Gynecology:

Primary and Secondary Amenorrhea

Lecturer: Abigail Elsie Castro, MD

Transcriber: Patrick Angelo R. Bautista February 2020

References and Legends

• {💻} Powerpoint and {📕} Gynecology Manual
• {📖} Chapter 38, Comprehensive Gynecology 7th Ed.

Table of Contents
I. Amenorrhea 1
II. Delayed Menarche 2
III. Primary Amenorrhea 2
o Breast Absent, Uterus Present 3
o Breast Present, Uterus Absent 4
o Breast Absent, Uterus Absent 5
o Breast Present, Uterus Present 6
IV. Secondary Amenorrhea 6
o CNS and Hypothalamic Causes 6
o Pituitary Causes 7
o Ovarian Causes 7
o Uterine Causes 7
Summary of Diagnostic Tests and Treatment 8

I. AMENORRHEA
• absence of menses during the reproductive years (15-44 yrs old)
o Physiologic: pregnancy, post-partum
o Pathologic: endocrine and anatomic disorders
• Amenorrhea is a symptom and not a pathologic entity and
should not be used as a final diagnosis.
• Although the absence of menses causes no harm to the body, in a
woman who is not pregnant or post-partum, it is abnormal and
thus is a source of concern.
• Primary Amenorrhea
o absence of menses in a woman who has never menstruated
by the age of 16.5 years.
• Secondary Amenorrhea
o absence of menses for an arbitrary time period, usually longer
than 6 to 12 months.

Normal Sequence of Physical and Endocrine Events in Puberty

Event Age Hormone
Breast development (thelarche) 10 – 11 Estradiol
Appearance of pubic and 10.5 – 11.5 Androgens
axillary hair (pubarche)
Maximal growth velocity 11 – 12 Growth hormone
Menarche 11.5 – 13 Estradiol

Primary Amenorrhea
• Leon Speroff
o No period by age 14 in the absence of growth or development Stages of Sexual Differentiation
of secondary sexual characteristics • Genetic Sex, Gonadal Sex, Phenotypic Sex, Sex of Rearing
• Comprehensive Gynecology
o A 14-year-old showing no breast budding already needs Genetic Sex XX XY
Phenotypic Sex (-) Müllerian duct (+) Wolffian duct
further evaluation
due to MIH
• ASRM Practice Committee 2004
Internal Genital Uterus Vas Deferens
o Failure to initiate breast development Organs Fallopian tube Prostate
• When puberty begins, it usually lasts for about 4-5 years ending in Upper 1/3 of Vagina
sexual maturity. External Genital Labia minora Penis
• Mean interval from Thelarche to Menarche = 2.3 yrs (SD of 1 yr) Organs Labia majora Scrotum
• That is why, 14-year-old showing no breast budding already Mons pubis
needs further evaluation. Sex of Rearing Female Male
Genetic Sex: established during fertilization by haploids (XX or XY)
• Gonad is still a totipotential cell (still unknown) → travels to the
TH TH
gonadal ridge at 5 -6 weeks AOG and reach it → absence of the Y
→ develop into an ovary; presence of Y → develop into testes
Phenotypic sex:
• Presence of Y → Anti-Mullerian Hormone/Substance/Factor →
Wolffian Duct → male genitalia
• Absence of Y → (-) Anti-Mullerian Hormone/Substance/Factor →
Mullerian Duct → uterus, cervix, fallopian tube, vagina
Sex of rearing:
• should not be replaced. Even if you found out that a girl turns out to be
an XY, you have to continue on the rearing as a female. Changing this
would have a psychological impact on the person, family, community.

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II. DELAYED MENARCHE HPO Interactions {📖}

• onset of menses in women older than 16.5 years who has no Before Puberty
reproductive abnormalities. • circulating levels of LH and FSH are low with an FSH/LH ratio >1.
• The CNS–hypothalamic axis is extremely sensitive to the negative
Primary Amenorrhea Delayed Menarche feedback effects of low levels of circulating estrogen.
Requires further endocrinologic Requires reassurance only
Before the Onset of Puberty
evaluation
• As the critical weight or body composition is approached, the CNS–
hypothalamic axis becomes less sensitive to the negative effect of
Factors Affecting Onset of Menarche {📖}
estrogen and GnRH is secreted in greater amounts, causing an
Body Fat Composition increase in LH and, to a lesser extent, FSH levels.
• The mean time of onset of menarche was previously thought to occur • Episodic pulses of LH during sleep are still absent.
when a critical body weight of ∼48 kg (106 lb) was reached.
o However, it is now believed that body composition is more During Puberty
important than total body weight in determining the time of • Episodic pulses of LH occurring during sleep
onset of puberty and menstruation. o initial endocrinologic change assoc. with the onset of puberty
o Thus, the ratio of fat to both total body weight and lean body • Activation of Positive Gonadotropin response to ↑ levels of E2
weight is probably the most relevant factor that determines the o the last endocrinologic event of puberty
time of onset of puberty and menstruation. o results in the midcycle gonadotropic surge and ovulation
• Those moderately obese, between 20-30% above the ideal body
weight, have an earlier onset of menarche than non-obese women.
• Malnutrition, such as occurs with anorexia nervosa or starvation, is III. PRIMARY AMENORRHEA
known to delay the onset of puberty.
• Leptin
o adipocyte hormone
o One of the major links between body composition and the
hypothalamic-pituitary-ovarian axis, and thus menstrual cyclicity
o produced by adipocytes and correlates well with body weight.
o important for feedback involving gonadotropin-releasing
hormone (GnRH) and luteinizing hormone (LH) pulsatility
o binds to specific receptor sites on the ovary and endometrium.
• Ghrelin
o a gastric peptide; interacts with leptin in this regard particularly
when menstrual function is perturbed.

Strenuous Exercise
• Well-nourished individuals with prepubertal strenuous exercise
programs resulting in less total body fat have also been shown to
have a delayed onset of puberty.
• It is greater in those athletic activities requiring lower body weight,
and where success is more subjective (ballet, gymnastics) as
compared with swimming.
• Young women with strenuous exercise programs have sufficient
estrogen to produce some breast development and thus do not
need extensive endocrinologic evaluation if concern arises about the
lack of onset of menses.
• For girls engaged in premenarchal athletic training, menarche is
delayed 0.4 year for each year of training.
• Those who exercise strenuously should be counseled that they will
usually have a delayed onset of menses, but it’s not a health problem.
o They should be told that they will most likely have regular
ovulatory cycles when they stop exercising or become older.
• Metabolic Features of Amenorrheic Athletes:
o ↑ serum FSH
o ↑ insulin-like growth factor-binding protein 1 (IGFBP-1)
o ↓ insulin insulin-like growth factor (IGF)

Stress
• Emotional stress can lead to inhibition of the GnRH axis.
• The mechanism involves an ↑ secretion of corticotropin-releasing
Classification of Disorders with Primary Amenorrhea Guide
hormone (CRH), releasing adrenocorticotropic hormone (ACTH),
opioid peptides (β-endorphin, cortisol) Breasts
• CRH itself is known to inhibit GnRH. (-) (+)
(-) 3 2
Uterus
(+) 1 4

I: Failure (gonadal, hypothalamic, pituitary)

II: No uterus = uterovaginal agenesis
III: Enzyme deficiency
IV: Dysfunctional

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1. Classification I: Breast (-), Uterus (+) • Cardiac abnormality

Sample Case #1: 16.5-year-old female, no breast budding, presence
of uterus via pelvic exam, confirmed by ultrasound.
First thing to do: Check the Serum FSH Level
o coarctation of the aorta, mitral valve prolapse, aortic
aneurysm, bicuspid aortic valve
• Renal abnormalities:
o horseshoe kidney, unilateral pelvic kidney
• Diagnosis: usually made before puberty

Mosaicism (X/XX, X/XXX, X/XX/XXX) {📖}

• A wide variety of chromosomal mosaics are associated with primary
amenorrhea and normal female external genitalia.
o X/XX – most common
o X/XXX
o X/XX/XXX
• Clinical Features:
o Generally taller and have fewer anatomic abnormalities than
individuals with a 45 X karyotype.
o Some of them may have a few gonadal follicles and ∼20% have
sufficient estrogen production to menstruate.
o Occasionally, ovulation may occur.

Structurally Abnormal X Chromosome (46XX) {📖}

• 46 XX karyotype but part of one X is structurally abnormal.
• Deletion of the long arm of the X chromosome (Xq)
o normal height has been reported to occur
o In Reindollar’s series, these individuals were all relatively short.
o They have no somatic abnormalities.
• Deletion of the short arm of the X chromosome (Xp)
o The individual will be short.
1.1Gonadal Failure (Hypergonadotropic Hypogonadism) {📖}
o A similar phenotype occurs in those with isochrome of the long
↑ LH, FSH; ↓ Estradiol, Progesterone arm of the X chromosome.
• most common cause of primary amenorrhea • Other X chromosome abnormalities include:
o occurring in almost 50% of those with this symptom. o ring X chromosome
• most frequently caused by a chromosomal disorder or deletion of all o minute fragmentation of the X chromosome
or part of an X chromosome, but it is sometimes caused by another
genetic defect and, rarely, 17α-hydroxylase deficiency. Pure Gonadal Dysgenesis (46 XX / 46 XY with gonadal streaks)
• The chromosomal disorders are usually caused by a random meiotic • As noted, this abnormality may have a familial/genetic
or mitotic abnormality (nondisjunction, anaphase lag) and thus are association and has been reported in siblings.
not inherited. o Abnormalities in genes involved in gonadal development
• However, if gonadal development is absent in the presence of a 46, XX • Clinical Features:
(called pure gonadal dysgenesis), a gene disorder may be present,
o normal stature and phenotype
because it has been reported to occur in siblings.
o absence of secondary sexual characteristics
• Deletion of the entire X chromosome (Turner syndrome) or of the
o primary amenorrhea
short arm (p) of the X chromosome results in short stature.
• Some of these women have a few ovarian follicles, develop
o Deletions of only the long arm (q) usually do not affect height.
breasts, and may even menstruate spontaneously for a few years.

• 46 XY gonadal dysgenesis
• A fibrous tissue band (gonadal streak) is present in place of the ovary.
o result of an abnormal testis in utero.
• When ovarian follicles are absent, synthesis of ovarian steroids and
o There can be incomplete forms with some degree of testicular
inhibin does not occur.
tissue, but in this context the “pure” form as a dysgenetic streak
• Breast development does not occur due to low circulating E2 levels.
as in other forms of ovarian dysgenesis and previously has been
• Because the negative hypothalamic-pituitary action of estrogen and
referred to as Swyer syndrome.
inhibin is not present, gonadotropin levels are markedly elevated,
• If a Y chromosome is present (as in 46 XY gonadal dysgenesis) or is
with FSH levels being higher than LH.
found as part of a mosaic karyotype, with or without any clinical
• Estrogen is not necessary for mü llerian duct development or wolffian
signs of androgenization, gonadectomy should be performed.
duct regression, so the internal and external genitalia are
phenotypically female.
17 ɑ-Hydroxylase Deficiency (with 46 XX karyotype)
Occasionally, mosaicism, abnormal X chromosome, pure • A rare gonadal cause of primary amenorrhea without breast
gonadal dysgenesis (46,XX), or Turner syndrome (45,X) may development and normal female internal genitalia.
have a few follicles that develop under endogenous gonadotropin • Clinical Features:
stimulation early in puberty and may synthesize enough estrogen to o primary amenorrhea without breast development
induce breast development and a few episodes of uterine bleeding, o normal female internal genitalia
resulting early in premature ovarian failure, usually before age 25. o Na retention → hypernatremia, hypertension
Rarely, ovulation and pregnancy can occur. o K excretion → hypokalemia
o ↓ cortisol → ↑ ACTH levels
Turner Syndrome (45X) o ↑ mineralocorticoid – 17α-hydroxylase is not necessary for
• Clinical Features: conversion of progesterone → deoxycortisol / corticosterone
o primary amenorrhea o low set hairline and ears o ↑ serum progesterone levels – progesterone is not
o absent breast development o no 2° sex characteristics converted to cortisol.
o short stature (<60 inches) o wide spaced nipples • In addition to sex steroid replacement, these individuals need
o webbing of the neck o hypothyroidism cortisol administration.
o short 4TH metacarpal o pigmented nevi • They usually have cystic ovaries and viable oocytes.
o cubitus valgus o edema of the feet, hands • Pregnancies have been documented following IVF–embryo transfer
o broad shield-like chest (IVF-ET), despite low levels of endogenous sex steroids.

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1.2Hypogonadotropic Hypogonadism 2. Classification II: Breast (+), Uterus (-)

↓ LH, FSH; ↓ Estradiol, Progesterone
• No need for Karyotyping, all are XX
• Hypothalamic failure will respond to GnRH stimulation
• Pituitary failure will not respond to GnRH stimulation
Sample Case #2: 16.5-year-old female, no menses but with breast
budding. On IE, cannot palpate uterus. On ultrasound, no uterus.
Patient has ovaries evidenced by the development of breasts (which
need estrogen secreted by the ovaries)
Diagnosis: Check first serum testosterone and observe for pubic
and axillary hair

CNS-Hypothalamic Pituitary Disorders {📖}

Differential diagnosis is easily made because:
• the low estrogen levels are caused by an abnormal or absent signal
• Women with congenital absence of the uterus (46 XX karyotype)
to the ovary resulting in very low circulating gonadotropin levels.
o are endocrinologically normal females
• The cause of low gonadotropin production may be morphologic or
• Those with androgen resistance (46 XY karyotype)
endocrinologic.
o are endocrinologically male, with male testosterone levels
CNS Lesions {📖}
2.1 Congenital Absence of Uterus (Uterine Agenesis, Uterovaginal
• Any anatomic lesion of the hypothalamus or pituitary can cause low
Agenesis, Mayer-Rokitansky-Küster-Hauser Syndrome) 46 XX
gonadotropin production.
• These lesions can be: • 2ND most frequent cause of primary amenorrhea
o Congenital (stenosis of aqueduct, absence of sellar floor) o It occurs in 1 in 4000 to 5000 female births and accounts for
o Acquired (tumors) ∼15% of individuals with primary amenorrhea.
• Prolactin-secreting pituitary tumors (prolactinoma) • The Hox genes are important for uterine development.
o most of the CNS lesions • Mutations (e.g. in Hox-A13) have been found in genetic syndromes
o results in hyperprolactinemia (↑ prolactin levels) with uterine abnormalities (hand-foot-genital and Guttmacher
• Non–prolactin-secreting pituitary tumors (chromophobe syndromes) and also in cases of bicornuate uterus.
adenomas) and craniopharyngiomas o To date, however, no abnormalities have been found in cases
o may not be associated with hyperprolactinemia of congenital absence of the uterus.
o rarely cause primary amenorrhea with low gonadotropin levels • Clinical Features
• Thus, all individuals with primary amenorrhea and low gonadotropin o normal ovaries
levels, with or without an elevated prolactin level, should have CT o regular cyclic ovulation, normal endocrine function
scan or MRI to rule out the presence of a lesion. o normal breast and pubic and axillary hair development
o shortened or absent vagina
Inadequate GnRH Release (Hypothalamic Failure) {📖} o normal pubic hair
• Those without a demonstrable lesion and a low gonadotropin level o absence of uterus
were previously thought to have primary pituitary failure § in 7-10%, there are 2 non-fused rudimentary horns.
(hypogonadotropic hypogonadism). § On occasion one or both horns may have some
• However, when they are stimulated with GnRH, there is an ↑ in FSH functioning endometrium.
and LH levels, indicating that the basic defect is either: § obstructed outflow → cyclic pelvic pain (severe at times)
o Hypothalamic with insufficient GnRH synthesis or • Associated anomalies: frequent; mostly isolated defects but can
o CNS neurotransmitter defect also be genetically inherited.
resulting in inadequate GnRH synthesis, release, or both. o Congenital renal abnormalities (∼1/3)
• Kallmann Syndrome: Clinical Features o Skeletal abnormalities in (∼12%)
o anosmia, normal height o Cardiac and other congenital abnormalities
o ↑ in growth of long bones → greater wingspan-to-height ratio o Defects in the bones of the middle ear → deafness
• Women in this category are normal endocrinologically and have
Isolated Gonadotropin Deficiency (Pituitary Failure) {📖} been able to have children using a surrogate / gestational carrier.
• Rarely, individuals with primary amenorrhea and low gonadotropin • Management:
levels do not respond to GnRH, even after 4 days of administration. o Mechanical dilatation of vagina
o This is known as isolated gonadotropin deficiency. o Surgical reconstruction of vagina (McIndoe)
• They almost always have an associated disorder such as thalassemia
major (Fe deposits in the pituitary) or retinitis pigmentosa.
• Occasionally, this pituitary abnormality has been associated with
prepubertal hypothyroidism, kernicterus, mumps encephalitis.

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2.2 Androgen Resistance (Testicular Feminization) 46 XY

• Rare genetically transmitted disorder; incidence of 1/60,000.
• Androgen receptor synthesis or action does not occur.
• It is an X-linked recessive or sex-linked autosomal dominant
disorder, with transmission through the mother.
• Clinical Features:
o normally functioning male gonads that produce normal male
levels of testosterone, dihydrotestosterone
o Because of a lack of receptors in target organs, there is lack
of male differentiation of the external and internal genitalia.
§ external genitalia remain feminine
§ Wolffian duct development, which normally occurs as a
result of testosterone stimulation, fails to take place.
o Müllerian duct regression induced by AMH/MIS
(glycoprotein synthesized by the Sertoli cells of fetal testes),
this process occurs normally because steroid receptors are
unnecessary for the action of glycoproteins.
§ no female or male internal genitalia
§ normal female external genitalia
§ a short or absent vagina
o Absent / scanty pubic and axillary hair
§ as a result of a lack of androgenic receptors
o Breast development is normal or enhanced.
§ testosterone inhibits breast proliferation; the absence of
androgen action allows even low levels of estrogen to
cause unabated breast stimulation.
• Estrogen levels the normal male range; LH is slightly elevated.
• intraabdominal or inguinal testes have an increased risk of
developing a malignancy (gonadoblastoma or dysgerminoma)
o However, these malignancies rarely occur before age 20.
• Management:
o Recommended that the gonads be left in place until after
puberty is completed to allow full breast development and
epiphyseal closure to occur.
o After these events occur, (around age 18) remove gonads.
• Patient Education: patients must be informed of the following
o they have an abnormal sex chromosome, without specifically
mentioning a Y chromosome, because it is widely known that
an XY karyotype indicates maleness.
o However, some families choose to have full disclosure and a
complete understanding of the abnormality.
o because psychologically and phenotypically these individuals
are female and have been raised as such, the term gonads
should be used instead of testes.
o they can’t get pregnant because they do not have a uterus
o their gonads must be removed after age 18 because of their
high potential for malignancy

Summary of Classification II: Breast (+), Uterus (-)

Breast (+), Uterus (-) Androgen resistance (testicular feminization) Congenital absence of uterus (RKH Syndrome)
Karyotype 46 XY 46 XX
Heredity Maternal X-linked recessive; 25% risk of affected Not known
child; 25% risk of carrier
Axillary and Pubic Hair Absent to sparse, scanty Normal female body hair, ovulatory
(+/-) Ovulatory and PMS-like symptoms None Normal ovulatory female; Biphasic basal temp
Hormone levels Endocrinologically normal male Endocrinologically normal female
Other anomalies Rare Frequent
Management • Remove gonads after breast development, • Mechanical dilatation of vagina
epiphyseal closure (usually at 18 y.o.) • Surgical reconstruction of vagina (McIndoe)
• Counselling • No hormonal therapy needed
• ERT • Evaluate for additional renal, skeletal, cardiac,
• Other anomalies rare; no need to evaluate other congenital abnormalities
Pregnancy and Menstruation Will never menstruate Will never menstruate
Cannot have children May have their own genetic children via ART using
a surrogate recipient

3. Classification III: Breast (-), Uterus (-) 3.1 17 ɑ-Hydroxylase Deficiency (with 46 XY karyotype)
• Individuals with no breast or uterine development are rare. • Individuals have testes present but lack the enzyme necessary
• They usually have a: to synthesize sex steroids → female external genitalia
o male karyotype • Why (-) uterus?
o elevated gonadotropin levels o XY → (+) testes → (+) AMH-MIS → Mullerian duct regress →
o testosterone levels in the normal / below-normal female range female internal genitalia regress
o Low testosterone levels → male internal genitalia do not
develop.
• Why (-) breast?
o enzyme deficient → no sex steroids
o Insufficient estrogen synthesized to develop breasts

3.2 17, 20-Desmolase Deficiency {📖}

• A similar lack of sex steroid synthesis occurs in males with a 17,20-
desmolase deficiency.

3.3 Agonadism (Vanishing Testes Syndrome) {📖}

• Individuals with agonadism have no gonads present.
• because the female internal genitalia are also absent, it has been
postulated that testicular AMH-MIS production occurred during fetal
life but the gonadal tissue subsequently regressed.

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4. Classification IV: Breast (+), Uterus (+) c. Stress and Exercise

• Genetically Female – no need to karyotype • ↑strenuous activity → ↓LH FSH → ↑β-endorphins, catechol estrogen
• 2ND largest category • lowered body fats → ↑ catechol estrogens
• Profile similar to Secondary Amenorrhea o Both stress and exercise can increase brain-derived factors that
o thus, should be subcategorized and treated similarly as women can inhibit GnRH release (CRH, opioid peptides)
with secondary amenorrhea. o inhibition of the GnRH axis is characterized by higher levels of
• Just a dysfunction of hypothalamic, pituitary, ovarian, uterine catechol estrogens and opioid peptides (β-endorphin).
cause. Hence, it is reversible. • Catechol estrogen: ↑ dopamine → (-) GnRH → no LH
o catechol estrogen can suppress the release of GnRH, LH
discussion continued under Secondary Amenorrhea • β-endorphins → (-) NE effect on GnRH → (-) GnRH
because their profiles are similar. o β-EP can inhibit LH

IV. SECONDARY AMENORRHEA d. Weight Loss

• Amenorrhea associated with weight loss appears to be due mainly
Sample Case #3: 16.5-year-old female doesn’t have her menarche to failure of normal GnRH release, with the lack of a pituitary
yet or had a menarche then afterwards, it stopped. response under extreme conditions.
• Hypoleptinemia as well as GH and thyroid dysfunction
contribute to these findings.
o Simple weight loss: Hypothalamic dysfunction
o Severe weight loss: Possible additional pituitary disorder
• Anorexia Nervosa
o Severe psychiatric disorder
o uncommon in men and rare in blacks and Asians
o Patients have a hypothalamic disorder interfering with normal
GnRH. Pituitary dysfunction also occurs when the weight loss
becomes severe.
1) Normal T4, abnormally low T3
2) Elevated GH
3) High cortisol
4) Low ACTH and DHEAS
5) LH pattern similar to pre-pubertal girls
• If amenorrhea is present without galactorrhea, hyperprolactinemia,
or hirsutism, the symptom can result from disorders in the CNS- Extreme weight loss due to Hypoleptinemia = anorexia nervosa
hypothalamic-pituitary axis, ovary, or uterus.
• Causes: e. Polycystic Ovary Syndrome (PCOS)
o CNS-Hypothalamic causes (62%) • heterogenous disorder that may present with oligo-/amenorrhea.
o Pituitary causes (16%) • Women need not be overweight or obese, or have symptoms and
o Ovarian causes (12%) signs of hyperandrogenism
o Uterine causes (7%) • most have elevated serum LH but LH level may be also normal and
measurement of LH is not required as a diagnostic criterion.
A. CNS-Hypothalamic Causes • Diagnosis: by visualizing polycystic ovaries on ultrasound,
particularly in the absence of classic findings such as
a. CNS Structural Abnormalities hyperandrogenism.
• The same anatomic lesions in the brain stem or hypothalamus,
discussed as causing primary amenorrhea (by interfering with PCOS: Diagnostic Criteria
GnRH release), can also cause secondary amenorrhea. 1990 NIH: 2003 ESHRE/ASRM:
• Hypothalamic lesions requires both criteria requires 2 of 3 criteria
o craniopharyngiomas, granulomatous disease (tuberculosis, 1. Chronic anovulation (OA) 1. Oligo- and/or anovulation (OA)
sarcoidosis), and sequelae of encephalitis 2. Clinical and/or biochemical signs 2. Clinical and/or biochemical signs
o When such uncommon lesions are present, circulating of hyperandrogenism (HA) of hyperandrogenism (HA)
3. Polycystic
ovaries (PCO)
gonadotropins and E2 levels are low, and withdrawal uterine
bleeding will not occur after progestogen administration. With exclusion of other etiologies (Androgen excess disorders / AED)
Diagnosis of PCOS: Exclusion of Related Disorders
1. Syndromes of severe insulin resistance (Hyperandrogenic-insulin
↓ gonadotropin levels → ↓ FSH, LH → ↓ estradiol levels → amenorrhea
resistant acanthosis nigricans / HAIR-AN syndrome)
2. 21-Hydroxylase deficient non-classic adrenal hyperplasia
b. Drugs 3. Cushing’s syndrome
• Phenothiazines, some antihypertensives, and other drugs can 4. Androgen-secreting neoplasms
also produce amenorrhea without hyperprolactinemia, although 5. High-dose exogenous androgens
6. Hyperprolactinemia
usually the PRL level is elevated.
7. Thyroid dysfunction
o Anyone with 2° amenorrhea should have a detailed medication
history obtained, even if galactorrhea is not present.
• OCPs inhibit ovulation by acting on the hypothalamus to suppress
GnRH and directly on the pituitary to suppress FSH and LH.
• Post-pill amenorrhea
o persistence of hypothalamic-pituitary suppression for several
months after oral contraceptives are discontinued
o This OCP–induced suppression should not last >6 months
o Thus, the reason for amenorrhea persisting >6 months after
discontinuation of OCP is probably unrelated to their use, except
that the regular withdrawal bleeding produced by OCPs masks the
development of this symptom.

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f. Functional Hypothalamic Amenorrhea C. Ovarian Causes (Hypergonadotropic Hypogonadism)

• Women with secondary amenorrhea who: • The ovaries may fail to secrete sufficient estrogen to produce
o do not ingest drugs endometrial growth if the follicles are damaged as a result of:
o do not engage in strenuous exercise o infection
o are not undergoing environmental stress o interference with blood supply
o have not lost weight o depletion of follicles caused by bilateral cystectomies
o have no pituitary, ovarian, or uterine abnormalities • Cystic Degeneration of the Ovaries
• No cyclic alterations in LH pulsatility → no pulses or only 1 pattern o women becoming amenorrheic after a variable period of time has
seen throughout menstrual cycle (persistent luteal pattern) elapsed following medical treatment of a bilateral tubo-ovarian
• Possibly due to: abscess, after bilateral cystectomy for benign ovarian neoplasms,
o CNS neurotransmitter abnormality or sometimes after a hysterectomy during which the vascular
o Increase opioid activity supply to the ovaries is compromised.
• Hypothalamic-pituitary “dysfunction” • Premature Ovarian Failure / Premature Ovarian Insufficiency
o When sufficient GnRH is produced to facilitate gonadotropin o Occasionally, the ovaries cease to produce sufficient estrogen to
stimulation of the ovaries producing E2 levels sufficient to stimulate endometrial growth several years before the age of
proliferate the endometrium (usually about 30 pg/mL) physiologic menopause.
• Hypothalamic-pituitary “failure” o When this condition occurs before the age of 40, the term
o When the E2 levels fall below 40 pg/mL. POF or POI is used instead of premature menopause to best
• Accordingly, the functional or biologic estrogen status of these describe the clinical entity.
patients can be suggested by administering a progestogen. o Causes:
o If endogenous E2 has been sufficient to allow the endometrium to § Ovarian sclerosis
proliferate, then progestogen administration will result in § Gonadal Irradiation
withdrawal bleeding. § Chemotherapy
• This can also be determined by visualizing the endometrial stripe by
§ Autoimmune associations (thyroid disease)
ultrasound scan. If thickness is <4 mm, hypoestrogenism is present.
• The importance of knowing the estrogen status of these patients is
that with the severe hypoestrogenism of hypothalamic “failure,” bone
D. Uterine Causes
loss occurs in these young women at a critical time, when attainment • The likelihood of the diagnosis is strengthened when a sound
of peak bone mass should be occurring (up to age 30). cannot be passed into the uterine cavity.

B. Pituitary Causes (Hypoestrogenic Amenorrhea) a. Intrauterine adhesions or synechiae (Asherman syndrome)

• can obliterate the endometrial cavity and produce 2° amenorrhea.
a. Neoplasms
• Causes:
• Although most pituitary tumors secrete prolactin, some do not and o Post-abortal curettage (30%)
may be associated with the onset of 2° amenorrhea without o D&C in non-pregnant patient
hyperprolactinemia. o Severe endometritis or fibrosis following a myomectomy,
• Chromophobe adenomas – are the most common non–prolactin- metroplasty, or cesarean delivery
secreting pituitary tumors
• Adenomas that may also not secrete prolactin: b. Missed abortion or Endometrial tuberculosis
o Basophilic (ACTH-secreting) adenoma
• Rarely, can also cause endometrial destruction.
o Acidophilic (GH-secreting) adenoma
§ Along with 2° amenorrhea, frequently have other symptoms
produced by these lesions and present to the clinician with
symptoms of acromegaly or Cushing disease.

b. Non-Neoplastic Lesions
• Pituitary cells can become damaged or necrotic as a result of:
o anoxia
o thrombosis
o hemorrhage
• Sheehan Syndrome
o When pituitary cell destruction occurs as a result of a
hypotensive episode during pregnancy.
• Simmonds Disease
o When the disorder is unrelated to pregnancy.
• Evaluation:
o It is important to diagnose this cause of 2° amenorrhea because,
unlike hypothalamic disorders, pituitary damage can be
associated with ↓ secretion of other pituitary hormones, (ACTH
and TSH) in addition to LH and FSH.
o Thus, these women may have 2° hypothyroidism or adrenal
insufficiency that may seriously impair their health, in addition
to their decreased estrogen levels.

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2° Amenorrhea: Diagnostic Evaluation 2° Amenorrhea: Management

• History and Physical Exam Management depends on:
• Ancillary Diagnostic Tools • Diagnosis
o CBC, Urinalysis • Desire for Pregnancy
o TSH assay
o Serum E2, Progesterone Challenge Test, Endometrial imaging Diagnosis Management
(Transvaginal Ultrasound) Non-prolactin secreting tumors Excision of lesion
o Serum FSH, Prolactin Pituitary adenoma Medical therapy
Macroadenoma (>2 cm) who fail to Surgical therapy
E2 above 30-40 pg/mL plus respond to medical therapy or have
PCO on UTZ Diagnosis: PCOS poor compliance with regimen
No PCO on UTZ (+) History of drug ingestion, stress, weight loss, (bromocriptine)
exercise PCOS of HP dysfunction Desires pregnancy:
Diagnosis: HP dysfunction Clomiphene citrate
Self-limiting, not life threatening Does not desire pregnancy:
Cyclic MPA
E2 low plus
HP failure (POF) Desires pregnancy:
Low FSH Diagnosis: CNS lesions / HP failure
Exogenous gonadotropins
If history of drug ingestion, stress, weight loss,
Donor eggs
exercise not present,
CT / MRI is warranted. Does not desire pregnancy:
E-P replacement
High FSH Diagnosis: POF
Antithyroid & Antinuclear bodies
Karyotype

V. SUMMARY OF DIAGNOSTIC TEST/ WORK-UPS AND MANAGEMENT {📕}

CATEGORY DISEASE DIAGNOSTIC TEST MANAGEMENT

I Hypergonadotropic hypogonadism Karyotyping

Breast absent, Uterus present
Serum FSH
II
Breast present, Uterus absent
Serum testosterone +
Observation of pubic / axillary hair
Hypogonadotropic hypogonadism
Congenital absence of uterus
(Mayer-Rokitansky-Küster-Hauser
Syndrome)
Androgen insensitivity / resistance
(Testicular Feminization)
Serum Electrolytes (Na, K)
Serum Progesterone
17-ɑ-OH progesterone, DOC
BP monitoring
Prolactin
CT Scan / MRI
TSH, T3, T4
Normal female testosterone
Normal pubic and axillary hair
Normal male testosterone
Absent pubic and axillary hair
a. 0.625 mg conjugated equine estrogen
(CEE) – for breast proliferation
b. Cortisol replacement + sex steroid
treatment – for 17ɑ-hydroxylase
deficiency
c. If with Y chromosome – excision of the
streak gonads
d. If no Y chromosome – excision of
gonads not necessary
e. If no Y chromosome but with signs of
Hypergonadism – excision of gonads
a. Estrogen-progestogen treatment – to
induce breast development and cause
epiphyseal closure
b. Chances of pregnancy – ovulation can
be induced using human menopausal
gonadotropins, pulsatile GnRH
a. Renal scan
b. Surgical reconstruction of an absent
vagina (McIndoe procedure)
c. Chances of pregnancy: IVF, surrogacy
a. Excision of gonads after 18 yrs old
b. Thereafter, estrogen replacement
therapy should be administered

III 17-ɑ-OH deficiency (46 XY) a.Excision of gonad

Breast absent, Uterus absent
Karyotype (46, XY)
IV
Breast present, Uterus present
TSH, FSH, Prolactin, Serum
Estradiol, Progestin Challenge Test
Agonadism (Vanishing Testes)
17, 20-desmolase deficiency
DIAGNOSTIC TEST
a. Hypothyroidism – elevated TSH
b. Hyperprolactinemia – Prl >100 ng/mL
c. Anovulation-PCOS – (+) withdrawal bleed after PCT;
E2 30-40 pg/mL
d. Hypothalamic amenorrhea – (-) withdrawal bleed
after PCT; low E2; low FSH, (+) lesion on MRI
e. Ovarian Failure – (-) withdrawal bleed after PCT; low
E2; high FSH
b. Hormonal therapy
Referred to an endocrine center for the
extensive evaluation necessary to
establish the diagnosis
MANAGEMENT
Hypothalamic amenorrhea
a. lesions in the hypothalamus – craniopharyngiomas
b. Drugs (phenothiazines, some antihypertensives, OCP
→ postpill amenorrhea)
c. weight loss – gain weight
d. stress, exercise – avoid strenuous activities, gain wt
e. anorexia nervosa – gain weight; refer to psych
f. PCOS – ovulation induction, progesterone, metformin

Hypoestrogenic amenorrhea (pituitary)

a. Chromophobe adenoma – excision
b. Sheehan syndrome – hormone replacement
c. Simmond disease – hormone replacement

Hypogonadotropic amenorrhea (ovarian)

a. Premature Ovarian Failure – hormonal replacement

Endometrial destruction
a. IUAs or synechiae (Asherman) – estrogen therapy
b. Endometrial TB – medical therapy

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