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Select a topic from this list to view a detailed description of the study:
1) Neuroendocrine & Gonadal Control of Male Reproduction
William F. Crowley (PI)
Project Number: 2 U54HD28138
Source: NIH
Period: 5/1/91-3/31/05The Harvard-wide Specialized Center for Reproduction brings to bear four investigative groups and several novel approaches to elucidating the neuroendocrine and gonadal control of reproduction in the male. Two of the projects focus upon the mechanisms underlying the neuroendocrine component of reproduction, while the other two explore the gonadal level, investigating both the seminiferous tubular control of spermatogenesis as well as Leydig cell control of steroidogenesis.
In Project I, Dr. William Crowley employs tandem phenotyping and genotyping approaches in patients with idiopathic hypogonadotropic hypogonadism (IHH). This is a human model in which a series of genetic defects result in failure of the neuroendocrine component of sexual maturation. In Project II, Dr. Ursula Kaiser explores the GnRH receptor’s second messenger pathways determining the differential expression of gonadotropin genes using LH?T2 cells which are of gonadotrope origin. In Project III, Dr. Patricia Donahoe examines the effects of Muellerian inhibiting Substance (MIS) upon steroidogenesis using the CYP17 gene as well as Leydig cell lines to explore the second messengers activated by the type II MIS receptor. In addition, she charts the developmental expression of this receptor and correlates it with steroidogenesis.
These projects are all highly synergistic and interactive. In addition, a common educational program provides a continuation of the correct climate both to train young investigators and provide for a mechanism of their emergence to independence.
2) Training Grant in Developmental and Reproductive Biology
William F. Crowley (PI)
Project Number: T32 HD07396
Source: NIH
Period: 7/15/91 – 4/30/07The Reproductive & Developmental Biology Training Program at the Massachusetts General Hospital provides its trainees with an intensive research experience in basic and/or clinical investigation under the attentive mentorship of a skilled faculty and complemented by a strong didactic program underpinning the sciences of reproductive and developmental biology. Trainees are selected from a highly talented applicant pool of M.D.’s, M.D./Ph.D.’s, or Ph.D.’s on the basis of their prior academic and/or research accomplishments, a strong future commitment to an academic career in biomedical investigation, and a personal interview indicating their proper motivation and future potential.
The PI (William Crowley) is a Professor of Medicine at Harvard Medical School and the Director of two NIH-funded Centers. He is an established senior scientist and recognized mentor who shares the governance of this program with an experienced committee of senior faculty members (Drs. Patricia Donahoe, Joel Habener, and Janet Hall) who serve as Co-Directors. The total training faculty consists of 13 active, well-funded scientists whose diverse expertise and investigative interests line a spectrum of reproductive and developmental research from fundamental developmental biology to bench-to-bedside translational clinical investigations.
Trainees are closely supervised by an active and individualized mentorship program overseen by the senior faculty and are encouraged to interact extensively with junior faculty who typically serve as in a co-mentorship role. An extensive program of rigorous didactic sessions interlaces tightly with individually strong, independent laboratory programs that remain at the heart of the trainees’ program and complements their 2-3 years of research experience. Typically, the training period involves several additional years as junior faculty that permits the consolidation of skills required for maximal competitiveness for subsequent independent support, the ultimate goal of their training program.
Click here to view a list Dr. Crowley's current and former trainees.
Research facilities (27,000 ft2) are fully equipped and recently modernized laboratories dedicated to the training faculty. The institutional investigators are highly funded by the NIH, the environment is superb, and reinforcement from the NIH Reproductive Sciences Center program is substantial. The track record of past trainees indicates substantial leadership in reproduction. [Click here to view Dr. Crowley’s list of current and former trainees.] This training grant represents a critical stabilizing element in all of these individual research programs and is thus a crucial link that enables talented trainees to achieve subsequent independent careers in Reproduction and Developmental Biology through stable funding, mentored research projects, and a rich didactic program.
3) Male Reproductive Physiology in the Human
William F. Crowley (PI)
Project Number: 5 R01 HD15788
Source: NIH
Period: 7/1/81-6/30/07Using the human disease model of men with idiopathic hypogonadotropic hypogonadism (IHH), it is possible to: a) control the timing and pace of their testicular maturation via administration of either exogenous gonadotropins or pulsatile GnRH; b) manipulate their gonadal sex steroid hormonal milieu by administration of steroid hormone inhibitors; and c) vary the dose and frequency of their hypothalamic input of GnRH. This ability to clamp the hypothalamic input to their pituitary via GnRH and contrast the responses of IHH men with those of normal and castrate men (whose hypothalamic-pituitary axis is unconstrained) allows us to dissect the hypothalamic from pituitary sites of action and address several physiologic issues that are not otherwise approachable in the human.
In Specific Aim #1, we explore the relative roles of gonadal sex steroids and Inhibin B (IB) in restraining FSH secretion across the full spectrum of gonadal development, where serum IB levels vary from prepubertal levels to those of normal adult men. Our preliminary results suggest that their relative roles appear to change during gonadal maturation. It also permits us to understand the role of the frequency of GnRH in FSH feedback and thus place it in context with both sex steroids and IB.
In Specific Aims #2 & 3, this model allows us to test the ability of FSH to increase Sertoli and germ cell number, testicular size, and sperm counts when administered to IHH men with immature gonads, and to then compare these results with those obtained when FSH stimulation is accompanied by that of LH via pulsatile GnRH therapy. During such studies we also have access to testicular tissue in these men and thus can validate both MIS and IB as markers of Sertoli cell numbers, proliferation, and maturation in a quantitative and statistically valid fashion that has not been previously possible. In collaboration with Dr. Martin Dym, we perform quantitative histomorphometry on these maturing gonads via serial testicular biopsies prior to and following four months of therapy. We then correlate these histologic findings with serial measurements of IB and MIS as well as other clinical and biochemical aspects of gonadal maturation.
Finally, in Specific Aim 4, the availability of serial testicular tissue in these men during Sertoli and early germ cell development allows us to gain insight into the specific genes activated in the human during early testicular development. These studies offer a unique approach to gain new insights into the physiology and developmental biopsy of the male reproductive axis. They also lay the groundwork that provides a context for the exploration of new tools to gain further insights into the complexities of reproductive dysfunction in the male.
4) The Genetics of Polycystic Ovarian Syndrome
William F. Crowley (PI)
Project Number: U01 HD44417
Period: 9/26/02-3/31/07The polycystic ovarian syndrome (PCOS) is a phenotypically complex disorder affecting 5% to 10% of women of reproductive age. Its protean manifestations include hyperandrogenemia, insulin resistance with glucose intolerance and an increased incidence of Type II diabetes, and a diffuse metabolic syndrome demonstrating many predisposing risk factors for early cardiovascular disease.
Given our past experience with phenotyping and demonstrating a striking familial tendency of this syndrome, we have initiated a unique collaboration with deCODE Genetics and the Icelandic population to identify the genes associated with this condition. Using Icelandic families, the Icelandic genealogy and the Icelandic health care system, we are exploring the genetic basis for this condition. We then plan to map the genotype/phenotype relationships in Icelandic women and contrast them to US women, to identify the male phenotype within the PCOD families, and to identify the long-term health impact of this condition in women and in men (including the incidence of diabetes, cardiovascular disease, and stroke using the Icelandic healthcare database).
Due to the unique combination of the genotyping facilities and statistical capabilities of deCODE Genetics, access to the Icelandic population and their genealogic history, the Icelandic health care database, and the homogeneous Icelandic population, these studies are much less difficult to undertake. In more heterogeneous populations where such extended family relationships with this disorder are unusual, it would be significantly more expensive and time-consuming to do the research.
5) Neuroendocrine Control of Reproduction in the Female (Training Grant)
Janet E. Hall (PI)
Project Number: K24 HD01290
Period: 6/14/99-5/31/04
Source: NIH/NICHD-NIARecent studies have highlighted the importance of Patient-Oriented Research, drawing attention to the relatively small number of investigators trained to conduct high-quality clinical research. Appropriate and committed mentoring is critical for attracting talented individuals to clinical investigation and providing them with quality training and career guidance at three specific points: 1) at the premedical and medical school level; 2) during specialty and subspecialty training; and 3) during the transition from Fellow to independent investigator.
Mechanisms have been established within the Reproductive Endocrine unit and Massachusetts General hospital, within the Partner’s Healthcare System and Harvard Medical School to recruit and provide the environment for training of such individuals.However, the success of each of these initiatives is critically dependent on the availability of qualified investigators who can teach by example and are committed and able to invest in mentoring the next generation. There is a particular need for rigorous and innovative patient-oriented investigation in the areas of reproductive health in women. This grant provides the mechanism for supporting the mentoring activities of the investigator, while ensuring that her own patient-oriented research efforts are not compromised.
An important area of the PI’s research is focused on the complex interrelationships between FSH, estradiol and the inhibins. While both estradiol and the inhibins appear to contribute to the negative feedback control of FSH in women, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. Coordinated secretion of estradiol and the inhibins is altered in reproductive aging (estradiol increased in the presence of low inhibin) and African-American women (increased estradiol relative to Caucasian women with identical inhibin levels). Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology.
A complementary area of research involves the neuroendocrine mechanisms that contribute to aging of the female reproductive system in the human. The underlying hypothesis is that there are changes in the physiology of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and pituitary responsiveness in women that are specifically related to aging. This project studies the age-related changes in pituitary function in postmenopausal women (using both clinical approaches and autopsy studies) and the age-related changes in gonadal steroid feedback on the hypothalamic-pituitary axis, investigating both negative and positive feedback and using PET scanning to address the sites of action of estrogen action in the brain. The information derived from these studies provides basic insights into the effects of aging on the brain in women and may also have important implications for our understanding of the potential neuroendocrine contributions to reproductive aging and menopause.
Taken together, these projects provide a strong program for training in clinical investigation that utilizes a variety of methodologies to address critical hypotheses in reproductive biology.
6) Aging and the Hypothalamic-Pituitary Reproductive Axis
Janet E. Hall (PI)
Project Number: R01 AG13241
Period: 8/1/95-02/28/08
Source: NIH/NICHDThe broad goal of this project is to examine the neuroendocrine mechanisms that contribute to aging of the female reproductive system in the human. The underlying hypothesis is that there are changes in the physiology of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and pituitary responsiveness in women that are specifically related to aging. Our studies concentrate on postmenopausal women in whom the absence of gonadal function makes it possible to investigate the independent effects of aging and gonadal hormones on the brain. Specifically, the age-related changes in pituitary function and the age-related changes in gonadal steroid control of hypothalamic and pituitary function are being explored.
In Aim 1, the pituitary contribution to the decline in gonadotropin secretion with age is being determined in vivo and in vitro, addressing the hypothesis that a decrease in pituitary response to GnRH-which is independent of changes in hypothalamic GnRH input-occurs with aging. Pituitary responsiveness to GnRH is being assessed in the presence of GnRH receptor blockade to control for antecedent GnRH stimulation. This aim also explores whether the decline in gonadotropin secretion that occurs with aging in postmenopausal women is associated with a decrease in gonadotrope number using human autopsy specimens.
Aim 2 investigates whether the negative feedback of estradiol on gonadotrope responsiveness to GnRH is altered with aging in vivo and whether there are changes in estrogen receptor ??(ER?? in vitro. Aim 3 determines the effect of aging on gonadotropin responses to short-term negative and positive feedback effects of gonadal steroids. In these studies, PET scanning is used to differentiate hypothalamic from pituitary sites of action. This aim investigates the hypotheses that negative feedback effects of estradiol are exerted at both the hypothalamic and pituitary levels in postmenopausal women and are maintained with aging, and that estrogen positive feedback is exerted primarily at the pituitary level in the human and declines with age in postmenopausal women.
The information derived from these studies will provide basic insights into the effects of aging on the brain in women and the degree to which aging affects the hypothalamic and pituitary responses to gonadal steroids. These studies may also have important implications for our understanding of the potential neuroendocrine contributions to reproductive aging and menopause.
7) FSH, Estradiol and Inhibin in Female Reproduction
Janet E. Hall (PI)
Project Number: R01 HD42708
Period: 7/10/02-5/31/07
Source: NIH/NICHDThe broad goal of this project is to continue to investigate the neuroendocrine and gonadal regulation of reproduction in women, focusing on the complex interrelationships between FSH, estradiol and the inhibins. There is now evidence that both estradiol and the inhibins contribute to the negative feedback control of FSH in women. However, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. There are two unique circumstances in which we have shown that the coordinated secretion of estradiol and the inhibins is altered: in reproductive aging, estradiol levels are increased in the presence of low levels of inhibin, while in African-American women (relative to Caucasian women), normal reproductive cycles are characterized by increased estradiol in the face of identical levels of inhibin. Determining the mechanisms responsible for these changes provides us with important insights into the interactions of inhibin, estradiol, and gonadotropins in normal reproductive physiology.
Aim 1 focuses on the relative contributions of estradiol and the inhibins to the negative feedback regulation of FSH secretion during the follicular and luteal phases of the normal menstrual cycle (using normal and GnRH-deficient women in whom estrogen secretion is altered by aromatase blockade). Aim 2 seeks to elucidate the mechanisms underlying the dichotomy between estradiol and inhibin secretion in reproductive aging by investigating inhibin and estradiol secretion in response to fixed FSH stimulation, as well as by determining the number of granulosa cells, inhibin subunit expression, and aromatase function and expression in antral and preovulatory follicles as a function of reproductive aging.
Aim 3 seeks to determine the feedback and feed-forward interactions between FSH, estradiol and the inhibins that result in an increase in estradiol levels across normal reproductive cycles in African-American women. Feedback is examined using an estrogen infusion protocol, while feed-forward examines the control of estradiol and inhibin secretion in preovulatory follicles. Understanding the feedback and feed-forward dynamics of the hypothalamic-pituitary and ovarian components of the reproductive system is critical to an appreciation of the pathophysiology of reproductive disorders. This information is ultimately required for the design of therapeutic options for patients with reproductive disorders, including infertility.
8) Impact of Sleep Disruption on Menstrual Cycle Dynamics
Klerman E (PI); Hall (PI Subcontract
Project Number: R01HD/MH40291
Source: NIH/NICHD-NIMH
Period: 3/01/02-02/28/05This project is testing the hypothesis that alterations in normal sleep patterns in the early follicular phase of the menstrual cycle will prevent the sleep-induced slowing of the GnRH pulse generator that is important in supporting FSH secretion.
9) Interplay Between Gonadal Steroids and Insulin in Men
Frances Hayes (PI)
Project Number: 5K23 DK02858
Source: NIH
Period: 6/01/00-3/31/04The overall goal of this project is to define the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Conducting studies in normal men, lean first degree relatives of type II diabetic patients, obese men with normal glucose tolerance, and men with type II diabetes will permit determination of whether the interaction between insulin resistance and testosterone is independent of body weight and glucose tolerance. Given the significant cardiovascular morbidity and mortality associated with obesity and type II diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important public health implications and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders.
Specific aims 1-3 of this project address the impact of insulin resistance on the reproductive axis in the male and specifically: i.) defines the dose response relationship between increasing insulin resistance and testosterone secretion in men; ii) localizes the defect induced in the hypothalamic-pituitary-gonadal (HPG) axis by insulin resistance, using frequent blood sampling studies as well as GnRH and hCG testing after endogenous gonadotropin blockade with a GnRH antagonist; and iii.) examines the impact on the HPG axis brought about by reducing insulin resistance with a thiazolidinedione in men with type II diabetes. Specific aims 4 and 5 address the impact of testosterone on insulin resistance and specifically: iv.) defines the dose-response relationship between increasing testosterone and insulin resistance by measuring insulin sensitivity with a glucose clamp--after induction of hypogonadism with a GnRH agonist and again after both physiologic and pharmacologic testosterone replacement; and v.) examines the impact of testosterone treatment on insulin resistance and glycemic control in type 2 diabetes.
The selective and sequential manipulation of sex steroid and insulin levels as outlined here will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causative determinants unequivocally defined.
10) Title of Project: Establishment of a Human Serum Bank
Frances Hayes (PI)
Source: Abbott Pharmaceuticals
Period: 12/01/01-Determination of the serum levels of reproductive hormones is a key component of the clinical evaluation and diagnosis of disorders of the reproductive system. Availability of gender and age-specific reference ranges is critical to their interpretation. The diversity of clinical applications for measurement of sex steroids requires assays that are highly sensitive, precise and accurate over wide analytical ranges. Current automated systems have not been well characterized with respect to clinical diagnosis. In order to establish normal ranges with a direct correlation to clinical diagnosis and to create an independent standard for comparing assay systems, it is imperative that reference ranges be carefully established for each system based on precise phenotyping of patients.
Accordingly, the aim of this study is to establish reference ranges for reproductive hormones: LH, FSH, testosterone, estradiol, progesterone, sex hormone binding globulin, inhibin A, and inhibin B based on carefully phenotyped normal volunteers and specific patient groups comprising women with polycystic ovary syndrome and women undergoing in vitro fertilization for infertility. This type of validation is beyond the financial capabilities or scope of practice of the routine clinical laboratory and can best be accomplished by collaboration between an academic research laboratory, a clinical investigator, and an industrial sponsor, as outlined in this protocol.
11) Mechanism and Regulation of Follistatin Processing
Alan Schneyer (PI)
Project Number: 5 R01 DK55838
Source: NIH/NIDDK
Period: 1/15/00-12/31/04Follistatin (FS) is a single chain glycoprotein that has been shown to irreversibly bind and neutralize activin, a pleotropic growth factor in the TGF-? superfamily. Although transcribed from a single gene, alternative splicing and posttranslational proteolytic modifications produce three core proteins differing in their c-terminus, tissue distribution, and in their biochemical and physiological properties.
Since activin is a critical regulator of ovarian folliculogenesis, bone formation, mesoderm formation, tissue fate determination, and other developmental and physiological processes, and since FS expression largely overlaps that of activin, FS actually functions as a critical “on/off switch” in governing the biological actions of activin. In addition, activin is a critical regulator of granulosa cell proliferation and differentiation within developing follicles. Since FS production increases throughout follicular development and granulosa cells secrete both activin and FS, it is clear that the interplay between these two molecules influences how granulosa cells and follicles mature during the normal menstrual cycle. Thus, the broad goal of this project is to define the regulatory mechanisms for FS posttranslational processing which ultimately determines the function and distribution of FS variants in the human--particularly as it concerns follicular development, but also as it applieds to other FS-sensitive tissues.
In the first Specific Aim, we focus on the isolation and purification of the FS315 processing protease using a cell line that we have demonstrated to have this important proteolytic activity. Once cloned, hormonal regulation of expression and activity will be determined. The second Specific Aim focuses on intracellular location of this protease and the distribution of processed and unprocessed FS within and outside the cell. In the third Specific Aim we characterize the functional differences between unprocessed and processed FS, examining both extracellular and potential intracellular activities of FS and activin. The results of these studies will form a better understanding of how different forms of FS are produced in different tissues and their differential biological activities, a necessary prerequisite to further studies designed to elucidate the physiology of FS in the human.
12) Physiology and Action of a new Follistatin Related Protein
Alan Schneyer (PI)
Project Number: 5 R01 HD039777
Source: NIH/NIDDK
Period: 8/01/01-7/31/06Follistatin-related protein (FSRP) is a recently discovered glycoprotein whose gene structure and activin binding properties are highly homologous to the activin binding protein follistatin (FS). FSRP was originally cloned as an overexpressed protein in a B-cell leukemia and is expressed in numerous cancer cell lines, suggesting that it may be involved with, or be a useful marker for a wide array of tumors. Unlike FS, however, FSRP is most highly expressed in the placenta and testis (FS is highest in the ovary and kidney), indicating that FSRP has unique functions in these tissues. Immunocytochemical studies have demonstrated that FSRP is highly concentrated in the nucleus of all cell lines and primary cells tested, but is secreted only by cells with the highest FSRP expression levels.
These observations suggest that regulation of FSRP intracellular trafficking is complex and unique, and further, that FSRP may have nuclear activities distinct from strictly non-nuclear FS. Overexpression of FSRP in transgenic mice disrupts follicular development, resulting in female infertility.Thus, the broad goal of this project is to determine the biological functions of FSRP in normal and pathophysiological circumstances, as well as to elucidate the biochemical features of this protein which govern its unique biology and distribution. Transgenic and knockout mice, along with several in vitro bioassays, are utilized to identify the normal and pathophysiological actions of FSRP (Specific Aim 1).
Intracellular trafficking, regulation of biosynthesis, and nuclear functions of FSRP are being examined in HeLa and human granulosa cells using pulse chase labeling, immunoprecipitation, and affinity chromatography (Specific Aim 2). The binding affinity and ligand specificity, as well as functional domains of FSRP responsible for these activities and FSRP’s nuclear localization are being examined using site directed mutagenesis and domain swapping with FS (Specific Aim 3). The results of this research will define the role(s) of FSRP in normal physiology, determine the mechanism whereby FSRP overexpression disrupts folliculogenesis, and define the novel regulatory mechanisms that result in nuclear localization and activity of a protein that is also secreted.
13) Establishing the Genetic Basis for Hypogonadotropic Hypogonadism
Stephanie Seminara (PI)
This project is funded by two sources:
Source: Hood Foundation
Period: 7/01/02-6/30/04Project Number: 1 R01 HD43341
Source: NIH
Period: 4/01/03-3/31/08At the time of puberty, gonadotropin-releasing hormone (GnRH), secreted by the hypothalamus, assumes its leadership position in a complex hierarchy of reproductive hormone signaling. GnRH stimulates the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary; these gonadotropins then stimulate the gonads to produce sex steroids and follicles/sperm. The actions of GnRH are complex--it is secreted in a pulsatile, as opposed to constitutive, fashion, and at variable frequencies throughout the reproductive cycle. Understanding what signals modulate the developmental fate and secretory actions of GnRH neurons, and by extension, normal pubertal development remains a major question within both child health and reproductive biology.
This project addresses these issues using a human disease model in which GnRH secretion is defective or absent. Patients with this condition, idiopathic hypogonadotropic hypogonadism (IHH), fail to undergo puberty and are infertile if untreated. Although congenital IHH is a rare disease and family sizes are typically small, a large inbred family of French Canadian descent with IHH and anosmia has been identified. A genome-wide scan has been performed and a chromosomal locus for the genetic defect has been identified. In this project, the candidate region is being further refined, a complete transcript map for the region is being developed, and RT-PCR is being used to screen the candidate genes for the precise genetic mutation. The mutation spectrum will then be juxtaposed against the baseline clinical/biochemical features of the patients, their neuroendocrine phenotypes, as well as their responses to physiologic replacement with exogenous pulsatile GnRH to develop robust genotype/phenotype correlations. It is hoped that this information will ultimately be used to understand numerous human diseases defined by abnormalities in GnRH secretion, including constitutional delay of puberty.
14) Recombinant Human Prolactin for Lactation Insufficiency
Corrine Welt (PI)
Source: March of Dimes
Period: 6/1/04-5/31/07Breast milk is the nutrition of choice for infants based on the medical and psychological advantages for both the mother and infant. Breast milk is particularly important for premature and low birth weight infants because it is more easily digested, appears to decrease the rates of infection and necrotizing enterocolitis and may enhance neurocognitive development. Mothers of premature or low birth weight infants in the neonatal intensive care unit often need to maintain their milk supply using a breast pump because infants are too ill or weak to suckle. Even when mothers follow strict pumping guidelines, however, breast milk production tends to decrease after 4-6 weeks, resulting in lactation insufficiency. Although dopamine antagonists are available to increase prolactin and, therefore, milk production, the medications are not FDA approved for this purpose and have side effects for both the mother and baby.
The broad goal of this proposal is to examine the efficacy and safety of recombinant human prolactin to treat lactation insufficiency in mothers of premature infants who are pumping to provide breast milk. The hypotheses include: 1) Recombinant human prolactin administration will increase breast milk quantity in women with lactation insufficiency; 2) There is a direct relationship between prolactin level and milk quantity; and 3) Enhancing breast milk production with recombinant human prolactin is safe for infants and mothers. To test these hypotheses, recombinant human prolactin or placebo will be administered subcutaneously, in a randomized, placebo-controlled manner, to mothers who are pumping breast milk for their premature infants and develop lactation insufficiency. Breast milk volume will be monitored at baseline and during prolactin or placebo injections and correlated with serum prolactin levels. Side effects in mothers and infants will be documented. An increase in milk volume during recombinant human prolactin, but not placebo, administration will provide insight into the importance of prolactin in the maintenance of milk volume during lactation. The data will also be necessary for development of recombinant human prolactin for treatment of lactation insufficiency, thus directly impacting the nutrition and outcome of premature infants.
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