Delayed : what does it look like? what to do?

Melina Dendrinos, MD Michigan Medicine Primary Care for Women Conference 12/5/19 Disclosures

• No significant financial interests or other relationships with industry relative to topics that will be discussed. Objectives

• After this lecture the learner will be able to 1. Review normal pubertal development 2. Recognize delayed menarche and create a differential diagnosis. 3. Describe a plan for initial evaluation of delayed menarche.

Puberty

• Complex sequence of biological events resulting in • Maturation of secondary characteristics • development () • Pubic and axillary hair development () • Accelerated linear growth • Attainment of reproductive capacity

Emans and Laufer, 2012 Onset of

• Mechanism of initiation of puberty is poorly understood • Inhibitory, stimulatory, and nutrition-dependent factors act on • Gradual changes in amplitude and frequency of GnRH pulses from the hypothalamus. • Timing of initiation is dependent on • • Health and nutrition

Emans and Laufer, 2012 Changes in GnRH pulsatility

• Prepubertal

• Early pubertal

• Late pubertal

Oxford Textbook of Endocrinology and Diabetes, 2011 Hypothalamic-pituitary-ovarian axis

• GnRH causes secretion of • Ovarian stimulation • Maturation of germinal • Synthesis of • LH acts on theca cells • Produce precursors • FSH acts on granulosa cells • Produce aromatase to convert precursors to

Emans and Laufer, 2012 Effects of

• Growth spurt • Increase in and redistribution of fat • Breast • Growth of ducts • Fat accumulation • Proliferation and keratinization of vaginal mucosa • Proliferation of endometrium Tanner staging - breast

• 1: elevation of papilla only • 2: elevation of breast and papilla, increased areolar diameter • 3: further enlargement of breast and • 4: further enlargement with projection of areola and papilla to form secondary mound • 5: projection of papilla only Bone Growth

• Low levels of estrogen stimulate bone growth • Increased GH, IGF-1 • Peak height velocity • ~6 months before menarche • ~11.5yo • Higher levels of estrogen • Decreased GH, IGF-1 • Closure of epiphyseal plates • Growth typically stops at bone age 15 Adrenarche

• Pubic hair, body odor, axillary hair, and acne • Usually lags by 6 months • Results from secretion of adrenal • Some contribution from Tanner staging – pubic hair

• 1: no pubic hair • 2: sparse growth along labia • 3: Darker, coarser hair spreads over junction of pubes • 4: Hair spreads over mons pubis • 5: spreads to medial surfaces of thighs, inverse triangle distribution Menarche

• The major landmark of puberty • Usually 12-13yo • 2-3 yr after thelarche • Usually at Tanner stage IV breast development, rarely before Tanner stage III • Coincides with deceleration of bone growth

• By age 15, 98% of have had menarche

Emans and Laufer 2012

Tanner and Marshall

• Cross-sectional study of British girls in 1969 The timing and tempo of puberty

• The first signs of puberty are between 8 and 13yo • 98.8% of girls • Breast development first • Pubic hair next • Lags 6mo • 11-12yo • Menarche follows • 12.8yo

• Determinants • Race • Lower age in Latina, black teens • Genetics • Overall health • Social environment • Body weight • and

Emans and Laufer 2012 Normal in Young Females

• Menarche (median age):12.43

• Mean cycle interval: 32.2 days (21-45 days)

• Length: 7 days or less • Flow: 3-6 pads or tampons per day • 80 cc per cycle

• Initial cycles are anovulatory • Menarche to regular cycles: 14 months • Menarche to ovulatory cycles: 24 months When to work up primary ?

Chumlea W C et al. Pediatrics 2003;111:110-113 Primary Amenorrhea

• Absence of menses at age 15 regardless of secondary sex characteristics

• Evaluation should be also considered when menstrual cycles have not occurred • 3 years after thelarche • 13yo and no breast development • 14yo and hirsutism • 14yo with history or exam suggestive of excessive exercise or disordered eating

ACOG Committee Opinion, 2015 Primary Amenorrhea - differential

• depends on • Hypothalamus • • Ovarian response • Open Outflow tract Primary Amenorrhea - differential

• Hypothalamus • Chronic disease • Stress, psychiatric illness • Competitive athletics, eating disorders • Kallmann syndrome • Drugs • Tumor, Irradiation Primary Amenorrhea - differential

• Menstruation is dependent on • Hypothalamus • Pituitary Gland • Idiopathic hypopituitarism • Tumor • Hemochromatosis • Infarction • Irradiation, Surgery • Hypo/hyperthyroidism Primary Amenorrhea - differential

• Menstruation is dependent on • Hypothalamus- • Pituitary Gland- • Ovarian Response- • Ovarian insufficiency • Gonadal dysgenesis • Turner’s syndrome • Autoimmune Oophoritis • idiopathic • PCOS • Tumor • Irradiation Primary Amenorrhea - differential

• Menstruation is dependent on • Hypothalamus • Pituitary Gland • Ovarian Response • Outflow tract • Not present • Agenesis of uterus/ cervix/ vagina • Blocked • Hymen-Imperforate • Vaginal septum Primary Amenorrhea - History

• CNS • Anosmia, headaches, nausea, visual changes, head trauma, irradiation • Secondary sex characteristics • Breast development, pubic hair, growth spurt • Obstructive symptoms • Cyclic pain • or • Stress, diet, or exercise changes • Family history • Medications Primary amenorrhea - Evaluation

• Physical Exam • Height & weight on growth curves • Tanner stage • External genital exam for outflow tract • Skin for hirsutism, acne, striae • Turner stigmata

• Labs • Urine hcg • FSH, LH, and E2 • TSH • • • [Additional labs per exam findings]

• Pelvic ultrasound

27 Primary amenorrhea evaluation

FSH low FSH high x2 FSH Normal High prolactin

PCOS AN / stress / tumor Ovarian failure Prolactinoma Anatomic issue [MRI brain] [chromosomes] [MRI brain] (Outflow obstruction, Uterine agenesis) Primary amenorrhea: +Breast / +Uterus

Low/Normal FSH High FSH • Outflow tract disorder • Premature Ovarian Insufficiency • Central hypothalamic process • Turner variant or XY (get karyotype) • Stress, chronic disease, exercise, eating disorders • Iatrogenic • Fragile X permutation • Endocrine disorder • Autoimmune: adrenal antibodies, • PCOS, high prolactin, thyroid thyroid antibodies and TFTs dysfunction, CAH Primary amenorrhea: +Breast / -Uterus

Get chromosomes: Get chromosomes: • 46 XX • 46 XY • Mullerian Agenesis • Androgen Insensitivity • MRKH Syndrome • Testosterone level () • 5 alpha reductase deficiency • Virilize at puberty • Testosterone level (male) Primary amenorrhea: -Breast / +Uterus

Low FSH High FSH • Congenital GnRH deficiency • 46 XY Gonadal dysgenesis • Central hypothalamic process • 46 XX POI • Stress, chronic disease, exercise, • 45 X Turner eating disorders • Prolactinoma or other infiltrative process • Constitutional delay Primary amenorrhea: -Breast /-Uterus

• Very rare • Agonadism • 17,20 desmolase deficiency • 17 alpha hydroxylase deficiency Primary amenorrhea - Conclusions

• Diagnosis dependent on pubertal status

• Look at the 4 compartments • Hypothalamus • Pituitary • Ovaries • Outflow tract

• Narrow down differential • FSH • Presence of and/or uterus

33 Questions?

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