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Hormone replacement therapy in women with amenorrhea
Impact of cigarette smoking on menstrual function
Effects of GnRH agonists
Analyzing three ablation techniques for cervical dysplasia
Hysterectomy for endometriosis-associated pain in younger women
Inadequate oral contraceptive instructions
Preemptive analgesia in laparoscopy
Hormone replacement therapy in women with amenorrhea
Secondary amenorrhea is seen in as many as 50% of competitive runners, 25% of recreational runners or joggers,
approximately 12% of swimmers and cyclers and 44% of dancers. This condition is often caused by hypothalamic amenorrhea, a condition characterized by an arrest of the hypothalamic drive on the pituitary-ovarian
system that results in lack of bleeding.
Estrogen replacement is indicated in women of reproductive age with hypothalamic amenorrhea just as it is in women with premature ovarian failure. Women with hypothalamic
amenorrhea or premature ovarian failure must also receive cyclic progestin therapy to prevent excessive endometrial growth. This often occurs after chronic exposure to estrogen alone. Progestins protect the
endometrium against risks of chronic unopposed estrogen, such as hyperplasia and cancer, or both, by inducing secretory transformation. Thus, shedding of the endometrium and vaginal bleeding is an expected
consequence of cyclic progestin treatment.
Progesterone is the natural progestin produced by the corpus luteum during the luteal phase. If administered orally, more than 90 percent is metabolized during the first
hepatic pass. This greatly limits the efficacy of oneÕs daily administration and can result in unphysiologically high levels of progesterone metabolites, which have also been indicated in causing dizziness and
drowsiness. Synthetic progestins, such as medroxyprogesterone acetate or norethindrone acetate, have been specifically designed to resist enzymatic degradation and remain active after oral administration. However,
these compounds exert undesirable effects on the liver (notably on lipids) and often cause psychologic side effects that can be severe enough to limit their use.
In this multicenter study by Warren et al, a
randomized parallel group of 127 women with secondary amenorrhea was followed for a three-month period of time. Estrogenized patients applied transvaginal progesterone (Crinone 4% or 8%) every other day for six
doses per month.
Efficacy was based on endometrial biopsy findings and withdrawal bleeding. Progestational stages were found in 92% (Crinone 4%) and 100% (Crinone 8%) of patients with evaluable biopsies.
Withdrawal bleeding was experienced by 81% (Crinone 4%) and 82% (Crinone 8%) of the patients studied.
No patient experienced any serious side effects related to treatment. The incidence of most side effects,
notably emotional liability, depression and sleep disorder, decreased with progesterone treatment compared with estrogen therapy alone. Compliance exceeded 98% for both doses.
Conclusion
Crinone, a transvaginal polycarbophil-based progesterone gel in both 4% and 8% strengths, represents a novel, effective and well-tolerated option for hormone
replacement therapy for women with secondary amenorrhea.
Warren MP, Biller BMK, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic
administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999; 180:42-48.
Impact of cigarette smoking on menstrual function
Cigarette smoking is a well-known developmental toxicant. It has been associated with adverse reproductive outcomes
such as infertility, reduced fecundity and younger-age menopause. Several studies have suggested that cigarette smoking increases menstrual disorders with an intermediate effect among exsmokers. These studies found
that smokers were more likely than nonsmokers to have oligomenorrhea and other aspects of abnormal menstruation, including irregular periods and intermenstrual bleeding. In this study, the effects of smoking on
menstrual cycle function were examined by using biologic measures rather than self-reporting.
Windham et al, from the University of California at Davis, performed a prospective study of 408 women. The women
collected urine daily for one to seven menstrual cycles, maintained daily diaries and completed detailed interviews. Smoking data from the diaries were averaged over each segment and verified by cotinine assay.
Urine samples were analyzed for metobolites of steroid hormones to define the day of ovulation and various menstrual characteristics, including segment, follicular, luteal phase, menstrual length, variability and
anovulation.
Heavy smoking (a minimum of 20 cigarettes per day) was associated with nearly four times the risk of a shortened cycle (less than 25 days), versus non-smoking (RR = 3.8, 95% C1 1.1/12.7). Mean cycle
length was 2.6 days shorter with heavy versus no smoking, due almost entirely to shortening of the follicular phase. Women who smoked an average of 10 or more cigarettes per day had significantly more variable
cycles and menstrual length than nonsmokers.
The data suggested there was a possible increased risk of anovulation and short luteal phase with greater smoking. Cycles of exsmokers with 10 or more pack-years (1
pack/day) of exposure were more likely to be short and have shorter luteal phases than the cycles for those who had never smoked.
Conclusion
The
deleterious effects found in this study of cigarette smoking on the menstrual cycle may explain, at least in part, associations with other reproductive endpoints such as decreased fecundity, early menopause and
infertility.
Windham GC, Elkin EP, Swan SH, et al. Cigarette smoking and effects on menstrual function. Obstet Gynecol 1999; 93:59-65.
Effects of GnRH agonists
The use of gonadotrophin-releasing hormone (GnRH) agonists has revolutionized medical therapy in gynecologic practice. These agents were
initially introduced as a treatment for endometriosis, but are now also being used in the management of infertility, menorrhagia, fibroids and pelvic pain. They have also been used for research because of their
dramatic and reversible effects on serum estradiol levels.
Early research investigated the effect of GnRH agonists on the uterus, specifically on benign fibroid growths. A new study by Weeks et al, from St. James
University Hospital in Leeds, England, undertook a double-blind placebo-controlled randomized trial of 51 women who were awaiting hysterectomy for dysfunctional uterine bleeding.
All patients had socially
disabling menorrhagia unresponsive to medical therapies and had been investigated to exclude uterine malignancy. Women were excluded from the study if they had been treated with a GnRH agonist within the preceding
six months; there was a suspicion of gross uterine pathologic condition; the ultrasonographic examination revealed uterine fibroids greater than 2.5 cm in diameter; or the women were taking any hormonal therapies.
The women were treated for eight weeks with either leuprolide acetate depot or placebo. Vaginal ultrasonographic examinations were performed before and after treatment.
In patients allocated to therapy with GnRH
agonists, the mean uterine volume decreased by 34%. Furthermore, the uterine artery pulsatility index increased from 2.25 to 2.70. This increase in pulsatility index corresponds to a decrease in uterine blood flow.
No significant changes were seen in the placebo group. The intersonographer variability was low and there was a high correlation between uterine size measured by ultrasonography before hysterectomy and uterine size
measured postoperatively in the pathology lab.
Conclusion
Treatment with gonadotropin-releasing hormone (GnRH) agonists appears to lead to
uterine shrinkage and an increase in the uterine artery pulsatility index, even in the absence of uterine fibroids.
Weeks AD, Duffy SRG, Walker, JJ. Uterine ultrasonographic changes with gonadotropin-releasing
hormone agonists. Am J Obstet Gynecol 1999; 180:8-13.l
Analyzing three ablation techniques for cervical dysplasia
For several decades, destruction of the transformation zone has been the standard of care for patients with
biopsy-proven squamous interepithelial lesions (SIL) of the cervix (cervical dysplasia) who have negative findings on endocervical curettage, satisfaction colposcopic examination and congruent Papanicolaou smear and
biopsy results. Such destruction, which is also known as ablation, employs several different techniques, each with several advantages and disadvantages.
Cryotherapy is reliable, easy to use and relatively
inexpensive. However, the treatment cannot be tailored to the size of the lesion and does not result in a tissue specimen. Laser vaporization is easily adjusted to the size of the lesion, but requires relatively
expensive equipment, a moderate amount of training, potentially toxic side effects (e.g., burns and eye injuries) and also yields no specimen.
Loop electrosurgical excision procedure (LEEP) is reasonably
reliable, easy to use, can be tailored to the size of the lesion and produces a tissue specimen. Unfortunately, this technique is very expensive. All three therapies have similar cure rates (80-90%) and similar
complication rates in terms of bleeding, cervical stenosis and infection.
In a study reported by Mitchell et al from the University of Texas Health Science Center, 498 patients were assigned prospectively and
randomly to treatment stratification by SIL grade, endocervical gland involvement and lesion size to undergo either cryotherapy, laser vaporization or loop excision. Of these, 390 had adequate follow-up ranging from
6 to 37 months (mean 16 months).
There were no statistically significant differences in complications, persistence (defined by disease present less than 6 months after treatment) or recurrence (defined by
disease present more than 6 months after treatment) (see Table 1 below).
Risk of persistent disease was higher among women with large lesions (risk ratio [RR] 18.9, 95% CI 3.2/110.6). Recurrence risk was higher
among women age 30 years and older (RR 2.1, 95% CI 1.2/4.3), in those with human papilloma type 16 or 18 and those who had prior treatment.
Conclusion
This prospective, randomized study supports a high success rate with cryotherapy, laser vaporization or loop excision. No significant differences in success rates were observed among the three groups in
the study population. This study indicates that additional attention should be directed toward higher-risk patients.
Mitchell MF, Tortolero-Luna G, Cook E, et al. A randomized clinical trial of cryotheraopy,
laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstet Gynecol 1998:92, 737-44.
Hysterectomy for endometriosis-associated pain in younger women
Endometriosis is a difficult disease to diagnose and treat. For some women, the pain can be chronic,
severe and debilitating. Among women undergoing laparoscopy for pelvic pain, grossly evident endometriotic lesions are present in 30-50% of patients. Conservative surgical therapies include vaporization, excystation
of implants, desiccation, presacral neurectomy and uterosacral nerve ablation.
More radical surgery (i.e., hysterectomy with or without bilateral oophorectomy) is usually reserved for patients with intractable
pain in whom other medical and surgical approaches have failed. Frequently, these patients choose TAHBSO only after their child bearing has been completed. A small group of women face this choice at a young age as
the only realistic hope for permanent cure. In many cases, however, such radical surgery produces results that are less than satisfactory with pain persisting or recurring.
Patients were asked to complete two
standardized surveys; the Disruption of Functioning Index and the Beck Depression Inventory.
The study group consisted of 16 women less than 30 years of age; the control group consists of 27 women greater than 40
years of age. Proportions in both groups were similar in terms of overall alleviation of pain. However, the study group was significantly more likely to report residual symptoms such as dyspareunia and dysuria. This
younger group more often reported a sense of loss after hysterectomy and reported more overall disruption in different aspects of their lives.
Conclusion
Women who undergo hysterectomy for pelvic pain and endometriosis before age 30 appear more likely than older women to report residual symptoms, a sense of loss and disruption from pain in different
aspects of their lives.
Macdonald SR, Klock SC, Milad MP. Long-term outcome of nonconservative surgery (hysterectomy) for endometriosis-associated pain in women <30 years old.. Am J Obstet Gynecol 1999;
180:1360-63.
Inadequate oral contraceptive instructions
Traditionally, it has been assumed that successful family planning is related primarily to the effectiveness of the
contraceptive method chosen. However, even when a highly effective method (such as an oral contraceptive pill) is chosen, studies have shown that up to 22% of women unintentionally become pregnant within the first 6
months after receiving a prescription from their health care provider.
Such unplanned pregnancies usually result from one of three errors in pill taking: (1) missing pills in one or more cycles without adequately
making them up; (2) overdosing to compensate for missing a pill; or (3) transition errors produced by stopping the cycle before taking all the active pills or starting the next cycle of pills prematurely. The most
common errors in pill taking result from inadequate counseling by the clinician or difficulty remembering instructions, or both.
Rickert et al from the University of Texas Medical Branch at Galveston sought to
determine demographic, reproductive and behavioral characteristics associated with inadequate recall of pill-taking instructions and whether patients with inadequate recall showed poor pill-taking compliance during
the last six months, placing them at additional risk for unplanned pregnancy.
The authors studied 150 sexually active women ages 13 through 40 years attending a university-based family planning clinic using
anonymous self-report measures that assessed demographic and reproductive characteristics, understanding of pill-taking instructions and compliance with contraceptive usage. Logistic regression was used to determine
factors associated with inadequate recall, which were further stratified by minority versus non-minority women.
Minority women with inadequate recall were almost six times more likely than minority women with
adequate recall not to know the name of the prescribed oral contraceptive and were three times more likely to have less than a high school education. As certainty of pill-taking instructions and general oral
contraceptive knowledge decreased, respectively, in the likelihood of inadequate recall. Also, such inadequate recall was associated with poor compliance.
Conclusion
From these date, it appears that women with inadequate recall may be identified at the conclusion of their visits to the doctor so that interventions to enhance their pill-taking skills
can be further provided.
Rickert VI, Berenson, AB, Williamson, AJ, Wiemann CM. Immediate recall or oral contraceptive instructions: Implications for providers. Am J Obstet Gynecol 1999: 180; 1399-4046.
Preemptive analgesia in laparoscopy
Laparoscopy has achieved prominence in gynecology for the evaluation and treatment of conditions ranging from aspects of
fertility to distinguishing benign from malignant neoplastic masses, as well as the evaluation of chronic pelvic pain. Although performed routinely in an out-patient setting, laparoscopy can be associated with
considerable discomfort and many women require postoperative analgesia for abdominal back and/or shoulder pain.
Because laparoscopy is commonly considered an elective procedure, reducing postoperative discomfort
will allow for rapid return to normal activity with minimal disruption. Persistent pain after trauma or surgery may be the result of a hyperexcitable state persisting long after the painful stimuli have been
removed, causing a patient to perceive pain from stimuli normally believed to be painless. Prevention of spinal hyperexcitability by blockade of the afferent nerve pathway from surgical site to sinal cord may
therefore decrease the amount and duration of postoperative pain perception.
Employing a procedure known as preemptive analgesia, anesthetic is administered before surgical incision and must be sufficient to
prevent afferent signals from reaching the spinal cord. The infiltration of local anesthetic at the surgical site before incision during a general anesthetic procedure is an example of this technique.
Ket et al
from the University of Tennessee studied 57 patients undergoing diagnostic laparoscopy. The patients were randomized to one of three blinded treatment groups. In treatment group A, patients received local
infiltration of 0.5% bupivacaine at the surgical site before incision and a saline placebo infiltration before incision closure. Treatment group B received the saline placebo before skin incision and bupivacaine
after laparoscopy, but before closure of the skin incisions. For treatment group C, saline was infiltrated as a placebo before and after laparoscopy. All patients underwent a standardized general anesthetic
induction and maintenance. Postoperative pain was evaluated using the modified McGill Present Pain Intensity scale. Pain and supplementary analgesic use were compared among the three groups.
By 24 hours after
surgery, patients in treatment group A reported significantly lower pain scores (McGill Present Pain Intensity scale: 0.5±0.9) than either treatment group B (1.6±1.3) or C (1.3±1.2). Group A patients also tolerated
a significantly longer time delay to their first analgesic medication than patients who received postincisional bupivacaine or patients who received no bupivacaine.
Conclusion
The preemptive administration of bupivacaine before laparoscopy results in decreased postoperative plain and should allow a more rapid return to normal activities. The
popular practice of infiltrating bupivacaine at time of incision closure does not offer any benefit in the control of pain after laparoscopy.
Ke RW, Portera SG, Bagous W, Lincoln SR. A randomized, double-blinded
trial of preemptive analgesia in laparoscopy. Obstet Gynecol 1998:91; 972-75.l
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