AMENORRHEA AND HYPOGONADISM

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AMENORRHEA AND HYPOGONADISM

• Esther I. Krug, M.D.
• Division of Endocrinology
• Sinai Hospital of Baltimore

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Normal menstrual cycle

• Tightly coordinated cycle of stimulatory and
  inhibitory hormonal effects resulting in the
  release of a single mature oocyte from a pool of
  hundreds of thousands of primordial follicles.
• By convention, 1st day of menses represents the
  first day of cycle.
• Follicular phase begins on day 1 and ends on the
  day of LH surge.
• Luteal phase starts on the day of LH surge and
  ends at the onset of next menses.

3

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AMENORRHEA

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Primary Amenorrhea

• Absence of menses
• - at age 16 in the presence of normal growth and
  secondary sexual characteristics.
• - at age 13 if no menses have occurred and there
  is absence of secondary sexual characteristics.

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Etiology of primary amenorrhea

• Chromosomal abnormalities causing gonadal
  dysgenesis - 50
• hypothalamic hypogonadism including functional
  hypothalamic amenorrhea - 20
• Absence of uterus, cervix and/or vagina,
  mullerian agenesis - 15
• Transverse vaginal septum or imperforate hymen -
  5
• Pituitary disease - 5
• Androgen insensitivity, CAH, PCOS - 5

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Gonadal dysgenesis

• Results in primary ovarian failure
• FSH due to absence of oocytes leading to
  reduction of (-) feedback from estradiol and
  inhibins A and B
• - Turners syndrome (45X)
• - Partial deletions (46XX) (could have pubertal
  development)

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Hypothalamic and pituitary disease

• Functional hypothalamic amenorrhea
• - Abnormal GnRH secretion LH, E2
• - Excessive exercise, anorexia, stress
• Congenital GnRH deficiency (rare)
• - idiopathic hypogonadotropic hypogonadism
• - Kallmanns syndrome (if anosmia present)
• Constitutional delay of puberty
• Tumors

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Receptor abnormalities and enzyme deficiences

• Complete androgen insensitivity syndrome
• - X-linked recessive (46XY)
• - resistant to T due to a defect in androgen
  receptor
• - testes present, produce mullerian
  inhibiting factor
• - growth spurt and breast development occur
• - T is in normal male range
• 5-Alpha-reductase deficiency
• - 46XY
• - may appear female or have ambiguous
  genitalia at birth
• - may present with virilization at puberty
  due to T
• - T DHT lack of
  masculinization
• - T-dependent processes (hair, voice, muscle
  mass) intact

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Secondary amenorrhea

• Absence of menses for more than 3 cycles or 6
  months in women who previously had menses
• - Pregnancy
• - Hypothalamic dysfunction 35
• - Pituitary disease 19
• - Ovarian disease 40
• - Uterine disease 5

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Amenorrhea
Primary
Secondary
HCG
()
(-)
Progesterone
Pregnancy/Chorio-carcinoma
Bleeding
Prolactin
Normal
FSH, LH
Increased
Normal/Low
Increased
Eval. Hyper-prolactinemia
PCOS
Hypothalamic amenorrhea Hypothyroidism
Ovarian failure
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Major Causes Of Secondary Amenorrhea
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Major Causes Of Secondary Amenorrhea(cont.)
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(-)
Secondary amenorrhea
Obtain ht, wt, PRL, FSH, T, TSH
()
Pregnancy
Beta-HCG
High T
Abnormal BMI
PRL
FSH
History of DC
R/o TSH, drugs, renal failure
Ovarian failure
Evaluate for Asherman syndrome
Obese
Too thin
MRI pituitary
Consider hypothalamic causes
HRT
Tx with dopamine agonist
Evaluate for hyperandrogenism
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Case 1

• 25 y.o. woman presents with amenorrhea of 7
  months duration
• She otherwise feels well, with no other health
  complaints
• What else do you need to ask?

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• Menarche age 12, regular menses in the past
• She is sexually active
• Not interested in pregnancy at this time
• Uses barrier contraception inconsistently
• Recent OTC urine pregnancy test was (-)
• No history of recent weight gain or loss
• Exercise - gym 30 min 3 times per week
• No history of depression or use of
  antidepressants
• Occasional yellowish watery nipple discharge
• Physical exam
• Normal visual fields
• Expressible nipple discharge RgtL
• What is your next step?

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• Serum HCG (-)
• Provera, 10 mg po qd for 7 days withdrawal
  bleeding
• Prolactin 220 ng/dL
• MRI of pituitary 5 mm microadenoma
• What is your diagnosis?
• How would you manage this case?

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• Dopamine agonists
• -Bromocriptine
• -Cabergoline
• Effectively suppress prolactin levels
• Allow for tumor shrinkage (30)
• Restore ovulation!!
• OCPs
• -Protect endometrium
• -Restore adequate estrogen levels
• -Prevent bone loss
• -Prevent pregnancy
• -Do not cause tumor shrinkage

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Case 2

• 24 yo woman presents with amenorrhea of 7 months
  duration
• She otherwise feels well, with no other health
  complaints
• What else do you need to ask?

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• Menarche age 12, irregular periods,
  occasionally skipping 2-3 months
• Weight gain of 40 lb over the last 3 years
• Some facial hair she waxes her face twice a
  month
• Sexually active, seldom uses birth control
• G0P0, not interested in pregnancy
• Minimal physical activity
• Family history of DM type 2 in mother
• Physical exam
• BMI 33 kg/m2, BP 130/80 mm Hg
• () acanthosis nigricans
• () hirsutism () moderately severe acne vulgaris
• () abdominal obesity
• What is your next step?

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• Serum HCG (-)
• Provera, 10 mg po qd for 7 days withdrawal
  bleeding
• Prolactin 25 ng/dL (nl lt 20ng/dL)
• LH 12 mIU/mL FSH 4 mIU/mL
• What is your differential diagnosis?

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Differential diagnosis

• Polycystic ovarian syndrome
• Non-classical congenital adrenal hyperplasia
• Androgen-secreting tumors (ovary, adrenal)
• Hyperprolactinemia
• Hypothyroidism
• Cushings syndrome
• Drugs (e.g. valproic acid)
• What tests would you order?

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Laboratory evaluation

• Serum total testosterone, SHBG
• DHEA-Sulfate
• Early follicular phase a.m. 17(OH)-progesterone
• ACTH-stimulation test if 17(OH)P ? 250mcg/dl
• Prolactin is elevated in up to 35 of patients
• 2-h OGTT
• Lipid panel
• 11 pm salivary cortisol
• Overnight 1 mg Dexamethasone suppression test
• LH/FSH ratio
• Pelvic U/S

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• Case 2 cont
• Total testosterone -74 ng/mL (nllt75)
• SHBG - 13 pg/mL
• 17(OH)Progesterone 150 ng/mL
• OGTT BG 95 240 180 mg/dL (0, 60, 120min)
• Cortisol (8 a.m.) 1 ng/dl after 1 mg Decadron
  at 11 p.m.
• T. Chol 205mg/dl, Trig 230 mg/dl, HDL 35 mg
  dl
• LDL 152 mg/dl
• What is your diagnosis? How would you manage this
  case?

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Complications of PCOS

• Infertility
• Spontaneous abortion
• Endometrial hyperplasia carcinoma
• Dysmetabolic Syndrome
• - Diabetes Mellitus/ impaired glucose
  tolerance - Dyslipidemia
• - Hypertension
• - Cardiovascular disease
• Depression/ social isolation

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Insulin

• Insulin resistance is a consistent finding in
  PCOS present both in obese and non-obese women.
• Prevalence of impaired glucose tolerance and type
  2 DM is gt 30 in women of reproductive age, which
  is 7 times higher than in population based
  studies of women aged 22 to 44 years.

Legro RS, et al, 1999
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Cardiovascular Consequences of PCOS

• Increased risk for CAD at a younger age
• -Risk of MI increased 7 times
• Hypertension is 3 times more likely
• Dyslipidemia is commonly present
• - increased VLDL, LDL, Triglycerides, low
  HDL
• Risk of diabetes is increased 7-fold

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Clinical Evaluation

• Clinical History
• Peripubertal onset, gradual worsening of symptoms
• Irregular menstrual bleeding with no premenstrual
  symptoms
• Gradual appearance of hirsutism
• Onset of obesity frequently correlates with
  menarche
• Occasionally infertility is a presenting feature

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Hyperandrogenism

• Hyperandrogenism is defined as presence of
  clinical signs of androgen excess even in the
  absence of elevated serum androgen levels.
• Signs of hyperandrogenism can be subtle.
• Hirsutism is present in up to 80 of patients.
• Acne or hair loss may be presenting complaints.
• Virilizing signs are very rare.

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PCOS Treatment

• Goals of treatment
• Ameliorate Symptoms
• hirsutism
• acne
• infertility
• Prevent Complications
• diabetes
• CVD
• Endometrial hyperplasia/carcinoma
• Goals depend on age, desire for pregnancy, etc.
  and may change at different stages of life.

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Treatment of PCOS

• Lifestyle changes, weight loss
• Endometrial protection OCPs
• Hirsutism/ acne OCP, anti-androgens
  (spironolactone)
• Insulin resistance/ IGT Metformin
• Ovulation induction Metformin, Clomiphene

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Case 3

• 20 yo woman presents with amenorrhea of 7 months
  duration
• She otherwise feels well, with no other health
  complaints
• What else do you need to ask?

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• Normal pubertal development
• Meharche age 12
• Intensive life-style modifications over last 15
  months
• Lost 25 lb
• Maintains strict low-fat diet
• Exercises 4 h weekly
• PE
• BMI -18 kg/m2
• Otherwise - wnl

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Labs

• Beta-HCG (-)
• LH 2 IU/mL
• FSH 4.1 IU/mL
• E2 28 ng/dl
• TSH 1.3 mIU/mL Free T4 1.1 ng/dL
• PRL 5.8
• DXA spine Z-score -2.3

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Functional Hypothalamic amenorrhea

• Characterized by central hypogonadism due to
  abnormal GnRH secretion
• Associated with weight below target level and
  exercise, severe restriction of fat consumption
• Female athlete triad - amenorrhea, disordered
  eating and osteopenia
• Low leptin level may be present

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Consequences of hypothalamic amenorrhea

• Infetility (reversible)
• Vaginal dryness, breast atrophy
• Osteopenia
• Repeated stress fractures
• May cause adverse CV consequences
• Low BMI may be linked to higher mortality
  according to NHANES data

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Treatment

• Increased caloric intake to match energy
  expenditure
• Reduced exercise
• HRT may be indicated
• Bisphosphonates should not be used

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Case 4

• 51 y.o. generally healthy woman
• C/o amenorrhea of 7 months duration
• Has been having profuse night sweats
  necessitating changing her night gown twice every
  night
• Episodes of extreme warmth with profuse
  diaphoresis up to 10 times daily
• Frequent mood swings, crying spells
• What is the diagnosis?
• What other questions you need to ask?

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Menopause

• Natural Menopause - permanent cessation of
  menstruation resulting from the loss of ovarian
  follicular activity.
• Median age - 51.4 years is influenced by
• Familial factors
• Current smoking (1.5 years earlier menopause)
• Multiparity (later menopause)
• Increased BMI (later menopause)
• Nulliparity (earlier menopause)
• Medically treated depression (earlier menopause)
• Toxic chemical exposure (earlier menopause)
• Higher cognitive scores in childhood (later
  menopause)

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• Perimenopause - the period immediately prior to
  menopause and the first year after menopause.
  Median age - 47.5 years.
• Symptoms
• 90 of women experience 4-8 years of menstrual
  cycle changes before menopause.
• Menorrhagia occurs in 10 of healthy women.
• Hot flashes are experienced by 75 of women.
• Only in 10-15 of women hot flashes are severe.
• Sleep disturbances
• Vulvovaginal changes
• Psychological disturbances

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• Case 3, cont
• The patient has intact uterus
• Had normal mammogram 2 months ago
• Normal Ob/Gyn exam 3 months ago
• No family history of breast cancer
• No personal or family history of thrombo-embolic
  disease
• No family history of premature CAD
• Patients mother broke her hip at the age of 80
  years
• Physical exam is unremarkable
• What would you do next?

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Case 3, cont

• You suggest to initiate HRT
• The patient is very concerned regarding health
  risks of HRT
• Does her potential risk exceed the benefit of
  HRT?

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Menopause and HRTImportant facts from HERS and
WHI

• Effects on CAD
• WHI 29 increased risk (37v30annually/10,000)
• HERS increased risk in first year of Tx
• Effects on the risk of CVA
• WHI 41 increased risk (29 v 21
  annually/10,000)
• HERS nonsignificantly increased risk
• Risk of venous thromboembolism
• WHI 111 increased risk (34 v 16
  annually/10,000)
• HERS 108 increased risk

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• Risk of breast cancer
• WHI 26 increase (NS)
• HERS 27 increase (NS)
• Risk of colon cancer
• WHI 48 decreased risk (S)
• HERS 19 decreased risk (NS)
• Risk of osteoporotic fractures
• WHI 34 decrease (hip), 34 decrease (spine)
• HERS 61 increased risk hip (NS), 13
  decreased risk spine (NS)

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Estrogen-only arm of WHI

• Enrolled 10,739 women aged 50-79 who had
  undergone hysterectomy
• Conjugated equine estrogens or placebo
• - Increased risk of CVA
• - Decreased risk of osteoporotic fractures
• - No effect on breast or colon Ca risk
• - No effect on CAD

46
Current recommendations

• Treatment of menopausal symptoms is primary
  indication for HRT
• Progesterone should be used in women with intact
  uterus
• ERT should not be used for prevention of CAD
• Data should not be extrapolated to symptomatic
  women experiencing early or premature menopause
• Treatment should be limited to shortest duration
  consistent with treatment goals (HOPE trial
  demonstrated preservation of bone and equivalent
  symptom relief at lower doses without endometrial
  hyperplasia)
• Short-term HRT is defined as 3 to 5 years
• It is not possible to generalize WHI/HERS data to
  other estrogens/progestogens

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Case 4

• 35 y.o woman presents with c/o
• LE swelling
• Breast pain
• Severe bloating

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• Symptoms usually occur 1 week before her menses.
• Relief usully occurs within 1-2 days of onset of
  menses.
• She denies social difficulties, but states that
  the symptoms make her crazy.
• She denies marital discord, although she states
  that she feels bad for her husband
• Admits difficulties in job performance during the
  last week of each cycle

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• There is no ETOH/ drug abuse
• PMH unremarkable
• Her PE is overall wnl

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PMS criteria

• Presence of at least 1 of the following somatic
  and affective symptoms during the 5 days prior to
  menses in 3 consecutive cycles
• Affective
  Somatic
• Depression Breast
  tenderness
• Angry outbursts Abdominal
  bloating
• Irritability
  Headache
• Social withdrawal/ fatigue Swollen
  extremities
• Relief within 4 days of onset of menses
• Identifiable social/ economic dysfunction

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PMS

• Prevalence 4.6-14
• No cultural/ ethnic differences in prevalence
• Postulated to represent abnormal interaction of
  cyclic ovarian hormonal changes and central
  neurotransmitters.
• Serotonin, opioid, GABA systems are implicated.

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Treatment of PMS

• SSRIs
• Fluoxetine, 20 mg qd
• Response rate 60-75
• Side effects headache, anxiety, nausea (combined
  incidence 15)
• Cyclic therapy has been shown to be effective
• (starting on day 14 of each cycle)

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• GnRH agonists
• Women without premenstrual depression showed a
  benefit with leuprolide on all PMS rating scales
• GnRH agonists and add-back therapy
• Effcacy confirmed by meta-analysis
• Oral contraceptives - conflicting results
• Exercise, relaxation, reflexology - appear
  effective
• Aldactone - found effective in one double-blind
  placebo-controlled, crossover study

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• Agnus castus fruit extract (chasteberry extract)
  - in one placebo-controlled trial improved breast
  fullness, anger, irritability, headache.
• Vit. B6, E, D, Ca and Mg may have some efficacy

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Case 5

• 52 y.o. previously healthy man
• C/o decreased erections, low libido, fatigue
• Initially attributed symptoms to stress
• No improvement after 6 months of lifestyle
  changes
• No history of smoking, DM, HTN, or CAD
• Takes no medications
• What would you do next?

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Case 4, cont

• Normally virilized
• BMI 24 kg/m2
• BP 120/80 mm Hg
• Testes somewhat soft, volume 25 cm3
• What would you do next?

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Case 4, cont

• LH 3.2 mIU/mL
• FSH 2.1 mIU/mL
• T. Testosterone 170 ng/dL (nl gt 240 ng/dL)

58

Fatigue, poor libido, decreased erections

Testicular size
Normal
Small
LH, FSH, Testosterone
LH FSH Testosterone
LH FSH Testosterone
Central hypogonadism
Primary testicular failure
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Male hypogonadism

• Primary (low T, high FSH/LH)
• Chromosomal (Kleinfelter syndrome, XX male
  gonadal dysgenesis)
• Orchitis (mumps, HIV)
• Criptorchidism
• Toxins (ETOH, opiates, heavy metals)
• Drugs (cytotoxic drugs, etc)

60
Male hypogonadism

• Secondary (low T, low LH/FSH)
• Idiopathic GnRH deficiency
• Kallmann syndrome
• Prader-Willi syndrome
• Trauma, surgical, postirradiation
• Tumor (adenoma, craniopharyngioma)
• Vascular (pituitary infarction, carotid aneurysm)
• Infiltrative (hemochromatosis, sarcoidosis)
• Systemic illness,malnutrition
• Drugs (drug-induced hyperprolactinemia, sex
  steroids

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Andropause

• Decline in various physiological parameters with
  aging that is associated with decline in
  testosterone levels.

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Features of andropause

• Decline in
• Muscle mass
• Muscle strength
• Bone mass
• Libido and sexual performance
• Quality of life
• Cognition
• Mood

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Andropause

• BOTH CENTRAL (Hypothalamic-pituitary) and
• PERIPHERAL dysfunction

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Incidence of fractures by age and sex
65
Testosterone replacement

• Improvement in bone density
• Increase in lean body mass
• Improvement in mood and cognition
• Improvement in libido
• No improvement in erectile function

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Contraindications to testosterone replacement

• Prostate Ca
• Hematocrit gt 55
• Severe BPH
• CHF
• Severe sleep apnea

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Testosterone formulations

• T. enanthate (200 mg q 2 weeks)
• T. cypionate (200 mg q 2 weeks)
• Testoderm TTS 5/10 mg (non-scrotal)
• Androgel 5/10 g (non-scrotal)
• Testim (non-scrotal)
• Striant (buccal tablet q 12 h)

68
Treatment monitoring

• Assess efficacy and side effects in 3, 6, and 12
  months
• PSA and digital rectal exam baseline, 3,6,12
  months
• If PSA gt 4 ng/ml or increased 1.5 ng/ml/yr
  refer to Urology
• Hct - baseline, 3,6,12 months

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Thank You!