Ninety-five percent of ovarian cancers arise from the epithelial portion and only 5% are germ-cell tumors. As opposed to this, 90% of testicular cancers arise from germ cells.
The reason germ-cell tumors are less common in females is because a female germ-cell system only produces one egg per month (approximately 300-400 in a female’s life), whereas a male germ-cell system produces about 525 billion sperm cells over a lifetime. Less active cell multiplication means smaller chance of abnormal cell division.
20.1 Normal Menstrual Cycle
Day 1 of menstrual cycle is the first day of menses.
There are two phases, each lasting approximately 14 days in a 28-day cycle:
Follicle-stimulating hormone (FSH) stimulates the growth of ovarian follicles and secretion of estrogen by follicles.
A luteinizing hormone (LH) and FSH surge leads to release of a mature ovum from the ovarian follicle (ovulation), ending the follicular phase.
After ovulation, the remains of the follicle develop into the corpus luteum that produces estrogen and progesterone, which prepare uterine lining for implantation.
1 Anovulatory cycles result in unopposed estrogen secretion, as there is no formation of corpus luteum that secretes progesterone.
If fertilization does not occur, the corpus luteum withers away, and with decreasing progesterone, menstruation results (end of the cycle).
If fertilization occurs, the embryo starts making β-hCG, which signals the corpus luteum to continue producing progesterone and estrogen (which maintain the uterine lining).
20.2 Menstrual Pathologies
20.3 Abnormal Uterine Bleeding
In reproductive age patients, the first step is to rule out pregnancy.
Control bleeding and treat anemia if present and look for bleeding disorders (e.g., von Willebrand disease).
Oral contraceptive pills (OCPs) with estrogen and progesterone are first-choice agents. (In ovulatory dysfunction, it is important to decrease the risk of endometrial hyperplasia and cancer, by counteracting the effect of unopposed estrogen.)
2 Other choices include oral or injectable progesterone and levonorgestrel containing hormonal IUD. These also decrease risk of endometrial hyperplasia and cancer.
If patient does not want hormonal treatment:
Management of acute severe bleeding
Address hemodynamics first—IV fluid resuscitation and transfusion as needed. Treat underlying blood disorder if present (e.g., give von Willebrand factor concentrate for von Willebrand disease).
For hemodynamically unstable patient, NSIM is intrauterine tamponade (balloon or gauze packing), then uterine curettage. For persistent bleeding, start IV estrogen. Emergency hysterectomy might be needed in refractory cases.
For hemodynamically stable patient, NSIM is high-dose oral estrogen.
20.3.1 Secondary Amenorrhea
Criteria: No menses for > 3 months in a previously regular menstrual cycle, or > 6 months in previously irregular menstrual cycle.
MCC is pregnancy, so first do β-hCG testing. If pregnancy is ruled out, look at the following algorithm for workup.
3 The following algorithm can also be used for workup of hypo/oligomenorrhea with some minor changes.
aIf there is evidence of hyperandrogenism (e.g., hirsutism, acne), also check serum testosterone level. Think of polycystic ovary syndrome (PCOS).
bBoth hypo- and hyperthyroidism can cause amenorrhea. In hypothyroidism, thyrotropin-releasing hormone stimulates both thyroid-stimulating hormone (TSH)
and prolactin secretion. Prolactin inhibits gonadotropin-releasing hormone (GnRH; low FSH and LH).
cThis results in hypergonadotropic hypogonadism. Look for symptoms of hot-flashes and/or atrophic vaginitis.
dCauses of hypogonadotropic hypogonadism are:
• Excessive exercise or weight loss
• If there is no obvious etiology, NSIDx is MRI to look for pituitary disorders. Sheehan’s syndrome (postpartum pituitary necrosis) is a potential cause, if there is a history of pregnancy-related hemorrhage.
eThe idea behind progestin challenge is that a woman with sufficient estrogen level will have withdrawal bleeding after a dose of progesterone, indicating that amenorrhea is likely due to progesterone deficiency, e.g., chronic anovulation in conditions such as PCOS.
Hypergonadotropic hypogonadism (menopause or premature ovarian failure) a | |||
Normal or slightly highb | |||
aPremature ovarian failure can be due to chemotherapy/radiation, autoimmune conditions, Turner’s syndrome, etc. | |||
bPCOS patients are typically obese and have a higher testosterone level. Peripheral conversion of testosterone into estrogen in the adipose tissues maintains the estrogen level. | |||
20.4 Polycystic Ovary Syndrome (PCOS)
Background: Exact etiology is unknown. Main problem is abnormal steroidogenesis in ovaries with increased androgen production. It is the MCC of infertility in women.
:
Hyperandrogenism (hirsutism, acne, androgenic alopecia).
Irregular menstrual cycle, amenorrhea, and anovulation.
Due to issues with follicular development and regression, there are multiple immature follicles in ovaries. These look like cysts in ultrasound (polycystic-looking ovaries).
Insulin resistance, acanthosis nigricans, weight gain, obesity, and type 2 diabetes. Diagnostic evaluation:
Pelvic US will show ovaries that look like they have multiple cysts in them.
PCOS is a diagnosis of exclusion: rule out conditions that present similarly to PCOS (i.e., other causes of late-onset virilization and hyperandrogenism). Check 17-OH progesterone level, TSH, prolactin, IGF-1, cortisol, and testosterone levels.
6 Remember, not all women with US findings of multicystic ovaries have PCOS. Other causes of hyperandrogenism can also lead to similar picture in ultrasound.
Nonclassic congenital adrenal hyperplasia, due to mild 21-hydroxylase deficiency with some 21-hydroxylase activity present | ||
Ovarian hyperthecosis (idiopathic hyperplastic increase of luteinized thecal cells that overproduce androgen)a |
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Cushing’s syndrome (they may have hirsutism and oligo/amenorrhea) | ||
aThis is thought to be due to genetic mutation. Similar in pathophysiology, luteoma (which can occur with normal pregnancy) and hyperreactio luteinalis (associated with abnormally high β-hCG, which occurs with multiple gestation, molar pregnancy, ovulation induction, etc.) can result in transient hyperandrogenism. | ||
bNormal DHEA with elevated testosterone suggests extra-adrenal sources (typically ovaries). Elevated DHEA suggests adrenal virilizing tumors. | ||
Abbreviations: DHEA, dehydroepiandrosterone; LH, luteinizing hormone. | ||
First step is weight loss (this not only decreases insulin resistance and risk of diabetes, but may also restore ovulation).
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Metformin is used as an adjunctive treatment in patients with obesity, diabetes mellitus (DM), or impaired fasting glucose.c | |
aRemember that chronic anovulation is associated with increased risk of endometrial hyperplasia and cancer due to unopposed estrogen effect. | |
bLetrozole is an aromatase inhibitor that decreases estrogen production and thus removes negative feedback effect on FSH. | |
cStudies have not shown protective effect of metformin on endometrium. | |
20.5 Contraception
FYI: Given in order of somewhat effective to highly effective (e.g., failure rate of spermicides is ≈ 25-33%; failure rate of vasectomy is ≈ 0.15%).
Calendar method (avoid intercourse near predicted ovulation days) | |
Hormonal transdermal patch (combined estrogen/ progesterone) | |
Hormonal progesterone injection—depot medroxyprogesterone acetate (DMPA) |
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Intrauterine device (IUD) Two types—copper IUD and hormonal IUD (hormone is levonorgestrel—a progesterone agonist) |
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20.5.1 Short Note on Oral Contraceptive Pills (OCP)
Formulary: A 28-pill OCP pack has 21 hormone pills (known as active pills). The additional seven pills are placebo pills (containing sugar or iron) to help the user stay in the habit of taking a pill every day.
Mechanism of action: Combination of estrogen and progesterone prevents mid-cycle LH surge and follicular maturation. Progesterone also works by making endometrium less suitable for implantation, and by making cervical mucus thick (this might be the reason for the decreased risk of PID).
Absolute contraindications to OCP:
History or risks of venous thromboembolism.
Tobacco use (more than half a pack per day) and age ≥ 35.
Liver disease (cirrhosis, liver cancer, etc.).
Clinical history of atherosclerotic cardiovascular disease (ASCVD; e.g., coronary artery disease), or high ASCVD risk (e.g., uncontrolled diabetes).
Hypertension (systolic of ≥ 160 mmHg or diastolic of ≥ 100 mmHg).
Migraine without aura in > 35 years of age or with tobacco abuse.
20.6 Differential Diagnosis of Dysmenorrhea
and Pelvic Pain
Primary dysmenorrhea (most common) Pathophysiology: Due to prolonged uterine contractions likely mediated by prostaglandins | Presentation: recurrent crampy suprapubic pain that occurs with or just before the menses | Rx: Exercise and heat application is 1st line. If not responding, 2nd line is NSAIDs like ibuprofen or hormonal therapy (combination OCPs or progestin-only pills). If 1st line NSAIDs fail, 2nd line NSAIDs is mefenamic acid (a specific type of NSAIDs for menstrual pain). For patients who desire contraception, use combination OCPs or progestin-only pills. |
Pathophysiology: presence of endometrial stroma and glands outside the uterus | Presentation depends on location of endometriosis: Typically, pain is cyclical with/ without menses. fixed retroverted uterus (endometrial cells “glue” the uterus to posterior pelvic structures), tender nodular masses along uterosacral ligaments or in cul-de-sac, etc. | Abdominal/transvaginal US may show ectopic endometrial tissue.
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For symptomatic or enlarging endometriomas, first SIM is laparoscopic management (it is important to rule out ovarian malignancy). | ||
Pathology: Benign tumor arising from smooth muscles in uterus. It is the MC pelvic tumor in women. It is more common in African-American women. | Presentation: Can be asymptomatic and often an incidental finding on US. Symptomatic patients may have any of the following:
Pelvic exam: May reveal asymmetrically enlarged uterus with an irregular surface. | For asymptomatic patients, just follow up. For most patients with symptomatic fibroids, treatment of choice is surgery.
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Presentation: Painful, heavy, prolonged menses, and chronic pelvic pain. Pelvic exam: Symmetrically enlarged tender uterus on pelvic exam. | NSIDx: Transvaginal US reveals symmetrically enlarged uterus; cystic areas can be seen within the myometrium. Rx: Hysterectomy is curative and provides a definitive dx. Because of diffuse involvement, myomectomy is usually not feasible. | |
Presentation: Fever, nausea, abnormal vaginal discharge, dyspareunia, etc. Pelvic exam: Cervical motion tenderness, uterine/adnexal tenderness | NSIDx: Cervical specimens for microscopy, nucleic acid amplification tests (NAATs) for C. trachomatis and gonorrhoea (+/-Mycoplasma genitalium). Do not forget pregnancy test and screening for other STDs (HIV, HBV, HCV). Rx: Antibiotics (see PID section, later in this chapter for further info) | |
aGnRH agonists are leuprorelin, nafarelin, buserelin (+ relin), etc. Continuous stimulation by GnRH agonist paradoxically results in downregulation of gonadotropin secretion. | ||
Abbreviations: HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; STDs, sexually transmitted diseases. | ||
20.7 Premenstrual Syndrome (PMS) and Premenstrual Dysmorphic Disorder (PMDD)
Workup: Ask patient to keep a menstrual diary to record symptoms; the symptoms should occur in the second half of menstrual cycle, impair daily functioning, and improve after menses.
20.8 Menopause
Definition: Expected cessation of menstrual cycle in old age (ovarian senescence); usual age of onset is > 45 years. (!)
8 Obese women usually have milder symptoms, as fat tissue aromatase converts androgen into estrogen.
Early signs may include menstrual irregularities and anovulatory cycles (menopausal transition).
Pain during intercourse due to atrophy or dryness of the vagina and cervix.
Increased frequency of urination/dysuria due to atrophic urethritis.
Workup: It is a clinical diagnosis, but can be confirmed by elevated FSH and low estrogen level.
Treatment: Hormone replacement therapy (HRT) for short-term management of moderate to severe menopausal symptoms (most importantly hot flashes).
Combination estrogen/progesterone for patients with uterus and estrogen only for patients without uterus (see the table below).
Topical lubricants and/or topical estrogen for atrophic vaginitis.
