History of Present Illness

A 32-year-old G0 presents with complaints of postcoital bleeding for the past three years. She reports a two-year history of levonorgestrel intrauterine device (LNG IUD) use and is currently amenorrheic with the exception of the postcoital bleeding. Prior to using the NG IUD, she used combination oral contraceptive pills. She states the bleeding occurs immediately after intercourse and is now occurring more regularly. The bleeding will fill several pads and takes a day or two to resolve. A year ago, she had her cervix chemically treated with Monsel’s solution, which she said reduced the bleeding for approximately eight weeks before it returned. She has a history of an abnormal Pap test in her early 20s, but reports that her most recent cytology was normal and co-testing was negative for high-risk human papilloma virus (HPV). She is unsure of the date of her most recent evaluation. She is sexually active with one male partner, denies a history of sexually transmitted infections, and uses the IUD for contraception.

Her medical history is otherwise unremarkable. She denies any other history of easy bleeding or coagulopathy. She drinks alcohol occasionally and has never used tobacco. She denies any history of sexual or physical abuse. She works as a school teacher. Her family history is negative for any gynecologic, breast, or colon cancers.

Physical Examination

General appearance

Comfortable, well appearing

Temperature

98.6°F

Pulse

72 beats/min

Weight

135 lbs

Height

65 inches

Respirations

16 breaths/min

BMI

23 kg/m²

Abdomen

Soft, non-tender, non-distended. No rebound or guarding.

Vulva/Vagina

Normal external genitalia and urethra, no vulvar lesions, pink, well-ruggated vagina. Small amount of blood in the vault.

Cervix

IUD strings are visualized at external cervical os, small area on posterior cervix with increased vasculature versus transformation zone. Area bleeds easily when touched with a Q-tip. Spatula and cytobrush are used to collect Pap smear, HPV, gonorrhea, chlamydia, and trichomonas probe. After Pap sample is collected, a moderate amount of blood is noted from the posterior cervix. Silver nitrate is applied with excellent hemostasis.

Uterus

Small anteverted, normal cervical contour

Adnexa

No masses or tenderness.

Urine hCG

Negative

Wet prep

pH 4.5, negative for yeast, clue cells, or trichomonads

Pap smear

Satisfactory for evaluation, negative for intraepithelial lesion or malignancy. High-risk HPV negative

Gonorrhea, chlamydia, trichomonas negative

Imaging

Pelvic ultrasound demonstrates a normal size uterus with endometrial thickness of 5 mm and an IUD in correct location. Normal ovaries bilaterally.

How Would You Manage This Patient?

This patient has postcoital spotting from an area of increased vascularity on her cervix. Initial work-up did not reveal an underlying medical, infectious, or pathologic cause of the cervical friability. The patient returned for colposcopy, with a targeted biopsy of the area, which returned as squamous metaplasia with reactive epithelial changes. She was prescribed 1 g of azithromycin for empiric treatment of nongonococcal, non-chlamydial cervicitis in a final attempt at conservative management. When this failed and she continued to be bothered by the ongoing postcoital bleeding, she presented for a loop electrosurgical excision procedure (LEEP). A shallow LEEP of the posterior cervix was successfully performed in the office, with roller ball cautery of the LEEP bed to achieve hemostasis, followed by application of Monsel’s solution. She maintained pelvic rest for six weeks following the procedure and her symptoms resolved. Pathology on the LEEP specimen showed squamous metaplasia with severe chronic inflammation.

Friable Cervix with Negative Evaluation

A “friable cervix” refers to a cervix that bleeds easily, and often presents as postcoital or post-traumatic bleeding. Postcoital bleeding is not an uncommon complaint of reproductive-aged women presenting for gynecologic care. Surveys of reproductive-aged women have reported the annual incidence of postcoital bleeding to be between 3.4 and 12.6 percent, with a higher incidence in younger women and lower incidence in postmenopausal women [1, 2]. While it is important to rule out underlying pathology, such as cervical cancer, the cause of cervical friability and postcoital bleeding is more commonly a benign etiology. In fact, over 60 percent of women who report postcoital bleeding will have resolution of their symptoms with expectant management alone [3].

Bleeding originating from the cervix should be distinguished from abnormal uterine bleeding or structural causes such as polyps, as the evaluation and management differ. If abnormal uterine bleeding is suspected, the work-up may include a pelvic ultrasound or endometrial biopsy, especially if no lesion is identified on the cervix. Structural causes, such as cervical or endometrial polyps, can be removed. Cervical polyps can typically be removed easily with forceps in the office and the base cauterized as necessary.

A common cause of postcoital bleeding or cervical friability is cervical ectropion, which can be secondary to the physiologic process of endocervical columnar epithelium replacing squamous epithelium on the external cervical os. The columnar epithelium is more fragile than the squamous epithelium and therefore more prone to bleeding with contact [4]. Cervical ectropion is often associated with estrogen high states, such as pregnancy or estrogen-containing oral contraceptive pills. Therefore, in evaluating patients with ectropion, thorough history taking including medication history and exposure to hormonal changes is an important initial step. Of note, there is no indication for evaluation or treatment of asymptomatic women with cervical ectropion outside of routine screening, as ectropion alone is not necessarily pathologic or symptomatic [5].

The patient should also be evaluated for vaginal or cervical infections. Though postcoital bleeding has been reported as a predictor for chlamydia cervicitis [6], screening should also rule out infection with gonorrhea, trichomoniasis, and bacterial vaginosis. Herpes simplex virus should also be ruled out if there is evidence of cervical ulcerations. If a specific infectious cause cannot be identified, azithromycin or doxycycline can be used as empiric treatment for cervicitis [7].

A Pap test with HPV co-testing should be collected on women with postcoital bleeding, or cervical friability, though there are no consensus guidelines on whether or not colposcopy needs to be performed in the setting of normal cytology and negative HPV [4]. Visible lesions should be biopsied. The incidence of cervical intraepithelial neoplasia and invasive cancer associated with postcoital bleeding is dependent on the baseline risk of cervical pathology in the specific population being screened; in countries with adequate cervical cancer screening programs, the risk of CIN 2 or greater is extremely low [1].

Once the above etiologies have been ruled out and an area of cervical friability is identified, resolution or induction of squamous metaplasia can be achieved with topical hemostatic agents such as silver nitrate, Monsel’s solution, or Amino-cerv. Monsel’s (ferric subsulfate) solution penetrates denuded mucosa and causes a coagulation necrosis via thrombosis in the small vessels supplying the traumatized area. It has no effect on the normal surrounding epithelium; complete re-epithelialization and healing takes four weeks [8]. Amino-cerv is an alternative topical agent, which is reported to promote cervical healing. It is a combination of amino acid, antifungal, and urea, which work to promote cell growth. In one study, it was reported to improve cervical healing by four weeks in 83 percent of the women who received the treatment [9]. In settings where available, cryotherapy (the application of carbon dioxide or nitrous oxide via a probe at −89°C) has also been reported to be efficacious in over 72 percent of women with postcoital bleeding as a result of ectropion [10]. Cryotherapy may be more readily available in resource-limited settings. However, if these modalities are unavailable or result in inadequate treatment, a shallow LEEP procedure may be performed. Patients are counseled on the importance of pelvic rest after the procedure. The depth of the excised specimen should be minimized as the procedure is done for therapeutic and not diagnostic purposes, optimizing cervical integrity and future fertility outcomes.

Key Teaching Points

1. 
   

   1. Malignancy, infection, pregnancy, and structural abnormalities should be ruled out prior to empiric treatment of postcoital bleeding

   
   
2. 
   

   2. Conservative treatment includes altering hormonal medications, prescribing a course of antibiotics, application of Amino-cerv, or topical cauterization with silver nitrate or Monsel’s solution

   
   
3. 
   

   3. A small loop electrosurgical excision procedure (LEEP), roller ball ablation, or cryotherapy may be necessary for ultimate resolution of the symptoms

History of Present Illness

A 28-year-old nulliparous patient presents with a complaint of absent menses for the past six months. She states she has occasional hot flashes and some vaginal dryness with associated dyspareunia. She performed a home pregnancy test that was negative. She notes no headache, visual changes, or galactorrhea. She exercises regularly, but has not noted any weight changes, or hot or cold intolerance. Her hair and skin are unchanged. She is engaged to be married next spring, and has been mutually monogamous with her fiancé for the past two years. She currently works as a social worker and enjoys her job. She does not smoke or use illicit drugs, and she only rarely drinks alcohol. She reports having a younger sister, who is well, but a brother and a male cousin with mental retardation.

Physical Examination

General appearance

Well-appearing young woman, alert and oriented, in no apparent distress

Temperature

37.0°C

Pulse

68 beats/min

Blood pressure

110/70 mmHg

Respiratory rate

14 breaths/min

Height

66 inches

Weight

130 lb

BMI

21.0 kg/m²

HEENT

Normocephalic, anicteric sclerae, no oral cavity lesions, good dentition

Neck

Supple, full range of motion, no thyromegaly, bruits, or adenopathy

Cardiovascular

Normal S1 and S2, no murmurs, regular rate and rhythm

Lungs

Clear to auscultation bilaterally

Abdomen

soft, non-tender, no masses, no inguinal adenopathy

External genitalia and escutcheon

Normal

Vagina

Decreased rugae with mild atrophic changes; physiologic leukorrhea

Cervix

Nulliparous, closed/long/posterior, no cervical motion tenderness

Uterus

Normal size, anteverted, mobile, non-tender

Adnexae

No palpable masses or tenderness

Extremities

No cyanosis, clubbing, or edema; normal reflexes

Urine pregnancy test

Negative

FSH

42 mIU/ml

Estradiol

45 pg/ml

TSH

1.25 mIU/ml

Prolactin

13 ng/ml

Electrolytes

Sodium 140 mEq/ml, Potassium 4.2 mEq/ml

Hematocrit

39%

Pelvic sonogram

7 cm uterus with no fibroids, endometrium normal with 3.5 mm thickness; ovaries normal size bilaterally measuring 1.3 × 1.7 × 1.6 cm; a few subcentimeter follicles are seen; no free fluid in the cul-de-sac.

How Would You Manage This Patient?

This patient has secondary amenorrhea with a history, physical examination, and initial laboratory testing that are concerning for primary ovarian insufficiency (POI). Her FSH and estradiol were repeated in one month and resulted as 56 mIU/mL and 30 pg/mL, respectively, confirming a diagnosis of POI. At this point, a karyotype was ordered and confirmed 46 XX, Fragile X mutation testing (FMR1) was positive for 70–85 CGG repeats, and adrenal antibodies were negative. The patient was extensively counseled about the diagnosis of being a Fragile X premutation carrier and referred for genetic counseling.

The patient and her partner opted to pursue conception and were referred to the Reproductive Endocrinology team. Following controlled ovarian hyperstimulation with FSH, several eggs were harvested and fertilized, and five showed sufficient maturation and development. Pre-implantation genetic diagnosis (PGD) yielded three females and two males, and the patient underwent single embryo transfer of one of the female embryos. She subsequently conceived, and a second-trimester amniocentesis confirmed a 46 XX fetus, with no expansion of the CGG repeats. The patient was followed up for an uneventful pregnancy, and she delivered a baby girl at 39 weeks gestation. Following cessation of lactation, she started combination oral contraceptives with 30 mcg ethinyl estradiol and 1 mg of norethindrone acetate, and continues to be well three years later.

Secondary Amenorrhea

Secondary amenorrhea is defined as the absence of menses for three months after the establishment of regular cycles, or after six months in patients with irregular menses. After pregnancy, menopause is the second most common reason for cessation of menstruation. Other causes that must be considered include endocrine (thyroid disease, hyperprolactinemia, hypothalamic or pituitary dysfunction, primary ovarian failure, androgen excess), traumatic or iatrogenic (postsurgical, such as uterine synechiae), hypothalamic (anorexia, bulimia, stress), environmental (toxins), pharmacologic (exogenous hormones or certain psychotropic medications), infectious (e.g., tuberculous endometritis), immunologic, or genetic. This case will focus on secondary amenorrhea caused by POI resulting from Fragile X premutation.

Primary Ovarian Insufficiency Due to Fragile X Premutation

POI is the term used to describe accelerated ovarian senescence before the age of 40 years. Prior names for this clinical condition include “premature ovarian failure” and “premature menopause.” Both of these terms are somewhat misleading and have fallen out of favor because many such patients express some residual folliculogenesis, and hence may not be entirely infertile [1]. Other authors have advocated the term “Premature Ovarian Dysfunction”[2, 3, 4].

The exact prevalence of POI is not known; however, as many as 1–2 percent of women will experience a significant decline in ovarian activity prior to age 40 [3]. While most causes are idiopathic or presumably autoimmune, one must exclude abnormalities of the X chromosome or other genetic causes that may indicate systemic disease. In the absence of historic environmental or infectious exposures, a karyotype and microarray analysis will help define the etiology. See Box 16.1 for a complete list of potential causes of POI.

The association of Fragile X premutations and POI was first reported by Conway and colleagues [5]. Numerous subsequent reports confirmed those observations and expanded upon them. Although the prevalence of Fragile X premutation as the etiology of sporadic POI is approximately 1–8 percent, the incidence is much higher in those patients with a related family history [1, 3].

The gene for Fragile X syndrome (FMR-1) is located on the long arm of the X chromosome. It codes for production of the fragile X mental retardation protein that has been found to suppress translation of messenger RNA in the brain [6, 7]. As a result, untranslated mRNA may accumulate in the dendrites, thus disrupting function. The disorder results from an increase in the number of cytosine–guanine–guanine (CGG) repeats in the noncoding region of the gene. In the normal case, there are fewer than 55 such repeats; when the number of repeats exceeds 200, the Fragile X syndrome results. The “intermediate number,” between 55 and 200 repeats, is referred to as the premutation state (see Table 16.1). Males are affected far more than females because they have only one X chromosome; if they have more than 200 CGG repeats, they will suffer from Fragile X syndrome. As a result of having a second X chromosome, with inactivation or underexpression of the abnormal X chromosome, women rarely have the full disorder. They may, however, have a variety of other conditions, including ataxia or mild cognitive disorders.

Although women who have the premutation are typically asymptomatic, they are at risk for developing premature ovarian insufficiency, as in the patient described above. There is debate as to whether the underlying pathophysiology of ovarian dysfunction associated with FMR-1 premutation is caused by an accelerated rate of follicle atresia or a diminished initial number of follicles [8]. In addition, women with the Fragile X premutation may pass off an expanded number of CGG repeats to their offspring. This generational increase in number of CGG repeats appears to occur during oogenesis and post-zygotic mitosis and means that a woman who carries a premutation is likely to pass along the full mutation and thus have an affected child. When a male has the premutation, he typically will develop tremor and ataxia; however, males who carry the premutation are less likely to pass on an amplified number of CGG repeats to their progeny.

In addition to discussion with the patient, family members should be informed and counseled about the possibility of carrying the premutation and offered testing accordingly. It is important for women with the Fragile X premutation to understand that unlike in true menopause, when follicles have been exhausted, there may still be active follicles, even in the face of an early decline in ovarian function. As a result, women with POI due to the Fragile X premutation may continue to be fertile for several years, but the exact likelihood of fertility preservation is hard to predict.

Counseling of couples is extremely important. It is advised that women be counseled prior to pregnancy about reproductive options and the potential risk to their offspring. Women with the Fragile X premutation may opt to undergo genetic testing of the fetus via chorionic villus sampling (CVS) or amniocentesis. It should be noted that the placenta may not always reflect the exact number of CGG repeats, so amniocentesis is more reliable than CVS in this situation. Alternatively, with the development of PGD, couples may choose to undergo in vitro fertilization (IVF) with PGD and implant only unaffected embryos [6]. Couples may also choose to undergo IVF with donor eggs, particularly if POI has already been diagnosed.

In addition to reproductive concerns in Fragile X premutation carriers, there are emotional changes that may accompany any woman faced with declining estrogen, which may be even more important when it occurs significantly earlier than anticipated or than in her cohorts and friends. The principal medical issues that should be addressed include bone loss, cardiovascular disease, and an increased risk of endocrine and/or autoimmune dysfunction (hypothyroidism and diabetes) [1, 3, 9, 10]. Since endocrine disorders are more commonly found in women who suffer from idiopathic or immune-mediated POI, screening for hypothyroidism and diabetes mellitus with an annual TSH and Hemoglobin A1 C is appropriate.

Estrogen deprivation in young women causes vasomotor symptoms and urogenital atrophy in addition to increasing the risk of bone loss and excess cardiovascular morbidity and mortality; therefore, women with POI require estrogen replacement. These patients may benefit from doses found in combination estrogen–progestin oral contraceptives (OCPs), especially in those wishing to avoid pregnancy. It is also reasonable to use the lower doses in postmenopausal hormone replacement regimens, but these options are less reliable at preventing ovulation in patients who desire contraception. Transdermal estradiol 0.025–0.05 mg per day or oral regimens including estradiol 1 mg daily or combined equine estrogens 0.625 mg daily will provide sufficient bone support and may reduce cardiovascular risk in young patients. In patients with an intact uterus, progestogens in the form of a progestin-containing IUD or oral progesterone (100 mg daily or cyclic for at least 12 days per month) must be added to avoid endometrial hyperplasia or adenocarcinoma. The combination of transdermal estrogen with concomitant use of a progesterone-containing IUD is a good alternative to oral progestin administration and is gaining popularity, as it may be a safer approach by avoiding “first pass” metabolism. Patients should be counseled about reported risks of combination HRT [11]; however, it does not appear that younger patients have the same degree of risks as do older women. Vitamin D and calcium supplementation might also provide additional bone support when used in concert with a regular, weight-bearing exercise regimen.

Key Teaching Points

• 
  

  As many as 1–2 percent of women will experience POI defined as ovarian dysfunction prior to age 40 years.

  
  
• 
  

  Testing for premutation of the FMR-1 gene is indicated in young women with hypergonadotropic amenorrhea and is more likely to be positive when there is a family history of mental retardation.

  
  
• 
  

  Counseling is indicated to provide emotional stability and reproductive likelihood; many such patients are not truly “menopausal” and hence they are not infertile.

  
  
• 
  

  Referral to genetic counselors and reproductive endocrinologists should be offered to assist patients and their partners in understanding options for future fertility and risks of expansion to full mutation in offspring.

  
  
• 
  

  To avoid complications of estrogen deprivation, supplementation with either OCPs or HRT is indicated.

History of Present Illness

A 27-year-old female, gravida 0, presents as a new patient for her annual gynecology exam. She reports her last menstrual period as very light and occurred approximately four months prior to this visit. She reports menarche at age 12. She describes fairly regular, monthly periods while in high school. Her periods, however, became increasingly erratic while in college. She notes that at first she would skip her period for a month or so at a time but then would go several months without having a cycle. Her longest period without a cycle was eight months. She reports having been seen at her college’s clinic for evaluation of her periods but cannot recall what labs were drawn. She was started on a birth control pill at that time with resumption of periods every 28 days. She continued the pill until approximately one year ago and has only had three spontaneous periods since.

She reports the provider she saw at the college clinic attributed her irregular cycles to her cross-country runs. Though she has always been athletic, she became increasingly so while in college, running at least five miles daily. She was especially mindful of her diet during training and admits to having restricted calories to maintain a slimmer figure in the past.

Her past medical history is notable for a prior stress fracture in her right foot, sustained while training for a marathon. She has had no prior surgeries. She does not smoke but does drink one or two glasses of wine per week. She is currently in law school and applying for a federal clerkship. She continues to be an active runner, running approximately 30 miles per week. When asked about her self-image, she reports feeling as though she is at her ideal body weight and is fearful of weight gain. She is sexually active in a committed relationship and anticipates getting engaged within the year. She and her boyfriend inconsistently use condoms for contraception.