1 The impact of exercise, energy deficiency and stress on the adolescent menstrual function: what s a clinician to do? The Alvin Goldfarb Lectureship Debra K. Katzman, MD, FRCPC Professor of Pediatrics, Division of Adolescent Medicine, Department of Pediatrics The Hospital for Sick Children and University of Toronto Senior Associate Scientist, Research Institute Director, Health Science Research Undergraduate Medical Education, University of Toronto School of Medicine Disclosure Research Funding National Institute of Health Canadian Institute of Health Research Thrasher Foundation Catalyst Grant SickKids Canadian Pediatric Surveillance Program Other LWW 1

2 Objectives At the completion of this presentation, participants should be able to: 1. Define functional hypothalamic amenorrhea (FHA) 2. Outline the alterations in hormones and other factors that occur in FHA 3. Describe the medical and psychiatric consequences of FHA 4. Summarize the evidence-based treatment strategies for adolescent females with FHA Case Presentation A 15-year-old female presents for evaluation of secondary amenorrhea Menarche - 12 years Started running for exercise and sport at age 14 years Soon after, menstrual periods became lighter and less frequent LNMP 6 months ago Weight loss 2.3 kg (5 lbs.) over the past 3 months Runs 10 km (6 mi) per day, 5 x per week BMI = 19 kg/m 2 Pain on palpation along the fourth metatarsals 2

information is the LEAST important for you to explore? a.

3 Case Presentation What s a clinician to do? Case Presentation Which of the following pieces of historical information is the LEAST important for you to explore? a. Dietary and exercise history b. Eating attitudes and behaviors c. Psychosocial stressors d. Family history 3

4 Case Presentation Which group of lab tests would be MOST helpful in determining the patient s diagnosis? a. Estradiol, LH, FSH, toxicology screen b. Estradiol, LH, FSH, pregnancy test c. Estradiol, pregnancy test, toxicology screen d. LH, FSH, pregnancy test Case Presentation Based on the information provided, what would be the MOST likely diagnosis? a. PCOS b. CNS tumor c. Late-onset congenital adrenal hyperplasia d. Functional Hypothalamic Amenorrhea 4

5 What is Functional Hypothalamic Amenorrhea? Menstruation is a Vital Sign (Number 651, ACOG, 2015) Identification of abnormal menstrual patterns in adolescence may improve early identification of potential health concerns Primary Amenorrhea Lack of spontaneous menses in females with normal secondary sexual development by age 15 years (Neinstein, 2016) Secondary amenorrhea After previous uterine bleeding, no subsequent menses for 6 months or a length of time equal to three previous cycles (Neinstein, 2016) 5

6 Functional Hypothalamic Amenorrhea Functional hypothalamic amenorrhea (FHA) occurs when the hypothalamic-pituitary-ovarian axis is suppressed due to an energy deficit stemming from Stress/psychological distress Weight loss, disordered eating, eating disorders Excessive exercise Characteristics of FHA can occur during or after puberty, resulting in primary or secondary amenorrhea classified as hypogonadotropic hypogonadism characterized by a low estrogen state without other organic or structural disease is a reversible form of GnRH deficiency 6

7 Functional Hypothalamic Amenorrhea Abnormal pulsatile secretion of GnRH Undetectable to variation in amplitude or frequency Dysregulation of FSH and LH levels Decreased ovarian production of estrogen Epidemiology ~3 % of FHA cases are primary amenorrhea (ASRM, 2006) FHA is one of the most common causes of secondary amenorrhea. FHA is responsible for 20 35% of secondary amenorrhea cases (ASRM, 2006) The incidence is higher in athletic women approximately 50% of women who exercise regularly experience subtle menstrual disorders and approximately 30% of women have amenorrhea (DeSouza, 2009) 7

8 Hormonal Disturbances Associated with FHA Types of FHA STRESS Functional Hypothalamic Amenorrhea f WEIGHT LOSS DISORDERED EATING EATING DISORDER EXCESSIVE EXERCISE 8

9 Hormonal disturbances associated with FHA The KEY pathologic trait in FHA is impairment of GnRH and gonadotropin secretion There are other physiological changes that occur Abnormal pulsatile secretion of GnRH Undetectable to variation in amplitude or frequency Dysregulation of FSH and LH levels Decreased ovarian production of estrogen Functional Hypothalamic Amenorrhea 9

Hormonal disturbance associated with FHA Physical or mental stress activates and increases corticotropin-releasing hormone (CRH) secretion in the CNS CRH modulates the hypothalamus pituitary adrenal

10 Hormonal disturbance associated with FHA Physical or mental stress activates and increases corticotropin-releasing hormone (CRH) secretion in the CNS CRH modulates the hypothalamus pituitary adrenal axis & hypothalamus pituitary ovary axis CRH stimulates secretion of ACTH from the pituitary and cortisol from the adrenal glands Increased secretion of glucocorticosteroids inhibits the release of GnRH and gonadotropins. Functional Hypothalamic Amenorrhea 10

11 Hormonal disturbances associated with FHA FHA reflects a state of estrogen deficiency Impairment in GnRH and gonadotropin pulsatile secretion results in profound hypoestrogenism Functional Hypothalamic Amenorrhea 11

low-to-normal level of thyrotropin, an increased level of reverse triiodothyronine

12 Functional Hypothalamic Amenorrhea Hormonal disturbances associated with FHA Disturbances in the hypothalamic pituitary thyroid axis. low-to-normal level of thyrotropin, an increased level of reverse triiodothyronine and a low level of triiodothyronine Represents a euthyroid sick pattern seen in chronic illness and starvation 12

13 Functional Hypothalamic Amenorrhea Functional Hypothalamic Amenorrhea 13

14 Neuroendocrine alternation in FHA The precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play an important role in the physiological regulation of GnRH pulsatile secretion Evidence suggests that these substances may be involved in the pathophysiology of FHA Particular attention should be paid to such substances as kisspeptin, neuropeptide Y (NPY), ghrelin, leptin, corticotropin-releasing hormone (CRH), b-endorphin and allopregnanolone. Neuroendocrine alternation in FHA: Ghrelin Ghrelin is a peptide that stimulates appetite Women with FHA are characterized by elevated ghrelin levels l compared with healthy women Exercising or underweight amenorrheic patients are characterized by a significantly greater serum ghrelin elevation than those who remain with stable weight Ghrelin inhibits the hypothalamic pituitary gonadal axis and is responsible for the prolongation of amenorrhea in subjects who have regained normal weight 14

15 Neuroendocrine alternation in FHA: Leptin Leptin is an adipose tissue-derived hormone Serum leptin levels represent energy availability Low energy availability = low serum leptin Leptin plays a crucial role in the link between metabolic and hormonal signals and their impact on the reproductive axis Patients suffering from hypothalamic amenorrhea are characterized by considerably lower serum leptin concentrations compared with age-, weight- and body fatmatched eumenorrheic controls (Tataranni et al 1997; Kopp et al 1997) History Menstrual history Vital sign Menarche, cycle frequency, duration of menses, LNMP, timing of amenorrhea Exercise history Weight loss behaviors/body image/abnormal eating attitudes and behaviors Medications OCP, continuous COC, DMPA, antipsychotics, GnRH agonists (luporn) PMH Chronic illness Cranial irradiation Prolactin Galactorrhea, H/A, visual field defect Thyroid Estrogen-deficiency Hot flashes, libido vaginal dryness Sexual history Family history Genetic Mood/Stress 15

16 Physical exam Growth curves Weight loss, weight fluctuations, delay in growth spurt and pubertal onset Lack of smell or anosmia Lanugo hair, Russell s sign, parotid swelling, dental enamel erosion Sexual Maturity Rating Clitoromegaly Hirsutism, acne, voice changes, male baldness Constitutional Growth Delay 16

17 3/30/

Estradiol CBC and blood chemistry MRI Data in support of the

18 Laboratory Assessment Consider Pregnancy test β-hcg Pelvic U/S Thyrotropin and free thyroxine Prolactin FSH LH Estradiol CBC and blood chemistry MRI Data in support of the cost effectiveness of the specific screening assessments are lacking! 18

Data in support of the cost effectiveness of the specific screening

levels of FSH Low or low-to-normal levels of LH Low estradiol CBC and blood

19 Laboratory Assessment Consider Pregnancy test β-hcg Pelvic U/S Thyrotropin and free thyroxine Prolactin FSH LH Estradiol CBC and blood chemistry MRI Data in support of the cost effectiveness of the specific screening assessments are lacking Laboratory Assessment Consider Pregnancy test β-hcg Pelvic U/S Thyrotropin and free thyroxine Prolactin Low or low-to-normal levels of FSH Low or low-to-normal levels of LH Low estradiol CBC and blood chemistry MRI 19

20 An Approach to Diagnosis of Primary Amenorrhea and FHA An Approach to Diagnosis of Secondary Amenorrhea and FHA 20

21 Differential Diagnosis If the diagnosis is FHA then Key diagnostic tool is a GnRH stimulation test FHA shows a positive response of the gonadotropins to exogenous GnRH. This test easily distinguishes hypothalamic dysfunction from pituitary diseases, where hypogonadism is also characteristic Medical and Psychiatric Consequences of FHA 21

22 Important consequences on women s future health FHA should not be understood only as amenorrhea This is a much more challenging clinical picture Hypoestrogenemia has a negative influence on different aspects of female health Bone health Reproductive health Cardiovascular health Mental health Important consequences on women s future health FHA should not be understood only as amenorrhea This is a much more challenging clinical picture Hypoestrogenemia has a negative influence on different aspects of female health Bone health Reproductive health Cardiovascular health Mental health 22

23 Bone Health Adolescence is a critical time for bone mass accrual in bone mass per yr. Age Theintz, 1992 Bone Health Peak bone mass ne mineral content Bon Age 23

24 Bone Health Main hormones that exert a positive influence on PBM GH IGF-I Cortisol Sex Steroids Positive impact on PBM Bone Health Potential factors in FHA that impact PBM Low GH Low IGF-I High cortisol Low Sex Steroids Low Calcium Low Vitamin D Undernutrition Low body weight Excessive Exercise Decrease Formation and Resorprtion 24

25 Bone Health Women with FHA have reduced BMD and bone mineral content Low BMD in adolescents and young women with FHA may impose life-long increased fracture risk Female athletes and adolescent with AN (with amenorrhea) are at increased for low BMD and stress fractures and skeletal fragility Important consequences on women s future health FHA should not be understood only as amenorrhea This is a much more challenging clinical picture Hypoestrogenemia has a negative influence on different aspects of female health Bone health Reproductive health Cardiovascular health Mental health 25

26 Reproductive Health FHA has both short- and long-term consequences for reproductive health Impairment of pulsatile GnRH secretion causes the impairment of pulsatile LH and FSH secretion. The final consequence is profound hypoestrogenism which determines anovulation - unable to become spontaneously pregnant Abnormal pulsatile secretion of GnRH Undetectable to variation in amplitude or frequency Dysregulation of FSH and LH levels Decreased ovarian production of estrogen Reproductive Health Evidence suggests that proper diagnosis and treatment of FHA are important due to the potential risk of infertility secondary to chronic amenorrhea (Hind, 2008) Teenagers with hypothalamic dysfunction and menstrual disturbances, do not necessarily have a bad prognosis in terms of menses or fertility (Devoto and Aravena, 2002 ) Adults with untreated FHA can develop atrophic changes in the urogenital mucosa and in the muscles of the uterus. 26

27 Reproductive Health Those with FHA who get pregnant increased risk of obstetric complications such as impaired weight gain and compromised intrauterine fetal growth (Becker, 1999) increased risk of miscarriage and preterm labor Important consequences on women s future health FHA should not be understood only as amenorrhea This is a much more challenging clinical picture Hypoestrogenemia has a negative influence on different aspects of female health Bone health Reproductive health Cardiovascular health Mental health 27

28 Cardiovascular Cardiovascular disease (CVD) is the leading cause of death in women in developed countries 1 in 4 female deaths (Kochanek KD, 2011; CDC, 2014) Proportionally more women die from CVD than men. Impaired cardiovascular function in FHA is linked to Hypoestrogenism (main cause) Negative energy balance Metabolic disturbances Cardiovascular: Hypoestrogenism Hypoestrogenism can lead to (Ouyang, Michos, Kara, 2006) endothelial dysfunction an impaired i bioactivity it of nitric i oxide perturbation in autonomic function activation of the rennin angiotensin system Lipid profile changes higher serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride concentrations vs. healthy individuals (Rickenlund, 2005; Friday, 1993) Premenopausal women with FHA increased risk of diabetes mellitus (WISE Study, 2008) 28

29 Important consequences on women s future health FHA should not be understood only as amenorrhea This is a much more challenging clinical picture Hypoestrogenemia has a negative influence on different aspects of female health Bone health Reproductive health Cardiovascular health Mental health Mental Health Mood in women is linked to serum sex steroid levels, particularly estrogen (McEwen, 2012) Hypoestrogenism in young women with FHA is strongly related to changes in serotonin, dopamine and allopregnanolone fluctuations These changes can modulate mood in amenorrheic women (Kormos, 2013) 29

30 Mental Health Women with FHA compared with eumenorrheic women have more dysfunctional attitudes greater difficulty in coping with daily stresses endorse greater interpersonal dependence (Gilles and Berga, 1993) Hypercortisolemia in patients with FHA patients Serum cortisol levels positively correlate with the Hamilton Rating Scale for Depression and Anxiety (Lawson, 2009) FHA patients present a particular susceptibility to restrictive disordered eating depressive traits psychosomatic disorders (Bomba, 2007) Evidence-based Treatment Strategies for Adolescents Females with FHA 30

31 Targeting Treatment for FHA STRESS Functional Hypothalamic Amenorrhea f WEIGHT LOSS DISORDERED EATING EATING DISORDER EXCESSIVE EXERCISE Targeting Treatment for FHA STRESS Functional Hypothalamic Amenorrhea f WEIGHT LOSS DISORDERED EATING EATING DISORDER EXCESSIVE EXERCISE 31

Targeting Treatment for FHA Reduction in Stress Functional Hypothalamic Amenorrhea f Nutritional rehabilitation Reduce Exercise Treatment of FHA Nutritional rehabilitation

32 Targeting Treatment for FHA Reduction in Stress Functional Hypothalamic Amenorrhea f Nutritional rehabilitation Reduce Exercise Treatment of FHA Nutritional rehabilitation Dietary regimens and reduction in exercise levels Reductions in stress Challenge Practical challenges arise convincing patients with FHA to change long-standing behaviors 32

33 Treatment of FHA: Nutritional Rehabilitation and Weight Nutritional rehabilitation Is there a critical weight? Perhaps a threshold level of body fat needed for menses Adrenal and ovarian androgens are converted to estradiol through aromatases activity within fat (Frisch et al, 1980) Adolescent girls with eating disorders Resumption of menses at 92% EBW (Golden, 1997) Uterine size and ovarian size and morphology Resumption of menses at 100% EBW (Treasure et al, 1988) Pelvic U/S (Mason et al, 2007) Adolescents with FHA have smaller uteri and ovaries compared to girls menstruating regularly (Bumbulien, et al 2015) Has been shown to assist in evaluating healthy weights/rom Non-invasive, well-tolerated, no radiation, good visualization of pelvic organs Uterus Tear drop to pear No endometrium to >3 mm endometrium Ovaries Prepubertal to pubertal - few small follicles to dominant follicle < 2 cm to 9 cm in length 33

Recovery of Uterus body< body body body adult cervix

to >3 mm endometrium Acknowledgement: Helen Mason,

George s University of London, London, UK Recovery of

5 2-4 2-9 4-9cm WEIGHT GAIN Prepubertal to pubertal - <1.

34 Recovery of Uterus body< body body body adult cervix longer width widens >1cm Tear drop to pear No endometrium to >3 mm endometrium Acknowledgement: Helen Mason, Biomedical Sciences, St. George s University of London, London, UK Recovery of Ovaries MULTIFOLLICULAR OVARY <1cm cm WEIGHT GAIN Prepubertal to pubertal - <1.0 cm to 4 to 9 cm in length. Acknowledgement: Helen Mason, Biomedical Sciences, St. George s University of London, London, UK 34

35 CASE: Susan Lask & Bryant-Waugh, Eating Disorders in Childhood and Adolescence, 2007 CASE: Susan Lask & Bryant-Waugh, Eating Disorders in Childhood and Adolescence,

36 CASE: Susan Lask & Bryant-Waugh, Eating Disorders in Childhood and Adolescence, 2007 CASE: Susan Lask & Bryant-Waugh, Eating Disorders in Childhood and Adolescence,

37 Treatment of FHA: Bone Loss Bone loss Weight gain and menses resumption Optimal strategy t for improving i bone accrual in AN Residual deficits persist (Misra, 2008; Bachrach 1991; Katzman 1991) What else can be done? Are there other regimens? Therapeutic Strategies with Oral EPs (Sim, 2011) Studies Comparing EP on BMD in AN Author (year) Study Design Description of Patients with AN Interventions Type of Control Assessment and Location of Bone Mass Duration of Follow- Up (Mos.) Golden (2002) Cohort 50 adolescent and young adult (13-21 years) µg No medication Lumbar spine, femoral neck DXA 12 Gordon (2002) RCT 61 (14-28 years) 20 µg EE/0.1mg levonorgestrel DHEA Lumbar spine, femoral neck and total body DXA 12 Grinspoon (2002) RCT 61 (14-28 years) 35µg EE/0.4mg norethindrone Placebo Lumbar spine, femoral neck, radius, and total body DXA 9 Klibanski (1995) RCT 48 ( years) mg Premarin/5 mg Provera No medication Spinal CT 18 Munoz-Calvo (2007) Cohort 20 (mean age 17.3 years) 35µg EE 12 No medication Lumbar spine DXA Strokosch (2006) RCT 146 adolescents (11-17 years) 35 µg EE Placebo Lumbar spine, femoral neck DXA 13 37

38 Treatment of FHA Oral estrogen First pass effect through liver Decreases IGF-1(bone trophic) levels by suppressing mrna of IGF-1 in liver Suppression of systemic IGF-1 in post-menopausal women (Weissberger, 1991) Transdermal estrogen Avoids the hepatic first-pass effect and does not have an impact on IGF-1 levels Provides constant serum levels similar to ovarian estradiol secretion Used in Turner syndrome and resulted increases in BMD (Naha, 2009) Have not been studied in AN Results Intent to treat repeated measures analysis Spine and hip BMD Z-scores increased significantly in girls with AN who received estrogen versus placebo (p<0.05) For the group as a whole Similar results in a post hoc analysis of mature girls alone (n=96) IGF-I levels did not change 38

39 % Change in Lumbar BMD p<0.05 p<0.05 p=.004 p<0.05 p=.004 p=.004 N= % Change in Hip BMD % Chan nge in Hip BMD AN E- AN E+ C p<0.05 p<0.05 p<0.05 P=0.047 N= m 0-12 m 0-18 m 39

40 Impact of adding Physiologic Estrogen 6 BMD at baseline 5 4 BMD at baseline Controls AN Impact of adding Physiologic Estrogen Add Physiologic og Estrogen BMD at baseline Controls AN 40

41 Impact of adding Physiologic Estrogen Catch-up growth Add Physiologic i Estrogen 3 BMD at baseline Controls AN Summary Physiologic estrogen replacement is an effective strategy to increase bone accrual in adolescents in FHA i.e. AN Bone accrual rates do need exceed that found in controls accrual is about the same No catch-up in BMD Physiologic estrogen found to be a potentially important treatment 41

42 Treatment: Bone loss Weight restoration 1300 mg of elemental calcium 400 to 1000 IU Vitamin D Treatment of FHA: Diet and exercise Dietary regimen and reduction in exercise levels in FHA are lacking Some uncontrolled studies suggest that t reduction in exercise + increases in diet help restore menstrual cycle Studies with increases fat in diet suggest restoration of higher ROM 42

43 Treatment of FHA: Psychosocial Approaches Strategies to alleviate stress may lead to ROM RCT(Berga, 2003; Michopoulos, 2013) 20-week RCT with CBT vs observation in 16 normal weight FHA ROM in 6 with CBT vs 1 observational group Uncontrolled study (Tschuggue, 2003) Hypnotherapy was followed by ROM in 9/12 women with FHA Treatment of FHA: Leptin Reference Study design Treatment Duration Participants Results Chou et al, RTC mg/kg; 36 weeks N= 20 7/10 tx mg/kg if no yrs. menstruated; no menses after 12 changes in BMI weeks Welt et al, 2004 Sienkiewicz et al, 2011 Prospective, Open label 0.08 mg/kg; 0.2 mg/kg, if no menses after 2 months 3 months N= 14 (8 pts and 6 C) yrs. Open label 0.08 mg/kg 18 months N= yrs. 3/8 had ovulatory cycle; 2/8 preovulatory follicular development and bleeding No menses, but increases in leptin and decreases cortisol 43

44 Key Recommendations for Practice Clinical recommendation Evidence rating References Practice Committee of American Society for Reproductive Medicine,(2008); Fertil Steril; Speroff L, Fritz MA, 2005; Nelson LM,2000. Gordon CM, 2010; Master- Hunter T, Heiman DL, Gordon CM, 2010; Nattiv A, Loucks AB, Manore MM, et al. 2007; Falsetti L, Gambera A, Barbetti L, et al Pregnancy should be excluded in all patients presenting with amenorrhea. In patients with FHA (especially with the female athlete triad), the primary treatment is weight restoration through nutritional rehabilitation and decreased exercise. C C Frisch et al, 1980; Golden et al, 1997; Weight threshold/percentage of body fat B SORT evidence rating system: A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. Key Recommendations for Practice Clinical recommendation Evidence rating References Modification in diet and exercise Psychosocial approaches, CBT C C Kopp-Woodroffe et al 1999; Laughlin GA et al Berga eta l 2003; Tschugguel et al 2003; According to the International Society for Clinical Densitometry, amenorrhea related to hypoestrogenism lasting 6 months is the indication to perform a densitometry (DEXA) of the spinal column C Gordon et al 2008; Bishop et al SORT evidence rating system: A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. 44

45 Case Presentation A 15-year-old female presents for evaluation of secondary amenorrhea Menarche age 12 years Started running for exercise and sport at age 14 years Soon after, menstrual periods became lighter and less frequent LNMP 6 months ago Weight loss 2.3 kg (5 lbs.) over the past 3 months Runs 10 km (6 mi) per day, 5 x per week BMI = 19 kg/m 2 Pain on palpation along the fourth metatarsals Case Presentation What s a clinician to do? 45

46 What s a clinician to do? History Detailed dietary and exercise histories Low energy intake Excessive exercising Runs 10 km (6 mi) per day, 5 x per week Eating attitudes and behaviors, body image - normal Psychological stressors - School What s a clinician to do? Physical examination Weight loss 2.3 kg (5 lbs.) over the past 3 months On history still till losing weight Weight loss consistent with low dietary energy intake with respect to high energy output (running) 46

47 What s a clinician to do? Laboratory assessment Urine pregnancy test negative Low serum estradiol Low levels of LH and FSH Plain films of foot Case Presentation 47

48 Case Presentation Impression No cause for amenorrhea except Excessive Exercise Low energy intake/weight loss Case Presentation What s a clinician to do? 48

$Case Presentation Multifaceted therapeutic approach Discussion re: excessive exercise and low energy intake with weight loss Stress fracture cessation of exercise Expected body weight required her to$

49 Case Presentation Multifaceted therapeutic approach Discussion re: excessive exercise and low energy intake with weight loss Stress fracture cessation of exercise Expected body weight required her to be at a weight that was 4 kg higher than current weight Increase caloric intake Consultation with other health professionals as needed Risks of FHA DEXA and low BMD Innovative treatments (i.e., leptin) may pose as an alternative strategy in the future? 49

Hypothalamic Amenorrhea: To Treat or Not to Treat with Estrogen Replacement. Hypothalamic amenorrhea NASPAG ACRM 2015

Hypothalamic Amenorrhea: To Treat or Not to Treat with Estrogen Replacement Meredith Loveless, MD Gina Sucato, MD MPH NASPAG ACRM 2015 Hypothalamic amenorrhea Functional hypothalamic amenorrhea Absence