Hodgen, G. D., & diZerega, G. S. (1981). Follicular phase treatment of luteal phase dysfunction. Fertility and Sterility, 35(4), 428-432. https://doi.org/10.1016/s0015-0282(16)45438-5
Hodgen GD, diZerega GS. Follicular phase treatment of luteal phase dysfunction. Fertil Steril. 1981;35(4):428-432. doi:10.1016/s0015-0282(16)45438-5
Dizerega, G. S., and G. D. Hodgen. "Follicular phase treatment of luteal phase dysfunction." Fertility and sterility, vol. 35, no. 4, 1981, pp. 428-432.
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Early FSH treatment partly preserved luteal function in monkeys
Early FSH treatment appears to partly preserve luteal function in monkeys with induced FSH deficiency. This 1981 experiment used 10 adult rhesus monkeys in two groups of five. With the lower dose of the FSH-suppressing fluid, each cycle had one timely ovulation. In the higher-dose group, none of the monkeys ovulated.
Key Findings
In the five monkeys given low-dose follicular fluid plus FSH-rich hMG, surgical inspection on cycle day 16 confirmed single ovulations on cycle days 13 to 15.
The low-dose group's intermenstrual interval was 26.3 ± 2.4 days (mean ± standard error). Its initial luteal progesterone rise resembled normal ovulatory cycles, and late luteal progesterone stayed below normal.
In the five monkeys given high-dose follicular fluid plus hMG, FSH stayed below normal and estradiol fell markedly (P < 0.05). No corpus luteum developed, and progesterone stayed at basal levels.
Estradiol also declined in the low-dose group (P < 0.05), yet stayed significantly higher than in the high-dose group (P < 0.05).
Radioimmunoassay LH levels were unaffected by follicular fluid in the low-dose group and not significantly affected in the high-dose group.
Interpretation
The study is a small animal experiment with 10 adult rhesus monkeys, five per dose group. The paper reports no untreated group and no hMG-only group. Comparisons with follicular fluid alone rest on the authors' earlier reports. The researchers induced the FSH deficiency themselves, so the model resembles spontaneous luteal phase dysfunction in women and monkeys without matching it exactly. Fertility was not measured. The authors say they cannot claim the corpus luteum returned to normal. That would take restored hCG responsiveness and normal fertility rates. The authors say clinical investigations are required to evaluate this approach for human infertility linked to some types of luteal phase dysfunction.
RRM Context
The paper reports that early follicular-phase FSH events help determine how the corpus luteum later develops and functions. Low progesterone after ovulation can therefore lead back to the follicular phase as a place to look for the cause. Restorative reproductive medicine reads the whole cycle as one system. Fertility awareness charting records how long the luteal phase lasts.
Our editorial summary of this paper, not the article's abstract.
Abstract
Previously, we demonstrated that selective suppression of serum follicle-stimulating hormone (FSH) in monkeys treated with charcoal-extracted porcine follicular fluid (pFF) in the early follicular phase induced luteal defects resembling those which occur spontaneously in women and monkeys. Here, we assessed whether luteal phase defects arising in association with induced FSH deficiencies during the early follicular phase can be treated by early FSH therapy. Rhesus monkeys were treated with pFF and human menopausal gonadotropin (hMG) (FSH:luteinizing hormone [LH], 3:1) on cycle days 1 to 3 or day 4, respectively. Daily femoral blood samples were analyzed for LH, FSH, and estradiol by radioimmunoassay. In the monkeys treated with the pFF-hMG combination, a single ovulation was uniformly noted at laparoscopy, and initial luteal phase elevations in serum progesterone levels were nearer those of normal ovulatory cycles than after pFF alone. These results suggest that FSH/LH treatment in the early follicular phase compensated, in part, for the pFF-induced deficiency in endogenous FSH levels.
To (1) review the events leading to peritoneal adhesion formation; (2) review traditional adhesion prevention adjuvants; (3) overview studies for adhesion prevention barriers including a perspective for their use; and (4) look toward the future of adhesion prevention. A great deal of effort has been dedicated to reduce adhesion formation because of the morbidity associated with adhesions and the associated economic burden, which considering only hospital costs and surgeons' fees, was $1,180 million in the United States. To understand the role of adhesion barriers in gynecological surgery, an appreciation of the cellular cascade and temporal nature of peritoneal repair is necessary. Evidence indicates that areas denuded of peritoneum will heal satisfactorily and that suturing of the peritoneum may increase adhesion formation. Physical barriers, including both mechanical and viscous solutions, are widely used to prevent adhesion formation by limiting tissue apposition during the critical stages of mesothelial repair. Clinical studies do not support the use of intraperitoneal, dextran for adhesion prevention. Theoretical considerations of peritoneal fluid dynamics indicate that crystalloid instillates should not prevent adhesion formation because of their short intraperitoneal residence. This prediction is consistent with clinical observation. The availability of Interceed (Johnson and Johnson Medical, Inc., Arlington, TX) and Gore-Tex Surgical Membrane (W.L. Gore, Flagstaff, Arizona) barriers provides substantial progress in postsurgical adhesion prevention. Although many investigators are incorporating adhesion prevention barriers into their routine clinical situations, physician acceptance is constrained by technical difficulties.
To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. Prospective, randomized, open label crossover protocol with 7 days between dosages. Academic institution. Fifteen normal postmenopausal women. All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. Serum P concentrations were measured in all groups. Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.
Tubal abrasions were surgically induced in 25 rhesus monkeys following demonstration of tubal patency. Five monkeys received dexamethasone, promethazine, and ampicillin perioperatively, five received intraperitoneal 10% dextran 40, five received intraperitoneal 32% dextran 70, and 10 received no additional therapy. Fimbrial biopsies were obtained from two additional monkeys treated with 32% dextran 70 before and postoperatively on days 2, 5, and 7. Only those treated with 32% dextran 70 retained tubal patency and avoided development of adhesions, involving fimbria, omentum, ovary, uterus, and bladder. Histologic examination of fimbrial biopsies demonstrated sufficient epithelial repair to have occurred during the 5 days 32% dextran 70 remained in the pelvin cavity to prevent adhesion formation.
Fifteen infertile women with inadequate luteal phase, histologically documented in at least two separate cycles, and normal midluteal plasma levels of progesterone (greater than or equal to 10 ng/mL), estradiol (70 to 300 pg/mL), and prolactin (less than 20 ng/mL) received "pure" follicle-stimulating hormone (pFSH), 150 IU intramuscularly, for 4 days (days 1 to 4 of the cycle). The endometrial defect was corrected in 7 of the 15 (46.7%) patients during the first treated cycle. Hormonal levels were similar in control and treatment cycles. Two of 5 patients with no additional infertility factors except luteal phase deficiency (LPD) became pregnant and carried to term singleton pregnancies. In 5 additional infertile patients with normal luteal function as assessed by endometrial histological study (2 cycles) and hormone measurements (first study cycle), a third biopsy was performed in a consecutive cycle under pFSH administration. In no case was the normal secretory pattern impaired. It is concluded that (1) some forms of LPD may be successfully treated by early follicular pFSH therapy and (2) pFSH does not alter the normal endometrial secretory pattern.
Thirteen women with luteal phase defects (LPD) confirmed by endometrial biopsies and 14 with histologically normal endometria were studied for early follicular and midfollicular phase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and for midluteal phase progesterone, estrogen, testosterone, and prolactin levels. The results showed that the women with LPD had significantly lower FSH levels and FSH/LH ratios in the early and midfollicular phases. LH levels, however, were similar in the LPD and normal women. During the midluteal phase, the LPD women showed significantly lower levels of progesterone and estrogen and normal levels of testosterone and prolactin. These findings reaffirm the prevailing concept that events surrounding follicular growth and development can indeed influence the quality of that cycle's corpus luteum. Furthermore, LPD as a result of hyperprolactinemia appears to be a different entity from that due to inadequate follicular phase FSH.
A deficiency in follicle stimulating hormone (FSH) levels during the early follicular phase of the menstrual cycle has been shown to result in luteal phase defect (LPD). A short course of human urinary FSH (uFSH) (Metrodin, Serono Laboratories) was given for a maximum of six cycles to 18 women with endometrial-biopsy-proven (EBX-proven) LPD. Adjunctive therapy in the form of midcycle human chorionic gonadotropin was given after the third therapy cycle. The uFSH therapy reduced the mean EBX lag time (2.0 +/- 0.6 days with therapy vs. 4.1 +/- 0.4 pretherapy, P less than .01), normalized the follicular phase length (15 +/- 0.4 days vs. 17.2 +/- 0.8 pretherapy, P less than .25) and increased the luteal phase length (12.7 +/- 0.4 days vs. 10.8 +/- 0.2 pretherapy, P less than .001). Twelve of 46 cycles (26%) in which uFSH was given without adjunctive therapy were anovulatory. Seven patients conceived; the result was seven viable pregnancies, all delivered at term. The cumulative pregnancy rate approached 48% by the sixth therapy cycle. uFSH therapy is useful for the correction of LPD and yields an acceptable pregnancy rate.
Luteal phase defect (LPD) accounts for a significant proportion of reproductive disorders, however its etiology is still debated. A prospective study was performed on 37 ovulatory women to determine whether LPD can occur in cycles characterized by completely normal folliculogenesis. Criteria for normal folliculogenesis included: a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presence of a dominant follicle that disappeared, an increase of serum progesterone, and normal serum levels of prolactin, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and LH. Thirty of 37 women fulfilled the above mentioned strict criteria and underwent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographic parameters of folliculogenesis and ovulation. Women with delayed endometrial development demonstrated slightly longer follicular phases (17.0 +/- 1.1 versus 14.5 +/- 0.3 days). Perfectly normal follicular and periovulatory events may be followed by deficient luteal phases.
PMID 6783446 6783446 DOI 10.1016/s0015-0282(16)45438-5 10.1016/s0015-0282(16)45438-5 Hodgen et al. 1981, Hodgen 1981
Cite this article
Hodgen, G. D., & diZerega, G. S. (1981). Follicular phase treatment of luteal phase dysfunction. Fertility and Sterility, 35(4), 428-432. https://doi.org/10.1016/s0015-0282(16)45438-5
Hodgen GD, diZerega GS. Follicular phase treatment of luteal phase dysfunction. Fertil Steril. 1981;35(4):428-432. doi:10.1016/s0015-0282(16)45438-5
Dizerega, G. S., and G. D. Hodgen. "Follicular phase treatment of luteal phase dysfunction." Fertility and sterility, vol. 35, no. 4, 1981, pp. 428-432.
