The Reproductive Endocrine Associates of the Massachusetts General Hospital: Fifteen Years of Integrated Clinical Practice and Investigation

Stephanie B. Seminara, Janet E. Hall, Ann E. Taylor, William F. Crowley, Jr. and Kathryn A. Martin

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Stephanie B. Seminara, Reproductive Endocrine Unit, BHX 505, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114.


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 Introduction
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 Typical cases: bench to...
 Case I
 Case II
 Case III
 Case IV
 Collaborative research with...
 Commitment to training
 Educational commitment
 References
 
The Reproductive Endocrine Associates is the clinical practice of the Reproductive Endocrine Unit, a division of the Department of Medicine of Massachusetts General Hospital (MGH). Founded in 1984, the Reproductive Endocrine Associates is focused on providing superior care to patients with a broad range of reproductive disorders. Moreover, because of its setting within a multidisciplinary research unit, the primary goal of this practice is to translate basic and clinical research insights to patient care as quickly as possible. This article aims to explore both facets of this unique practice–both as a reproductive endocrinology practice and as an integral link within an interdisciplinary research unit.

The Reproductive Endocrine Associates is composed of seven endocrinologists (six female, one male), all Board-certified in both internal medicine and endocrinology and metabolism. Patients are also seen by Clinical Fellows precepted by staff physicians in patient care sessions held daily and one evening per week. The physical layout of the clinic (861 ft2) includes one consultation room, two examination rooms, an ultrasound suite, and a teaching/coordination area for patients undergoing ovulation induction. The practice space is one floor below the administrative and professional staff offices, conference room, and research laboratory of the Reproductive Endocrine Unit. The close proximity of the clinic practice to the research space provides seamless professional continuity for the seven staff physicians, each of whom directs his/her own clinical research program. Patients are easily introduced to the newest protocols and therapeutic trials being conducted within the Unit. Although out-patient aspects of clinical investigation do take place within the practice space, almost all in-patient protocols are executed in the Mallinkrodt General Clinical Research Center (GCRC) on the MGH campus. The GCRC is a seven-bed, NIH-funded facility that is an invaluable resource for detailed studies of human reproduction.

The Reproductive Endocrine Associates has approximately 3200 patient-visits/yr. Over the past 15 yr, the number of patient-visits has increased 10-fold, and the faculty has doubled in size. For this uniquely situated practice, the largest percentage of new referrals comes from primary care physicians (41%). Nine percent are from other endocrinologists within the hospital, the Boston area, or around the world. Thirteen percent of patients are self-referred. The remainder of referrals derive from a variety of subspeciality services. Eighty-nine percent of the patients seen over the past 3 yr are female; 11% are male. The most common diagnostic categories seen within the practice include hyperandrogenic syndromes, hypergonadotropic hypogonadism, and hypogonadotropic hypogonadism (Fig. 1Go). The percentage of patients carrying specific diagnoses within each of these broad categories is summarized in Table 1Go. Due to the research interests of the Unit, patients with relatively rare diagnoses, including precocious puberty and virilizing ovarian/adrenal tumors, are also seen on a regular basis.



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Figure 1. Common diagnostic categories seen in the Reproductive Endocrine Associates.

 

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Table 1. Percentage of patients carrying specific diagnoses within major endocrine subdivisions

 

    Interfaces within a multidisciplinary research network
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The Reproductive Endocrine Unit, at its core, is a tightly interwoven collection of interdisciplinary research teams including Female Physiology, Male Physiology, Biochemistry, Genetics, and Assay Development. Although research interests span a wide spectrum from basic biology to clinical investigation, traditionally the Unit has focused on studies in humans. Each of the Reproductive Endocrine Associates staff physicians either leads or participates in one or more clinical research teams. Team meetings represent the cornerstone of intellectual activity within the Unit; hypotheses are first formulated and refined, protocols intensively reviewed and modified, primary data discussed, and publications planned.

Although other medical centers may use similarly integrated approaches to clinical care, the Reproductive Endocrine Unit is one of only two National Centers of Infertility Research funded by the NICHD and has received 10 yr of continuous funding. The broad goals of the Center currently are to understand 1) the intrafollicular environment in polycystic ovary syndrome (PCOS), 2) the role of gonadal proteins in determining fertility, 3) the control of FSH secretion, and 4) molecular defects in gonadotropin biosynthesis. These goals are integrated with the other "partner" National Center at 5-yr intervals. Therefore, different styles and approaches, representing the best reproductive science from two institutions, can be brought to bear on a single problem.

In addition, the Reproductive Endocrine Unit is the coordinating base of the Harvard-wide Reproductive Sciences Center, 1 of 17 Centers of Excellence also funded by the NICHD. This award is competitively bestowed upon research institutions that have established a critical mass of interdisciplinary investigators in reproductive biology. Composed of 28 investigators with 38 NIH grants, the Center provides critical core laboratories, consultations by core laboratory directors, and a Harvard-wide educational series in reproduction. Therefore, whether within the Reproductive Endocrine Unit, the National Center for Infertility Research, or the Reproductive Sciences Center, the clinicians of the Reproductive Endocrine Associates can avail themselves of a tremendously rich research network (Fig. 2Go).



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Figure 2. Relationship of the Reproductive Endocrine Associates to the Reproductive Endocrine Unit, National Center for Infertility Research, and the Reproductive Sciences Center.

 

    Typical cases: bench to bedside transitions
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Some of the most important contributions of the Reproductive Endocrine Unit over the past 2 decades include 1) the development of GnRH analogs for the treatment of precocious puberty, now the standard of care worldwide (FDA approved), 2) the optimal use of pulsatile GnRH to induce ovulation in women (similarly FDA approved) and sexual maturation in men with endogenous GnRH deficiency, 3) the use of GnRH analogs as a medical therapy for uterine leiomyomata, 4) the definition of the neuroendocrine defects in PCOS, 5) the elucidation of the physiology of the gonadal proteins (inhibin, activin, and follistatin), and 5) the exploration of genotype/phenotype correlations in a variety of reproductive disorders. None of these advances would have been possible without committed patients who have been invaluable collaborators in the research process. The following sections describe some typical cases seen in this practice. They are selected not to focus on specific management points per se but, rather, to illustrate the practice’s bench to bedside philosophy, a dynamic frame of reference that transforms a patient’s clinical presentation to an investigative question.


    Case I
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MO is a 30-yr-old woman who originally presented as an adolescent with primary amenorrhea and was told she would not be able to have children. Since then, she had been maintained on conjugated estrogen and progesterone therapy. When she was interested in fertility, she presented to the Reproductive Endocrine Associates for a second opinion. Her evaluation was notable for a history of 1) normal adrenarche, 2) low gonadotropin levels and a lack of a gonadotropin response to a single dose GnRH test but otherwise normal endocrine axes, 3) normal brain imaging, and 4) an inability to smell.

To understand the pathophysiology of hypogonadotropic states, the Reproductive Endocrine Unit has employed a tandem approach, studying both normal subjects and those with an absent program of endogenous GnRH secretion. Primate studies were the first to demonstrate that GnRH is secreted in a pulsatile fashion from the hypothalamus (1). Due to the short half-life of GnRH, LH and free {alpha}-subunit have been used as markers of GnRH secretion in the human. Within the Reproductive Endocrine Unit and the GCRC, hundreds of frequent sampling studies (every 5–10 min) have been performed to create robust normative databases of hypothalamic GnRH frequency at different stages of male and female development and across different stages of the menstrual cycle (Fig. 3Go). These studies have ultimately permitted an understanding of the spectrum of neuroendocrine abnormalities in patients with reproductive disorders. Frequent sampling studies in patients with hypogonadotropic hypogonadism (with or without anosmia) have allowed the identification of discernible abnormalities of GnRH secretion, including a complete absence of GnRH pulsatile activity, enfeebled but present LH pulses, and other abnormal patterns (2).



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Figure 3. Dynamics of pulsatile LH secretion in the early, mid-, and late follicular phases (EFP, MFP, and LFP), during the midcycle surge (MCS), and the early, mid-, and late luteal phases (ELP, MLP, and LLP) in normal women. Note the increase in LH/GnRH pulse frequency through the midfollicular phase, the dramatic increase in LH amplitude at the midcycle surge, and the slowing of the GnRH pulse generator through the luteal phases. FSH, estradiol (E2), and progesterone (P4) levels are also depicted across the cycle (36 ).

 
During the early years of the Reproductive Endocrine Unit, the administration of a physiological regimen of GnRH through a portable miniinfusion pump was demonstrated to induce normal puberty and fertility in GnRH-deficient men and women (3, 4). Over the past decade, the Unit has continued to refine the GnRH pump as a clinical and research tool. Because the pump can be programmed to different settings of GnRH dose and frequency, it is actively used as a probe of normal hypothalamic-pituitary-gonadal physiology in both men and women (5, 6, 7). Many patients with hypogonadotropic hypogonadism choose the pump for formal fertility therapy. In men, the induction of spermatogenesis may take months to years. However, in women, the development of a preovulatory follicle is seen within 2 weeks of pulsatile GnRH therapy.

After a baseline study demonstrated a complete absence of endogenous LH pulsations in MO, administration of iv pulsatile GnRH was begun. As documented by the Unit, the use of a closed system of prolonged iv cannulation is safe in the setting of careful out-patient monitoring (8). Similar to the vast majority of hypogonadotropic patients seen in the Reproductive Endocrine Unit, MO had an excellent response to pulsatile GnRH (9, 10). She recruited a single dominant follicle, mounted her own endogenous LH surge, and conceived during that cycle, leading to a healthy singleton pregnancy (Fig. 4Go).



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Figure 4. Serum levels of LH, FSH, estradiol (E), and progesterone (P) in patient MO with hypogonadotropic hypogonadism undergoing exogenous pulsatile GnRH replacement. Patient MO received 75 ng/kg pulsatile GnRH, iv, and had a single dominant follicle seen on ultrasound. Note the rising estradiol levels through her follicular phase, the endogenous LH surge, and the rising progesterone levels through the luteal phase. The positive serum hCGß symbol indicates pregnancy.

 
Similar to females, men with GnRH deficiency may qualify for pulsatile GnRH therapy in the Unit’s "pump program," if they demonstrate a complete absence of LH pulsatility. Twenty to 25 men participate in the program at any time, whether the clinical goals are virilization or fertility. While undergoing prolonged therapy, men receive incremental increases in GnRH dose until serum testosterone levels are in the normal male range. When testicular volume reaches a certain threshold size, ejaculates are examined for evidence of spermatogenesis (9).

By critically reviewing its 15-yr experience with hypogonadotropic hypogonadism, the Reproductive Endocrine Unit has demonstrated that approximately one third of patients have at least 1 other family member with hypogonadotropic hypogonadism, anosmia, or delayed puberty (11). Approximately 300 patients with GnRH deficiency (with or without anosmia) have been entered into a relational database. Combined with extensive family pedigrees and abundant biochemical data, this database will facilitate the longitudinal follow-up of patients necessary for sophisticated genetic studies. Although GnRH deficiency is a rare disease, understanding the genes that cause this condition will add fundamental insights into more common disorders of GnRH secretion, including constitutional delay of puberty and hypothalamic amenorrhea.

Follow-up. After delivering her first child, MO resumed estrogen and progesterone replacement therapy. One year later, she returned to the Reproductive Endocrine Associates for further ovulation induction with the GnRH pump. She is now the mother of two healthy daughters.


    Case II
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LB is a 31-yr-old woman who presented with secondary infertility of 1-yr duration. Despite a lengthy history of oligomenorrhea, she conceived spontaneously 3 yr earlier. Desiring a second child, but having only one or two menses per yr, LB presented to another facility for ovulation induction. She was referred to the Reproductive Endocrine Associates when other providers were unable to obtain any follicular response to high doses of recombinant FSH preparations.

The Reproductive Endocrine Associates is one of the few medical practices in the country to perform ovulation induction. Approximately 10% of all new referrals are for either primary or secondary infertility. A thorough history and examination are essential in the infertility population so that patients can be directed to the appropriate level of medical or surgical intervention. In LB’s case, such a review revealed that 3 yr earlier, she did not lactate postpartum. This, coupled with her negligible response to recombinant FSH as sole therapy, suggested that LB might have some degree of pituitary insufficiency. More detailed endocrine testing revealed secondary hypothyroidism in addition to her hypogonadotropic hypogonadism; a magnetic resonance imaging scan demonstrated a paucity of pituitary tissue. Because both LH and FSH appear to be required for appropriate steroidogenesis during folliculogenesis (12, 13, 14), ovulation induction was undertaken in the Reproductive Endocrine Associates using human menopausal gonadotropin, a gonadotropin preparation containing both LH and FSH.

Within the practice, multiple choices for ovulation induction are available, including clomiphene citrate, exogenous gonadotropins, and pulsatile GnRH. Despite the availability of newer recombinant preparations, all gonadotropin formulations are associated with a high rate of multiple gestation (as high as 24–50% in hypogonadotropic patients). In the Reproductive Endocrine Associates, gonadotropin therapy is administered in a step-up protocol to determine the threshold dose necessary for follicular development as originally pioneered by Brown and colleagues (15). This approach is used for all patients requiring exogenous gonadotropins for ovulation induction regardless of the specific diagnosis (i.e. hypogonadotropic hypogonadism, anovulation, idiopathic, etc.). An on-site expert ultrasonographer provides the required continuity to patients both within and between ovulation induction cycles. Within each cycle, the size of each follicle is monitored in combination with same day estrogen measurements, allowing subtle titration of gonadotropin doses. The physicians’ relatively conservative dosing approach with exogenous gonadotropins has yielded the lowest rate of multiple gestation in the literature (14.8%) while maintaining pregnancy rates comparable to those reported by other ovulation induction centers (10). There has never been a case of clinical ovarian hyperstimulation, a potentially life-threatening complication, within the ovulation induction program.

Pulsatile GnRH, which maintains normal pituitary feedback mechanisms, theoretically decreases the risk for multiple folliculogenesis and multiple gestation. A head to head comparison of pulsatile GnRH vs. exogenous gonadotropin therapy was conducted by the Reproductive Endocrine Unit in 41 patients with hypogonadotropic amenorrhea. Using life table analysis, the cumulative chance for conception was higher with GnRH therapy (96%) compared with exogenous gonadotropins (72%) (10). Although the risk of multiple gestation was low in both groups and not significantly different, all higher order multiple gestations (triplets) occurred in the gonadotropin-treated group.

Multiple gestations have far-reaching consequences, not only emotionally and financially to the couple, but to the health care system as a whole. To draw attention to this important issue, members of the Unit reviewed hospital charges for over 13,000 women undergoing assisted-reproductive technologies at Brigham and Women’s Hospital over a 5-yr period (16). The predicted charges for a singleton delivery were $9,845; for twins, $37,947; for triplets, $109,765. It was estimated that this teaching hospital would have saved $3 million dollars/yr if their multiple gestations due to assisted reproduction had been singletons. The observations from this study have had a far-reaching impact in the field of infertility; they continue to renew the commitment of the Reproductive Endocrine Unit and the clinic practice to improving the safety and efficacy of ovulation induction.

If a patient fails to conceive using exogenous gonadotropins, she is referred for in vitro fertilization (IVF). Uncovering prognostic factors that may help to determine which patients are more likely to have successful outcomes in IVF has been a challenge for many investigative groups. Recent studies by the Reproductive Endocrine Unit in collaboration with investigators at Brigham and Women’s Hospital have focused on the newly characterized gonadal proteins, inhibin A and B, as predictors of outcome in assisted reproduction (17). Conclusions from this work suggest that even in the prescreened population of patients currently being accepted into IVF programs, the combination of lower FSH and higher inhibin B levels is associated with a greater chance for pregnancy.

Follow-up. Using a human menopausal gonadotropin preparation (LH and FSH) at a dose of 150 U for 8 days, LB developed a single dominant follicle with a peak serum estradiol level of 460 pg/mL. She then received hCG for ovulation, followed by intrauterine insemination. A follow-up ultrasound at 6 weeks showed a single gestational sac and fetal heartbeat.


    Case III
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MD is a 21-yr-old woman who presented with oligomenorrhea (fewer than two menses per yr). Physical examination was notable for obesity; extensive areas of acanthosis nigricans on the neck, back, axillae, and between the breasts; and facial hirsutism.

PCOS is the most common endocrinopathy in premenopausal women. For years, investigators, clinicians, and patients have struggled with the terms polycystic ovary morphology, an ultrasound finding that can be seen in up to 22% of normally cycling women, and polycystic ovary syndrome, defined as chronic anovulation and hyperandrogenism (18). Of women with a diagnosis of PCOS within the practice, the most common presentations include oligomenorrhea (24%) and hirsutism (22%) as well as acne, other menstrual irregularities, infertility, scalp hair loss, and weight gain. Although PCOS is a heterogeneous disorder, considerable attention has focused on the insulin resistance seen in this syndrome, as suggested in MD by the presence of acanthosis nigricans. Although PCOS-related insulin resistance appears be a precursor of noninsulin-dependent diabetes mellitus (NIDDM) (19, 20), patients with PCOS may also be at increased risk for coronary artery disease (21, 22, 23) and dyslipidemia (24, 25).

Unlocking the pathophysiology of PCOS has been difficult. Several investigators have noted a high prevalence of obesity in PCOS, and a number of groups have described increased amplitude of LH secretion in these women. Investigators in the Reproductive Endocrine Unit were the first to demonstrate an increase in LH pulse frequency, suggesting hypothalamic involvement in this disorder (26). Despite this growing body of data, the relationship between body composition and gonadotropin secretion had never been studied in detail. Unit investigators have now examined gonadotropin abnormalities across a spectrum of body weight in PCOS patients (27). Almost all patients (92%), whether obese or lean, were shown to have an elevated LH to FSH ratio. Moreover, LH correlated strongly in an inverse fashion with body fat. That the relationship between LH and body fat is a continuously distributed variable suggests that LH and obesity are strongly related contributors to the PCOS phenotype. Thus, earlier views that lean and obese PCOS patients represent distinct etiological subsets may not be correct. PCOS may actually encompass one continuous diagnostic spectrum, a concept that has implications for genetic studies of this disorder.

The metabolic, reproductive, and cosmetic issues facing PCOS patients create many clinical challenges. Management of oligomenorrhea is usually accomplished through ovarian suppression with oral contraceptive therapy. However, both the estrogen and progestin components of oral contraceptives can exacerbate glucose intolerance and hyperinsulinemia (28). Although obesity is common in PCOS, insulin resistance is independent of body weight. Therefore, practitioners in the Reproductive Endocrine Associates aggressively evaluate each PCOS patient for abnormalities in glucose metabolism. Information garnered from oral and iv glucose tolerance testing is being used to develop simpler tests of insulin resistance for clinical practice. Antihyperglycemic and insulin-sensitizing agents, such as metformin and troglitazone, have been shown to reduce serum insulin levels and androgens in some PCOS patients (29, 30).

Patients with PCOS often have very brisk responses to exogenous gonadotropins, putting them at risk for ovarian hyperstimulation. The Reproductive Endocrine Associates has had excellent success in ovulation induction in PCOS patients using low dose gonadotropin therapy without GnRH agonist down-regulation (31). Pulsatile GnRH is also effective in approximately 60% of PCOS patients (32). Recent data suggest that the role of antihyperglycemic agents in PCOS may extend beyond hyperandrogenism to the management of oligomenorrhea and infertility. Metformin has recently been shown to increase the ovulatory response to clomiphene citrate in obese women with PCOS (33). Although not FDA approved for the treatment of anovulatory infertility, metformin may become one of a new family of fertility treatments for this population.

Follow-up. Patient MD met diagnostic criteria for NIDDM, making her one of a significant percentage of PCOS patients who exhibit impaired glucose tolerance (31.1%) and NIDDM (7.5%) at a young age (20). She was started on a formal weight reduction program, nutritional counseling, and metformin therapy. Spontaneous monthly menses resumed after 2 months of therapy, and her ovulatory status was confirmed with luteal phase progesterone levels. Her glycemic control continues to improve.


    Case IV
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BF is a 35-yr-old female with a history of metastatic gestational trophoblastic disease treated with methotrexate, etoposide, and actinomycin D. At the time of her original presentation, detection of placental hCG to monitor remission and early recurrence of trophoblastic tumors was difficult due to chemical homologies between hCG and LH. An hCG assay based on two high affinity antipeptide monoclonal antibodies (one directed against the carboxyl-terminal of the ß-subunit of hCG and one directed against the {alpha}-subunit of glycoprotein hormone) had recently been developed (34). Whereas conventional assays demonstrated persistent levels of hCGß, the newer immunoradiometric assay, with its greater sensitivity and specificity, demonstrated that BF had indeed achieved clinical remission 6 months after chemotherapy. Unfortunately, BF’s laboratory studies demonstrated a LH level of 87.2 IU/L and a FSH level of 64 IU/L, consistent with hypergonadotropic hypogonadism. She presented to the Reproductive Endocrine Unit to discuss her ovarian function and future fertility.

By definition, premature ovarian failure (POF) is amenorrhea and an elevated FSH level above the normal range in a woman under age 40 yr. POF is one of the most devastating diagnoses for women in their reproductive years. Some of the more common etiologies for this condition include primary gonadal disorders (gonadal dysgenesis or Turner syndrome), autoimmunity, and chemotherapy/radiation therapy. The biochemical hallmark of ovarian failure (elevated FSH levels) and its relationship to ovarian function have not always been clear. In perimenopausal women, elevated FSH levels can be documented before the cessation of menses. However, elevated FSH levels do not always mean that fertility is not possible. A number of pregnancies have been reported in women with POF, often during estradiol therapy.

Because of this latter observation, investigators within the Reproductive Endocrine Unit explored whether estrogen therapy could improve ovarian function in women with POF by performing a randomized cross-over trial (35). Thirty-seven patients, including patient BF, participated in this longitudinal study. Serial observations via transvaginal ultrasound demonstrated high levels of spontaneous folliculogenesis in these patients regardless of their treatment assignment. Overall, approximately 80% of the women grew a cyst greater than 10 mm, and close to half of the women ovulated. These observations demonstrate that the elevated FSH levels used as the biochemical hallmark of this condition occur much earlier than complete follicular dysfunction. Although estrogen replacement therapy did not improve fertility rates per se, it did not impede episodic follicular development.

Follow-up. Patient BF underwent weekly blood sampling and pelvic ultrasonography during the cross-over trial of estrogen replacement. As she and her husband still desired fertility, BF used the information on follicle development provided by the serial ultrasound monitoring to coordinate the timing of intercourse. She conceived during one of her monitored cycles and delivered a healthy child approximately 3 yr after her last chemotherapy treatment.


    Collaborative research with industry: the Clinical Trials Unit
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One of the newest additions to the clinical services provided by the Reproductive Endocrine Associates is the Clinical Trials Unit. This Unit has assembled the infrastructure to facilitate the transfer of new drugs and technologies to patients as quickly as possible. The Reproductive Endocrine Associates, with its extensive referral base, has facilitated the recruitment of patients to a variety of clinical trials. This Clinical Trials Unit works hand in hand with the Reproductive Endocrine Unit’s Reference Laboratory, allowing industrial sponsors access to the broad normative database that has been accrued in the Unit over the past 2 decades. The Reference Laboratory has received national recognition for the development of high quality reagents and innovative testing and provides rapid turn-around time and electronic user-friendly interfaces for accessioning and results reporting. The Unit is currently participating in studies on the use of insulin-sensitizing agents in PCOS, recombinant gonadotropins to induce spermatogenesis, and new GnRH antagonists for various reproductive disorders in both men and women.


    Commitment to training
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The Reproductive Endocrine Unit is an integral part of the General Endocrine Fellowship Training Program of Massachusetts General Hospital. Most endocrine programs include little or no formal training in reproductive endocrinology. However, the Reproductive Endocrine Unit and its clinical practice provide a strong tradition of excellence in clinical and research training. For first year Fellows in endocrinology, the Reproductive Endocrine Associates group practice is the nucleus of that training commitment. Patient care sessions occur daily, and every Fellow is partnered with one staff clinician in a year-long clinical mentorship. Fellows see primarily new patients so they can perform evaluations at the time of initial presentation. At the conclusion of the Fellowship training, the patients are transferred to the staff physicians rather than to new Fellows, so there is no loss of physician continuity. Fellows perform dynamic pituitary and glucose tolerance testing, observe ovarian ultrasounds, and participate in the management of ovulation induction cases with the staff physician. They may also participate in research admissions to the GCRC.

This commitment to training extends well beyond the fellowship years. Over the past 2 decades, approximately 50 Fellows have been trained in clinical and laboratory research within the Unit. The vast majority of these trainees sustain active academic careers and have been successful in garnering NIH or equivalent independent research support. The Unit has established a mentorship program for women and minorities particularly interested in pursuing academic careers in reproduction.


    Educational commitment
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The Reproductive Endocrine Associates has a strong commitment to education. Each year, staff members organize a weekly Clinical Conference Series, addressing a broad spectrum of topics within reproductive medicine. Speakers are invited from within the Reproductive Endocrine Unit, the Pediatric Endocrine Unit, Gynecology, Urology, Psychiatry, as well as from outside the institution. These lectures provide a core curriculum in clinical reproductive endocrinology for the first year Fellows. In the first 8 weeks, the lectures cover practical management issues of common reproductive problems. Over the ensuing 10 months, the speakers integrate clinical and basic research principles and their clinical applications. Approximately four sessions per yr are devoted to the presentation and management of complex reproductive cases. The Unit also conducts a weekly Journal Club. Articles may be chosen on any aspect of reproductive biology, whether clinical or basic. Assembling individuals from many different domains of research adds tremendous diversity to the discussion and commentary of each journal selection.

The Reproductive Endocrine Unit also has established a yearly curriculum for the Harvard-wide Reproductive Sciences Center Basic Science Seminar Series. Speakers come almost exclusively from outside MGH. Before the seminar, speakers spend a day within the Unit, visiting individually with staff members and Fellows to discuss specific research projects. Outside the Reproductive Endocrine Unit, the clinical staff participate in teaching at a national level. Activities of the staff include Clinical Symposia and "Meet the Professor" sessions at the Annual Endocrine Society meeting, continuing education courses sponsored by The Endocrine Society, and menopause symposia at the American College of Physicians.

In summary, the Reproductive Endocrine Unit and its associated clinical practice, the Reproductive Endocrine Associates, work synergistically in a dual mission of clinical care and clinical investigation for patients with reproductive disorders. This unique coupling occurs for multiple reasons, including 1) the ability of the staff to recognize that human conditions represent powerful physiological opportunities for investigation; 2) the firm belief that continual communication between clinical and basic research teams is required to improve patient care; 3) the continued commitment of all faculty members to make the most recent advances in therapy available to patients; and 4) the generosity of patients who share their time and enthusiasm.

Received February 8, 1999.

Revised March 12, 1999.

Accepted March 18, 1999.


    References
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  1. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. 1978 Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science. 202:631–633.[Medline]
  2. Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley Jr WF. 1987 The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab. 64:283–291.[Abstract]
  3. Hoffman AR Crowley Jr WF. 1982 Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. 307:1237–1241.[Abstract]
  4. Crowley Jr WF, McArthur JW. 1980 Stimulation of the normal menstrual cycle in Kallmann’s syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab. 51:173–175.[Abstract]
  5. Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley Jr WF. 1987 Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J Clin Endocrinol Metab. 64:1179–1185.[Abstract]
  6. Finkelstein JS, Badger TM, O’Dea LStL, Spratt DI, Crowley Jr WF. 1988 Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells. J Clin Invest. 81:1725–1733.[Medline]
  7. Martin KA, Welt CK, Taylor A, Smith JA, Crowley Jr WF, Hall JE. 1998 Is GnRH reduced at the midcycle surge in the human? Evidence from a GnRH-deficient model. Neuroendocrinology. 67:363–369.[CrossRef][Medline]
  8. Hopkins CC, Hall JE, Santoro N, Martin KA, Filicori M, Crowley Jr WF. 1989 Closed intravenous administration of gonadotropin-releasing hormone: safety of extended peripheral intravenous catherization. Obstet Gynecol. 74:267–270.[Abstract]
  9. Whitcomb RW, Crowley Jr WF. 1990 Clinical review 4: diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. J Clin Endocrinol Metab. 70:3–7.[Medline]
  10. Martin KA, Hall JE, Adams JM, Crowley Jr WF. 1993 Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 77:125–129.[Abstract]
  11. Waldstreicher J, Seminara SB, Jameson JL, et al. 1996 The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. 81:4388–4395.[Abstract]
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