The Menstrual Cycle

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On today’s episode we welcome Dr. Jay Huber. Jay is a 3rd year fellow in reproductive endocrinology and infertility at the Warren Alpert Brown School of Medicine, and today he demystifies the HPO axis, the menstrual cycle, and all of the hormonal interplay.

It’s always helpful to follow along to one of the “menstrual cycle” diagrams, one of which we include here for reference:

Wikipedia

As Dr. Huber reminds us, the ovary really runs the show due to its negative feedback effect on the hypothalamus. However, thinking top down:

  • GnRH is release from the hypothalamus in a pulsatile fashion, triggering release of FSH and/or LH, depending on the timing of the cycle.

  • In the follicular phase of the ovary, FSH stimulates development of a dominant follicle. Once the dominant follicle is large enough, it produces a high enough level of estrogen to give positive feedback to the hypothalamus. Further GnRH is released, promoting preferential LH release downstream, until an LH surge is triggered, giving us the ovulation event on day 14.

  • After this, the levels of LH and FSH decline in response to negative estrogen feedback, in the luteal phase of the ovary.

  • Simultaneously, the estrogen produced by the dominant follicle in the ovarian follicular phase above causes downstream effects on the endometrium, marking the proliferative phase here of endometrial growth in preparation for implantation.

  • Once the follicle releases the oocyte, the follicular cells become the corpus luteum, which then produces progesterone. Progesterone matures the endometrium to be ‘pro-gestational’ for implantation and the secretory phase of endometrial maturation occurs.

  • If no fertilization event occurs, the corpus luteum degenerates, and by day 23-25, progesterone withdrawal results in shedding of the endometrial lining. If a fertilization event occurs, beta-hCG prompts the corpus luteum to continue to make progesterone.

Further reading from the OBG Project:
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Managing AUB-O
PCOS: Making the Diagnosis

Menopause Part II: Hormone-Replacement Therapy

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Today we’re talking on menopause once more with Dr. Renee Eger, assistant professor and clinician educator at the Warren Alpert Medical School of Brown University. We spend the second half of our menopause series reviewing HRT and the Women’s Health Initiative (WHI).

You can read more about the WHI here. The study really is two study methodologies in one: there were up to three randomized-controlled trial arms, and an observational arm. The components concerning HRT are dealt with through one of the RCTs.

The RCT dealing with HRT enrolled women into one of three arms: a placebo, an estrogen-only arm in patients without a uterus, or and estrogen-progesterone combination in patients with a uterus. The study was halted at 5.2 years in the E-P arm due to an increase in coronary heart disease, breast cancer, VTE, and stroke, which outweighed a benefit noted in colorectal cancer and fracture risk. The E-alone arm was stopped at 6.8 years average follow up, when the risk of heart disease was found not to be different than placebo.

Subsequent studies, including the Heart and Estrogen/progestin Replacement Study (HERS) have demonstrated at least that E-P and E should not be used for primary or secondary prevention of coronary disease, and thus HRT should not be prescribed for these indications. However, many benefits are particularly pronounced in younger patients using HRT. Thus, the position of the North American Menopause Society (NAMS) reads (emphasis ours):

“For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture.

”For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia.

”Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.”

How should you prescribe HRT or other medications to relieve VMS? Below is a summary from ACOG PB 141. Check out CO 565 and CO 556 as well if you are really interested in the topic!

Menopause Part I: Diagnosis and Non-Hormonal Therapies

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Today’s episode features Dr. Renee Eger! Dr. Eger is an Assistant Professor at the Warren Alpert Brown University SOM, and is a North American Menopause Society (NAMS) Certified Menopause Practitioner. She is talking with us this week and next about menopause.

The ACOG PB 141 on Management of Menopausal Symptoms is an excellent resource for all therapies in use for menopausal symptoms. We’ll cover some additional resources for hormonal therapy on next week’s episode. The high yield points for today include:

-Menopause is the cessation of menses for 1 year. The average age of onset in the US is 51.
-Lifestyle modifications are first-line therapy for both vasomotor symptoms of menopause (VMS) and genitourinary syndrome of menopause (GUSM), formerly known as vulvovaginal atrophy.
-Paroxetine 7.5mg daily (Paxil) is the only FDA-approved non-hormonal pharmacologic treatment for VMS.

Polycystic Ovarian Syndrome (PCOS)

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Big shout out to Andrey Dolinko, MD, who suggested today’s topic!
ACOG PB 194 is an excellent resource for your studying on PCOS (membership required).

PCOS is a syndrome, diagnosed clinically by at least 2/3 of the Rotterdam criteria:
1. Hyperandrogenism - hirsutism, male pattern baldness.
2. Oligo- or amenorrhea - 3+ months without menses.
3. Polycystic ovaries on ultrasound - 12+ follicles or increased ovarian volume.

In terms of treatment, the big take home message is to understand whether your patient is planning on pregnancy or not. CHCs are the mainstay therapy of patients not desiring pregnancy due to their multimodal method of action - regulation of HPO axis, increased SHBG, and endometrial protection. Also remember metformin (insulin sensitization) and spironolactone, finasteride, or flutamide (anti-androgens) as other adjuncts in patients not desiring pregnancy.

In those desiring pregnancy, oftentimes the complaint will be infertility. While letrozole is now preferred for ovulation induction over clomiphene due to a higher live-birth rate, letrozole does not yet enjoy FDA approval. For the other symptoms of PCOS in patients desiring pregnancy, the first line therapy is lifestyle modification! The literature doesn’t support metformin for ovulation induction, but some may use it for its other benefits prior to pregnancy.

We didn’t discuss laparoscopic ovarian drilling in this episode, but that would be another surgical treatment for PCOS-related infertility.

Diagnosis and Workup of Secondary Amenorrhea

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Today's topic will be a follow up of last week: diagnosis and workup of secondary amenorrhea. This will be a broad overview, with much more detail to follow in the future! 

Again, the ASRM guidelines for amenorrhea are a helpful resource for further reading.

Additionally, the American Academy of Family Physicians (AAFP) has a guideline publication on amenorrhea. While it’s a bit outdated, they do supply a chart that can be a helpful framework for your studying or diagnostic evaluation!

And remember… did you get that pregnancy test yet?