Kamran S. Moghissi

A composite picture of the menstrual cycle

Abstract Ten ovulating women were studied to assess the interrelationships of various systemic, hormonal, and reproductive tract changes during normal menstrual cycles. Samples of blood, 24 hour urine specimens, vaginal smears, and cervical mucus were obtained every 2 days pre- and post-menstrually and daily in mid-cycle. Endometrial biopsies were performed at the onset of or immediately before menstruation, and the basal body temperature was recorded. Data for 10 cycles were fed into a computer, and mean reciprocal relationships were determined. The results were: (1) All endometrial biopsies reflected the late secretory phase; (2) there was a simultaneous mid-cycle surge of luteinizing hormone (LH) and folliclestimulating hormone (FSH), and serum concentrations of FSH and LH were significantly lower in the luteal phase compared to the follicular phase; (3) urinary peaks of estrone, estradiol and total estrogens occurred on the day before and that of estriol occurred on the day of the LH surge; (4) serum progesterone began to rise just before the LH peak, reached a high level 7 days after the LH peak, declined precipitately on Day 9, and rose again on Day 10, to decrease slowly until the onset of menstruation; (5) a significant relationship was observed between the LH peak and the basal body temperature; (6) urinary pregnanediol levels closely paralleled serum progesterone concentrations; (7) vaginal cytology revealed a karyopyknotic index peak the day following the LH peak; (8) properties of cervical mucus showed a remarkable relationship to the ovulatory estrogen peak.

OVARIAN CANCER RISK AFTER THE USE OF OVULATION-STIMULATING DRUGS

OBJECTIVE: To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer. METHODS: A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965–1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors. RESULTS: The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7). CONCLUSION: The results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks. LEVEL OF EVIDENCE: II-2

Causes of Infertility as Predictors of Subsequent Cancer Risk

Background: Although studies have found elevated risks of certain cancers linked to infertility, the underlying reasons remain unclear. Methods: In a retrospective cohort study of 12,193 U.S. women evaluated for infertility between 1965 and 1988, 581 cases of cancer were identified through 1999. We used standardized incidence ratios (SIRs) to compare cancer risk with the general population. Analyses within the cohort estimated rate ratios (RRs) associated with infertility after adjusting for other risk predictors. Results: Infertility patients demonstrated a higher cancer risk than the general population (SIR = 1.23; 95% confidence interval [CI] = 1.1–1.3), with nulligravid (primary infertility) patients at even higher risk (1.43; 1.3–1.6). Particularly elevated risks among primary infertility patients were observed for cancers of the uterus (1.93) and ovaries (2.73). Analyses within the cohort revealed increased RRs of colon, ovarian, and thyroid cancers, and of melanomas associated with endometriosis. Melanomas were linked with anovulatory problems, whereas uterine cancers predominated among patients with tubal disorders. When primary infertility patients with specific causes of infertility were compared with unaffected patients who had secondary infertility, endometriosis was linked with distinctive excesses of cancers of the colon (RR = 2.40; 95% CI = 0.7–8.4), ovaries (2.88; 1.2–7.1), and thyroid (4.65; 0.8–25.6) cancers, as well as melanomas (2.32; 0.8–6.7). Primary infertility due to anovulation particularly predisposed to uterine cancer (2.42; 1.0–5.8), and tubal disorders to ovarian cancer (1.61; 0.7–3.8). Primary infertility associated with male-factor problems was associated with unexpected increases in colon (2.85; 0.9–9.5) and uterine (3.15; 1.0–9.5) cancers. Conclusions: The effects of infertility may extend beyond gynecologic cancers. Thyroid cancers and melanomas deserve specific attention, particularly with respect to endometriosis.

Comparison of different treatment modalities of endometriosis in infertile women

This study was designed to evaluate the effectiveness of three therapeutic modalities in the management of stage I and II endometriosis. Management modalities consisted of (1) no treatment (controls, n=56); (2) oral medroxyprogesterone acetate (MPA), 30mg orally per day for 90days (n =36); and (3) danazol, 600 to 800mg daily for 6months (n =52). All patients were followed for at least 18months of exposure to pregnancy. Cumulative pregnancy rates were determined by life-table analysis. At 30months, pregnancies resulted in 55% of group I (controls), 71% of group II (MPA), and 46% of group III (danazol). There were no significant differences among these rates. Similarly, there was no significant difference between the cumulative pregnancy rates for stage I (59%) and for stage II (57%). Abortion rates for the various treatment modalities were the following: MPA 6.3%, danazol 11%, and no treatment, 14.3%. The spontaneous abortion rate in stage I and stage II disease was not significantly different. The results of this study suggest that a period of expectant management with correction of other infertility factors may be warranted in patients with mild to moderate endometriosis before medical therapy is contemplated.

Accuracy of Basal Body Temperature for Ovulation Detection

In 30 normally menstruating women, ages 19 to 41 (mean 24), gravida 0 to 5 (mean 0.7), basal body temperature (BBT) was correlated with serum luteinizing hormone (LH), progesterone, and estradiol or urinary estrogen levels assayed serially during one menstrual cycle. In 21 subjects (70%), a biphasic BBT correlated with an ovulatory hormonal pattern. Six women (20%) had a monophasic BBT but demonstrated a preovulatory estrogen peak, a midcycle LH surge, and a significant rise in serum progesterone levels during the luteal phase. The remaining three women (10%) showed anovulatory cycles (two women) or a deficient luteal phase (one woman) as determined by BBT and hormonal assays. The results indicate that in approximately 20% of ovulatory cycles the BBT failed to demonstrate ovulation.

Effects of microdose norgestrel on endogenous gonadotropic and steroid hormones, cervical mucus properties, vaginal cytology, and endometrium.

To determine the effect of microdose norgestrel on the hypothalamic-pituitary ovarian axis cervical mucus properties vaginal cytology and endometrial histology 6 healthy women were studied during 1 control and 1 treated menstrual cycle during which 75 mg norgestrel was administrered daily for 30 days. Gonadotropic and steroid hormones were assayed from blood and 24-hour urine every other day (daily during mid-cycle). Cervical mucus was tested every 1-2 days for quantity viscosity pH ferning spinnbarkeit cellularity sperm penetration and by protein electrophoresis. The womens basal body temperature and karyopyknotic index were determined and correlated with hormonal and cervical mucus studies. Endometrial biopsies were obtained between day 26-28 of both cycles. Results showed that norgestrel inhibited or suppressed luteinizing hormone and follicle-stiumulating hormone peaks and decreased progesterone in serum and pregnanediol in urine. Urinary estrogens increased in 3 women and decreased in 3. The cervical mucus became scanty viscous and cellular and demonstrated reduced spinnbarkeit and ferning; sperm migration through mucus was inhibited with 1 exception. Cervical mucus protein patterns revealed 3 ovulatory and 3 anovulatory changes. It appeared that breakthrough bleeding occurred essentially during anovulatory cycles. Typical biphasic karyopyknotic index was observed in only 2 cases. Endometrial changes incompatible with normal implantation occurred in all women. There were no significant differences in excretion of 17-ketosteroids and 17-hydroxysteroids during control and treated cycles. Data suggest norgestrel may exert contraceptive action by changing physical and chemical properties of cervical mucus altering endometrium inhibiting ovulation and disturbing hypothalamic pituitary ovarian function.

Prediction and Detection of Ovulation

This paper reviews and evaluates various methods for the prediction and detection of ovulation, with emphasis on the role this plays in management of infertility and in natural family planning. After spelling out the hormonal events which control the ovulatory process, techniques for ovulation detection and timing are discussed. These fall into 2 classifications: 1) direct assays of gonadotropins or steroid hormones in the serum or urine; and 2) evaluation of peripheral changes preceding, coinciding with, or succeeding ovulation. Since serial hormone assays are not practical in routine clinical practice, clinicians generally rely on peripheral or end-organ changes to determine alteration in circulating steroid hermone levels, but direct assays of gonadotropins and sex steroids would have to supplement these methods to determine the accuracy of commonly performed methods of ovulation detection. Tests based on hormone assays include daily assays of 1) serum or urinary lutienizing hormone (LH), 2) urinary estrogens (or estrogen metabolites) or serum estradiol, and 3) serum progesterone or urinary pregnanediol. Each assay is described in the text. Tests based on peripheral and systemic changes include ]) basal body temperature changes, 2) tests of physical properties of cervical mucus (appearance, spinnbarkheit, ferning, and burn test), 3) tests of the chemical content of cervical mucus (protein constituents and enzymes), 4) endometrial biopsy, 5) vaginal cytology, and 6) saliva sampling (measuring alkaline phosphatase levels which generally increase at time of ovulation). Tests based on hematologic changes, especially the decrease of blood basophil count at ovulation, are also discussed. Among the possible techniques of natural family planning discussed are the calendar method (Ogino-Knaus), the cervical mucus (ovulation) method, and the symptothermic method (basal temperature and calender combined) method.

Cyclic Changes of Cervical Mucus in Normal and Progestin-Treated Women

Samples of cervical mucus were obtained from 4 women for tests to determine specific cyclic changes. The tests performed determined the quantity viscosity acidity crystallization (fern test) length of the mucus thread (Spinnbarkeit) cellularity sperm penetration and protein electrophoresis of the cervical mucus. Samples were obtained and tested on the average of every 2 days during untreated normal cycles and during cycles of Norlestrin (2.5 mg norethindrone acetate and .05 mg ethinyl estradiol) administration. The results are graphed and discussed. General findings on Norlestrin-induced changes showed pronounced inhibition of sperm transmission through the cervical mucus absence of crystallization lowered Spinnbarkeit and a modified normal protein pattern.

Effects of stress and characteristic adaptability on semen quality in healthy men

Semen from 28 healthy volunteers was assessed for basic semen measure and percent of abnormal morphologic forms every 2 weeks for 6 months. Concurrent self-reports were obtained on abstinence, frequency of ejaculation, health behavior and status, experienced stress, social support, and life events. A single assessment of characteristic adaptability (ego resiliency) also was obtained. Significant between-subject positive correlations were reported among selected semen measures, abstinence, and ego-resiliency. Stress was correlated negatively with semen measures of volume and percent normal morphologic forms.

Postcoital Test: Physiologic Basis, Technique, and Interpretation

The postcoital test determines the adequacy of sperm and the receptivity of cervical mucus. It is the only test which evaluates the interaction between sperm and the female genital tract fluids. The Sims-Huhner test should be an integral part of an infertility investigation, but it must not be used as a substitute for semen analysis. Since cervical mucus accurately reflects the ovarian cycle, the PC test is a useful indicator of the endocrine preparation of the female reproductive system. It is also an important method for the evaluation of a variety of contraceptive steroids which may act directly or indirectly upon cervical secretion. For best results the test should be properly timed, meticulously performed, and knowledgeably interpreted.