Primary and Secondary Amenorrhea: Clinical Vignettes and Gynecologic Endocrinology

Primary Amenorrhea

The absence of menarche by age $13$ years in the absence of secondary sexual characteristics, or by age $15$ years in the presence of normal secondary sexual development.

Secondary Amenorrhea

The absence of menses for more than $90$ days in a woman with previously regular menstrual cycles.

Tanner Stage II (Female)

The initial stage of female pubertal development characterized by the appearance of a breast bud (thelarche) and sparse, straight or non-curly pubic hair.

Tanner Stage III (Female)

The pubertal stage characterized by enlargement of the breast and areola without separation of their contours, accompanied by dark, curly, and abundant pubic hair over the pubis.

Functional Pubertal Delay

A temporary delay in pubertal maturation and primary amenorrhea frequently seen in adolescent athletes with intense physical training, low body mass index ($\text{BMI} < 18.5\,\text{kg/m}^2$), and low-to-normal gonadotropins without structural hypothalamic-pituitary lesions.

Craniopharyngioma

A suprasellar mass often featuring calcifications that compresses the optic chiasm, clinically presenting with morning headaches, visual field defects, hypogonadotropic hypogonadism, and delayed puberty or primary amenorrhea.

Prolactinoma

A prolactin-secreting pituitary tumor that causes galactorrhea, bitemporal hemianopsia, and amenorrhea, diagnosed definitively by magnetic resonance imaging (MRI) and primarily managed with medical therapy (such as cabergoline).

Hyperprolactinemia-Induced Anovulation

A reproductive disorder wherein excess circulating prolactin inhibits the hypothalamic secretion and release of gonadotropin-releasing hormone ($\text{GnRH}$), resulting in low gonadotropins and chronic anovulation.

Hypercortisolemia-Induced Amenorrhea

Amenorrhea occurring in Cushing syndrome caused primarily by excess cortisol suppressing hypothalamic $\text{GnRH}$ pulsatile release, which consequently decreases $\text{LH}$ and $\text{FSH}$ levels.

Cyclophosphamide

An alkylating antineoplastic chemotherapeutic agent recognized for having high ovarian toxicity and inducing premature ovarian failure.

Imperforate Hymen

An obstructive genital tract abnormality presenting with primary amenorrhea, cyclical pelvic pain, hematocolpos, and hematometra, identified on ultrasound as a thin obstructing structure of several millimeters.

SHBG in Hyperthyroidism

An increase in hepatic synthesis and serum concentrations of sex hormone-binding globulin ($\text{SHBG}$), which contributes to oligomenorrhea and anovulatory infertility.

SHBG in Polycystic Ovary Syndrome (PCOS)

A decrease in hepatic production of sex hormone-binding globulin ($\text{SHBG}$) secondary to hyperinsulinemia, leading to elevated free circulating androgens and resultant hirsutism and acne.

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

Primary ovarian insufficiency occurring in female carriers of a premutation expansion of approximately $80$ CGG repeats in the FMR1 gene, presenting with elevated $\text{FSH}$ and infertility.

21-Hydroxylase Deficiency

The enzymatic defect responsible for approximately $90\%$ of congenital adrenal hyperplasia cases, causing virilization, primary amenorrhea, accelerated growth, premature pubarche, and hirsutism.

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome

Congenital aplasia or agenesis of the Müllerian ducts resulting in absence of the uterus and upper vagina in a phenotypic female with a $46,\text{XX}$ karyotype, functional ovaries, and normal breast and pubic hair development.

Morris Syndrome (Complete Androgen Insensitivity Syndrome)

A condition in phenotypic females with a $46,\text{XY}$ karyotype characterized by normal breast development, sparse or absent pubic and axillary hair, a blind-ending vagina, absent uterus, intra-abdominal testes, and serum testosterone in the male range.

Turner Syndrome

Hypergonadotropic hypogonadism characterized by a $45,\text{X0}$ karyotype, short stature, primary amenorrhea, absent secondary sexual development, streak gonads, webbed neck, cubitus valgus, and a short fourth metacarpal.

Pure 46,XX Gonadal Dysgenesis

A form of hypergonad