Payal Patel, M.D.Pediatric Endocrinology Fellow

February 27, 2014

16-year-old female with amenorrhea

Chief Complaintó 16 6/12yo F presents for evaluation of primary amenorrhea

HPIó

ó

ó

ó

2 months earlier: mentioned this lack of menstruation to the anesthesiologist during wisdom teeth extractionEvaluation was recommendedLabs done by her PCP showed “normal level of hormones”

She was then referred to endocrine

HPIó

ó

ó

Normal breast development which began in 5th or 6th gradeNo pelvic cramps, back pain, or lower abdominal painNormal linear growth, weight gain, and development

ROSó

ó

ó

óóóóóó

Constitutional: Negative for appetite change, fever, or unexpected weight changeEndo: Negative for temp intolerance or polyuria

HEENT: +Myopic, wears glasses.

CVS: Negative for palpitations or chest painGI: Negative for n/v/c/d or abdominal painGU: Negative for urgency, frequency and enuresisSkin: Mild acne. Neuro: Psych: Negative for mood changes or sleep problems

+AmenorrheaNegative for vision

changes

Negative for other skin lesions Negative for headaches or weakness

Further Historyó

ó

ó

ó

PMH: Primary amenorrheaPSH: Right knee arthroscopy at 15 yrsFH: Mother, sister, maternal aunt, maternal grandmother had menarche at ~13 yrs

SH: Lives with parents and younger brother. Older sister is in college. She is in the 11th grade and enjoys playing volleyball.

Physical Examó

ó

ó

ó

ó

ó

ó

ó

ó

Vitals: T 35.6 °C, HR 81, BP 122/82, RR 16, Wt 67.7 kg (86th%ile), Ht 164.2 cm (59th%ile), BMI 25.1 (86th%ile)

General: Well-developed, no distress

HEENT: clear oropharynx, PERRL, EOMINeck: No thyromegaly

CV/Pulm/Chest: RRR, CTAB,

GI: S/ND/NT.

GU:

Neuro: alert, no focal deficits, 2+DTRs

Skin: Warm.

Tanner 5 breasts, +axillary hair

No masses in inguinal region

nL external F genitalia with nL vaginal introitus, no clitoromegaly, Tanner 5 pubic hair

No hirsutism, acanthosis nigricans, or acne

Differential Diagnosis?

DDxó

ó

ó

ó

ó

ó

ó

ó

PregnancyImperforate hymenUterine agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome)Complete androgen insensitivity syndromePCOS

Non-classic CAHPrimary ovarian insufficiencyHyperprolactinemia

Labs/Imagingó

ó

ó

ó

ó

ó

ó

ó

ó

ó

FSH 7.2LH 4.2Estradiol 20 (30-400 pg/mL)Free testost. 6 (3-9 pg/mL)Total testost. 24 (15-60 ng/dL)

AMH 4.0 (0.9-9.5 ng/mL)

Karyotype 46,XXUrine preg. Negative

Bone age: c/w agePelvic U/S: Uterus not identified. Both ovaries visualized.

Clinical Questionsó

ó

How often is Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) associated with ovarian dysgenesis?What is the relationship between anti-Mullerian hormone (AMH) levels and fertility?

MRKHó

ó

ó

ó

ó

AKA Congenital Absence of the Uterus and Vagina (CAUV)Incidence = 1:4500 femalesMajority of cases appears to be sporadic

Autosomal dominant inheritance has been reported

Congenital aplasia of the uterus and upper part of the vagina due to incomplete development of the Mullerian duct

MRKHó

ó

ó

ó

ó

ó

ó

Normal development of secondary sexual characteristics46, XX karyotype1st clinical sign is usually primary amenorrheaSubdivided:

Type I (isolated) or Rokitansky sequence Type II MURCS (Mullerian duct aplasia, Renal dysplasia and Cervico-thoracic Somite anomalies)

MRKH & Ovarian Dysgenesis

Oppelt P, et al 2006.. Hum Reprod

AMH & Folliculogenesisó

ó

ó

ó

AMH is secreted by growing folliclesActs in the ovary by 2 major mechanisms

1: Inhibits initial recruitment of primary follicles2: Inhibits the sensitivity of antral follicles to FSH

Grynnerup AGA, et al. 2012. AOGS

Riggs RM, et al. 2012.

“poor responders”< 4 oocytes retreived

(n = 11)

“excessive responders”>15 oocytes retreived

(n = 38)

AJOG

AMH Levels & Fertility

Seifer DB, et al. 2011.Fertil Steril

Follow-upó

ó

ó

ó

ó

ó

ó

ó

ó

Patient seen by ob/gyn 1 month laterRepeat labs:

No immediate concerns noted. Low concern for hypoestrogenism at this time. Plan:

Repeat labs and pelvic U/S in 4 months

FSH 6.7LH 3.4Estradiol 28 (30-400 pg/mL)

DEXA- spine BMD appropriate for age

Summaryó

ó

ó

ó

ó

MRKH presents as 1o amenorrhea in a phenotypically nL female with 46,XX karyotype and nL 2o sexual characteristicsMRKH may be associated with ovarian and/or Fallopian tube malformations in up to 10% of patients

Research has shown a stronger correlation between AMH levels and # of retrieved oocytes than age, FSH, inhibin B, LH, or estradiol Therefore, AMH may potentially be used as an accurate assessment of ovarian reserve and prediction of oocyte retrieval rates

sensitivity (83-84%) and specificity (67-79%)

Referencesó

ó

ó

ó

ó

Morcel K, Camborieux L, Programme de Recherches sur les Aplasies Mulleriennes (PRAM) and Guerrier D. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome

2007;2:13.

Grynnerup AGA, Lindhard A, and Sorensen S. The role of anti-Mullerian hormone in female fertility and infertility – an overview. 2012;91:1252-60.

Oppelt P, Renner SP, Kellermann A, Brucker S, Hauser Ludwig KS, Strissel PL, Strick R, Wallwiener D, and Beckmann MW. Clinical aspects of Mayer–Rokitansky–Kuester–Hauser syndrome: recommendations for clinical diagnosis and staging.

2006;21(3):792–79.

Riggs RM, Hakan DE, Baker MW, Kimble TD, Hobeika E, Yin L, et al. Assessment of ovarian reserve with anti-Mullerian hormone: a comparison of the predictive value of anti-Mullerian hormone, follicle-stimulating hormone, inhibin B, and age.

2008;199-202.

Seifer DB, Baker VL, and Leader B. Age-specific serum anti-Mullerian hormone values for 17,120 women presenting to fertility centers within the United States. 2011;95(2):747-50.

¨

¨

´

. Orphanet J Rare Dis.

Acta Obstet Gynecol Scand

. Hum Reprod

Am J Obstet Gynecol

Fertil Steril