Michael R. Soules

Executive summary: stages of reproductive aging workshop (STRAW)

A select group of investigators attended a structured workshop, the Stages of Reproductive Aging Workshop (STRAW), at Park City, Utah, USA, in July 2001, which addressed the need in women for a staging system as well as the confusing nomenclature for the reproductive years.

A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause

BACKGROUND The primary determinant of reproductive age in women is the number of ovarian non-growing (primordial, intermediate and primary) follicles (NGFs). To better characterize the decline in NGF number associated with aging, we have employed modern stereology techniques to determine NGF number in women from birth to menopause. METHODS Normal human ovaries were collected from 122 women (aged 0-51 years) undergoing elective oophorectomy, organ donation or autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. Models to describe the resulting decay curve were constructed and evaluated. RESULTS NGF decay was best described by a simple power function: log (y) = ax(b) + c, where a, b and c are constants and y = NGF count at age x (R(2) = 0.84, Sums of Squares Error = 28.18 on 119 degrees of freedom). This model implies that follicles decay faster with increasing age. CONCLUSIONS Unlike previous models of ovarian follicle depletion, our model predicts no sudden change in decay rate, but rather a constantly increasing rate. The model not only agrees well with observed ages of menopause in women, but also is more biologically plausible than previous models. Although the model represents a significant improvement compared with earlier attempts, a considerable percentage of the variation in NGF number between women cannot be explained by age alone.

Stages of Reproductive Aging Workshop (STRAW)

A select group of clinicians and investigators met recently for the express purpose of developing a staging system for female reproductive aging. The group also addressed the confusing and redundant nomenclature that is commonly used to describe the late reproductive years. A summary and recommendations are presented.

Executive summary: Stages of Reproductive Aging Workshop (STRAW)

A select group of investigators attended a structured workshop, the Stages of Reproductive Aging Workshop (STRAW), at Park City, Utah, USA, in July 2001, which addressed the need in women for a staging system as well as the confusing nomenclature for the reproductive years.

The diagnosis of luteal phase deficiency: a critical review

Luteal phase deficiency is an ovulatory dysfunction problem that is subtle but real. It may be the most common ovulatory problem in women. Luteal phase deficiency has been clearly demonstrated in the research setting (1) in spontaneous cycles, (2) when follicular maturation has been impeded, and (3) when luteotrophic influences have been suppressed. The diagnosis of LPD in the clinical setting remains problematic and controversial primarily because there is no practical diagnostic method that has been validated. This article has reviewed the methods that have been used to diagnose LPD. BBT charts are insensitive; these charts reliably diagnose LPD only when there are persistent short luteal phases. There is disagreement whether ovarian follicular size, as determined by ultrasonography, is decreased in LPD; however, ultrasonographic diagnosis of LPD would require daily scans through ovulation, which makes this approach impractical. Mild hyperprolactinemia is a probable cause of LPD in a minority of patients; a physician should obtain a PRL level in LPD women with the realization that there is considerable sampling variability. Determination of serum gonadotropin levels (LH or FSH or both) is not practical for the clinical diagnosis of LPD. Random serum P levels, whether single or multiple, are not helpful in the diagnosis of LPD in individual patients. The secretory pattern of P results in such wide confidence limits that P samples from individuals cannot be compared to normal in a useful manner. Most of the controversy about the diagnosis of LPD has centered around the use of individual serum P levels. The timed endometrial biopsy relies on the endometrium as a bioassay of P over time. The endometrial biopsy has not been carefully validated in terms of its sensitivity or accuracy for the diagnosis of LPD. However, it remains the best current method for the diagnosis of LPD when the standard guidelines for its use are followed. As opposed to the other tests for LPD, awareness of the usefulness of the biopsy has increased as we have learned more about CL physiology. No current research method for the diagnosis of LPD appears to be a practical method that could be applied in the clinical setting. Specific secretory proteins from the endometrium and methods to measure hormone secretion that circumvent the secretory pattern hold promise for improved methods to diagnose LPD in the future.

Prevalence and manifestations of endometritis among women with cervicitis.

Thirty-five women referred from a clinic treating sexually transmitted diseases, because of suspected cervicitis, were studied for the presence of endometritis by transcervical endometrial biopsies and cervical and endometrial cultures. Fourteen (40%) of the patients had histologic evidence of endometritis. Findings that significantly correlated with endometritis included a history of intermenstrual vaginal bleeding, the presence of Chlamydia trachomatis, Neisseria gonorrhoeae, or Streptococcus agalactiae in the cervix, and the presence of serum antibodies to C. trachomatis or to Mycoplasma hominis.

Luteal phase defect: the sensitivity and specificity of diagnostic methods in common clinical use *

OBJECTIVE To assess the sensitivity and specificity of common clinical tests used for the diagnosis of luteal phase defect (LPD). DESIGN The sensitivity and specificity of these tests for predicting low integrated P levels over the luteal phase were calculated. SETTING Outpatient reproductive endocrinology and infertility clinic at a university medical center. PATIENTS Fifty-eight strictly defined normal women were used to determine normal integrated luteal phase P levels. The study population was a separate 34 women who either were normal (n = 15) or were being evaluated for infertility or recurrent abortion (n = 19). These 34 study subjects all had the following tests performed in the same menstrual cycle: daily reproductive hormone levels, daily assessment of preovulatory follicle size, late luteal endometrial biopsies, and BBT charts. MAIN OUTCOME MEASURES Basal body temperature, maximum preovulatory follicle size, dated endometrial biopsies, and serum P levels (single and multiple) were used in an attempt to predict which patients had low integrated P levels. RESULTS Unacceptably low sensitivity and/or specificity levels were found for the following tests: appearance of BBT charts, luteal phase length, and preovulatory follicle diameter. Timed endometrial biopsy was found to have marginally acceptable sensitivity and specificity levels whether dated by next menstrual period or midcycle events. The best test for the prediction of low integrated P was a single serum P level from the midluteal phase that was < 10 ng/mL (31.8 nmol/L) or a sum of three random serum P measurements that was < 30 ng/mL (95.4 nmol/L) (also obtained in the midluteal phase). CONCLUSIONS Luteal phase defect is a relatively uncommon but important cause of infertility and/or habitual abortion. The recommended test for the determination of LPD is a midluteal phase single serum P level < 10 ng/mL or the sum of three serum P levels that is < 30 ng/mL. The endometrial biopsy is a second line test that is only recommended when LPD needs to be evaluated in a treated cycle (ovulation induction or supplemental P).

High Serum Cortisol Levels in Exercise-Associated Amenorrhea

OBJECTIVE To determine whether basal cortisol levels are elevated in exercise-associated amenorrhea. DESIGN Survey, with hormone levels measured weekly for 1 month and patients followed clinically for 6 months. SETTING Volunteers were recruited through media advertisements and fliers. PARTICIPANTS Ninety-two women were enrolled; 71 (77%) completed the study. Subjects were grouped by menstrual and activity histories reported by a self-administered questionnaire. After 6 months, final groups were assigned: amenorrheic athletes, 19; eumenorrheic athletes, 35; a transition group of amenorrheic athletes who had resumed menses after entering the study, 7; and normal cyclic nonathletes, 10. INTERVENTIONS Four weekly resting blood samples (0800 to 1000 hours) were obtained and measured for cortisol, estradiol, progesterone, and prolactin levels. Lumbar bone mineral density was measured by dual-photon densitometry. MEASUREMENTS AND MAIN RESULTS Mean (+/- SE) cortisol levels were higher in amenorrheic athletes (585 +/- 33 nmol/L) than in eumenorrheic athletes (411 +/- 14 nmol/L), transition athletes (378 +/- 33 nmol/L), or nonathletic women (397 +/- 30 nmol/L) (P less than 0.01). Of nine women with abnormally high cortisol levels (greater than 579 nmol/L), eight were amenorrheic athletes, and one was a eumenorrheic athlete. Bone mineral density was lower in amenorrheic athletes than in the other three groups (P less than 0.01). CONCLUSIONS Increased glucocorticoid levels may be an etiologic factor in exercise-associated amenorrhea. High cortisol levels could also contribute to decreased bone density. The failure of amenorrheic athletes with hypercortisolemia to regain menses within 6 months suggests that they are at risk for a prolonged acyclic state.

Follicular development, ovulation, and corpus luteum formation in cryopreserved human ovarian tissue after xenotransplantation

OBJECTIVE To assess the competency of human frozen/thawed ovarian follicles matured in xenografts to form functioning corpora luteae after human chorionic gonadotropin (hCG) administration. DESIGN Prospective controlled animal study. SETTING University research laboratory. PATIENT(S) Three women (19, 28, and 36 years) who underwent oophorectomy. ANIMAL(S) Nineteen female severe combined immunodeficient (SCID) mice. INTERVENTION(S) Cryopreserved human ovarian tissues were grafted into the s.c. space of bilaterally oophorectomized SCID mice. All the animals were stimulated with pregnant mares serum gonadotropin (PMSG) for 4 weeks starting from 16 weeks after transplantation. Twelve animals were injected with hCG at the end of gonadotropin stimulation. MAIN OUTCOME MEASURE(S) [1] The rate of grafts with growing follicles, with antral follicles, and/or with corpora luteae. [2] The histologic assessment of follicles and corpora luteae. [3] The serum progesterone and estradiol level in animals with corpus luteum in the grafts. RESULT(S) [1] The rate of grafts with growing follicles and with corpora luteae was 33% to 100%, and 28% to 50%, respectively. [2] Corpora luteae in xenografts were all morphologically normal. [3] The progesterone levels were all above 3.0 ng/mL. CONCLUSION(S) This study showed that the cryopreserved human ovarian follicles can be matured to a stage at which they can form functioning corpora luteae in the host animal.

The future of human ovarian cryopreservation and transplantation: fertility and beyond.

OBJECTIVE To review the current progress in ovarian cryopreservation and transplantation and to discuss the obstacles with the clinical application of this technique. DESIGN The literature on ovarian cryopreservation and transplantation was reviewed to facilitate understanding and predict future directions. The studies related to this topic were identified through MEDLINE and other bibliographic databases, focusing on the most recent developments. CONCLUSION(S) The experimental evidence for low-temperature storage of ovarian tissue is encouraging. Although restoration of fertility with cryopreserved ovarian grafts has been successful in various animals, there are uncertainties about the optimum use of stored ovarian tissue in humans. Autotransplantation appears to be promising, but the potential risk of transmitting malignant cells in women with cancer is of great concern. The maturation of primordial follicles with xenotransplantation is encouraging, but the efficacy and the safety of this method need further investigation. Furthermore, the quality of oocytes that have been matured in a host animal is unknown. The development of in vitro culture systems for oocyte maturation is still in its infancy. There are many issues to be resolved in ovarian transplantation before the full clinical use of this emerging technique. Most of all, there is an urgent need to optimize the freeze/thaw procedure and to find the means to protect grafts from ischemia-reperfusion injury. Nevertheless, ovarian transplantation should prove to be clinically useful for women at risk for premature ovarian failure.